Author: "Pavel Flachs" - Searchworks@Jio Institute Digital Library Search Results

57 results on '"Pavel Flachs"'

1. Adipose tissue-specific ablation of PGC-1β impairs thermogenesis in brown fat

Author: Jiří Funda, Josep A. Villena, Kristina Bardova, Katerina Adamcova, Illaria Irodenko, Pavel Flachs, Ivana Jedlickova, Eliska Haasova, Martin Rossmeisl, Jan Kopecky, and Petra Janovska
Subjects: lipid metabolism, opa1, mice, adrenergic control, Medicine, Pathology, RB1-214
Abstract: Impaired thermogenesis observed in mice with whole-body ablation of peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β; officially known as PPARGC1B) may result from impaired brown fat (brown adipose tissue; BAT) function, but other mechanism(s) could be involved. Here, using adipose-specific PGC-1β knockout mice (PGC-1β-AT-KO mice) we aimed to learn whether specific PGC-1β ablation in adipocytes is sufficient to drive cold sensitivity. Indeed, we found that warm-adapted (30°C) mutant mice were relatively sensitive to acute cold exposure (6°C). When these mice were subjected to cold exposure for 7 days (7-day-CE), adrenergic stimulation of their metabolism was impaired, despite similar levels of thermogenic uncoupling protein 1 in BAT in PGC-1β-AT-KO and wild-type mice. Gene expression in BAT of mutant mice suggested a compensatory increase in lipid metabolism to counteract the thermogenic defect. Interestingly, a reduced number of contacts between mitochondria and lipid droplets associated with low levels of L-form of optic atrophy 1 was found in BAT of PGC-1β-AT-KO mice. These genotypic differences were observed in warm-adapted mutant mice, but they were partially masked by 7-day-CE. Collectively, our results suggest a role for PGC-1β in controlling BAT lipid metabolism and thermogenesis. This article has an associated First Person interview with the first author of the paper.
Published: 2022
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2. Preservation of metabolic flexibility in skeletal muscle by a combined use of n-3 PUFA and rosiglitazone in dietary obese mice.

Author: Olga Horakova, Dasa Medrikova, Evert M van Schothorst, Annelies Bunschoten, Pavel Flachs, Vladimir Kus, Ondrej Kuda, Kristina Bardova, Petra Janovska, Michal Hensler, Martin Rossmeisl, Rui Wang-Sattler, Cornelia Prehn, Jerzy Adamski, Thomas Illig, Jaap Keijer, and Jan Kopecky
Subjects: Medicine, Science
Abstract: Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.
Published: 2012
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3. Unmasking differential effects of rosiglitazone and pioglitazone in the combination treatment with n-3 fatty acids in mice fed a high-fat diet.

Author: Vladimir Kus, Pavel Flachs, Ondrej Kuda, Kristina Bardova, Petra Janovska, Michaela Svobodova, Zuzana Macek Jilkova, Martin Rossmeisl, Rui Wang-Sattler, Zhonghao Yu, Thomas Illig, and Jan Kopecky
Subjects: Medicine, Science
Abstract: Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy.
Published: 2011
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4. Additive Effects of Omega-3 Fatty Acids and Thiazolidinediones in Mice Fed a High-Fat Diet: Triacylglycerol/fatty Acid Cycling in Adipose Tissue

Author: Olga Horakova, Jan Kopecky, Jiri Funda, Katerina Adamcova, Petra Janovska, Ilaria Irodenko, Lucie Lenkova, Petr Zouhar, Martin Rossmeisl, Radek Pohl, Tomas Cajka, Pavel Flachs, M Hensler, Ondrej Kuda, Jerry R. Colca, and Kristina Bardova
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, insulin, obesity, Adipose Tissue, White, adipocytes, Adipose tissue, Mice, Obese, 030209 endocrinology & metabolism, lcsh:TX341-641, White adipose tissue, Diet, High-Fat, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Fatty Acids, Omega-3, medicine, Glucose homeostasis, Animals, Hypoglycemic Agents, glucose homeostasis, Triglycerides, lipogenesis, chemistry.chemical_classification, Nutrition and Dietetics, Pioglitazone, Chemistry, Futile cycle, Fatty Acids, Fatty acid, Metabolism, Lipid Metabolism, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Lipogenesis, Thiazolidinediones, lcsh:Nutrition. Foods and food supply, Food Science, Polyunsaturated fatty acid
Abstract: Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs&mdash, pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)&mdash, regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.
Published: 2020

5. Omega-3 index in the Czech Republic: No difference between urban and rural populations

Author: Nadezda Cadova, Martin Rossmeisl, Pavel Flachs, Jan Kopecky, Petra Janovska, Iva Stohanzlova, Dana Hamplová, Marina Oseeva, Veronika Paluchova, Ondrej Kuda, Tomáš Mráček, and Petr Zacek
Subjects: Czech, Adult, Male, Rural Population, Index (economics), Adolescent, Urban Population, Population, Omega 3 index, Biochemistry, Young Adult, Animal science, Fatty Acids, Omega-3, Humans, education, Molecular Biology, Aged, Czech Republic, chemistry.chemical_classification, Aged, 80 and over, education.field_of_study, Chemistry, Organic Chemistry, Cell Biology, Middle Aged, Eicosapentaenoic acid, language.human_language, Docosahexaenoic acid, language, lipids (amino acids, peptides, and proteins), Female, Rural area, Polyunsaturated fatty acid
Abstract: Naturally occurring long-chain omega-3 PUFA such as eicosapentaenoic acid (EPA; 20:5 ω-3) and docosahexaenoic acid (DHA; 22:6 ω-3) exert multiple effects on health, which are related to the intake of these lipids in the diet and correlate with the levels of omega-3 PUFA in the body. These levels are reflected by the omega-3 PUFA index, i.e. the EPA and DHA content as % of all fatty acids in red blood cells. The aim of this study was to evaluate omega-3 index in the Czech Republic, using blood samples collected from the capital city (n = 476) and the rural region (n = 388). The mean omega-3 index was 3.56 mol % with a maximal value of 8.10% and a minimal value of 1.12%. There was no difference in the index value between rural and urban / industrial regions, but this value was higher in subjects who reported eating fish or omega-3 PUFA supplements. In conclusion, the results indicated suboptimal values of the omega-3 index in the Czech population independent of the sampling region.
Published: 2018

6. The Effect of n-3 Fatty Acids on Glucose Homeostasis and Insulin Sensitivity

Author: Jan Kopecky, Martin Rossmeisl, and Pavel Flachs
Subjects: Blood Glucose, medicine.medical_specialty, Physiology, medicine.medical_treatment, Type 2 diabetes, Mice, Insulin resistance, Diabetes mellitus, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Homeostasis, Humans, Insulin, Glucose homeostasis, Evidence-Based Medicine, business.industry, Hypertriglyceridemia, General Medicine, medicine.disease, Treatment Outcome, Endocrinology, Diabetes Mellitus, Type 2, Metabolic control analysis, Insulin Resistance, Metabolic syndrome, business
Abstract: Type 2 diabetes (T2D) as well as cardiovascular disease (CVD) represent major complications of obesity and associated metabolic disorders (metabolic syndrome). This review focuses on the effects of long-chain n-3 polyunsaturated fatty acids (omega-3) on insulin sensitivity and glucose homeostasis, which are improved by omega-3 in many animal models of metabolic syndrome, but remain frequently unaffected in humans. Here we focus on: (i) mechanistic aspects of omega-3 action, reflecting also our experiments in dietary obese mice; and (ii) recent studies analysing omega-3’s effects in various categories of human subjects. Most animal experiments document beneficial effects of omega-3 on insulin sensitivity and glucose metabolism even under conditions of established obesity and insulin resistance. Besides positive results obtained in both cross-sectional and prospective cohort studies on healthy human populations, also some intervention studies in prediabetic subjects document amelioration of impaired glucose homeostasis by omega-3. However, the use of omega-3 to reduce a risk of new-onset diabetes in prediabetic subjects still remains to be further characterized. The results of a majority of clinical trials performed in T2D patients suggest that omega-3 have none or marginal effects on metabolic control, while effectively reducing hypertriglyceridemia in these patients. Despite most of the recent randomized clinical trials do not support the role of omega-3 in secondary prevention of CVD, this issue remains still controversial. Combined interventions using omega-3 and antidiabetic or hypolipidemic drugs should be further explored and considered for treatment of patients with T2D and other diseases.
Published: 2014
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7. Omega-3 phospholipids from fish suppress hepatic steatosis by integrated inhibition of biosynthetic pathways in dietary obese mice

Author: Barbora Stankova, Kristina Bardova, Pavel Flachs, Jaap Keijer, Jana Pavlisova, Evert M. van Schothorst, M Hensler, Marek Vecka, Dasa Medrikova, Ondrej Kuda, Ales Zak, Jan Kopecky, Martin Rossmeisl, and Eva Tvrzická
Subjects: Male, medicine.medical_specialty, Mice, Obese, long-chain omega-3-fatty-acids, Biology, adipose-tissue, chemistry.chemical_compound, Mice, Insulin resistance, Non-alcoholic Fatty Liver Disease, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, insulin sensitivity, Molecular Biology, Phospholipids, Triglycerides, chemistry.chemical_classification, Phosphatidylethanolamine, glucose-intolerance, Cholesterol, Fatty liver, Lipid metabolism, hepatobiliary axis, Cell Biology, medicine.disease, soybean lecithin, 3. Good health, Biosynthetic Pathways, Fatty Liver, Mice, Inbred C57BL, Endocrinology, chemistry, Liver, Human and Animal Physiology, Lipogenesis, WIAS, Fysiologie van Mens en Dier, liver-disease, lipids (amino acids, peptides, and proteins), Steatosis, polyunsaturated fatty-acids, krill oil supplementation, lipid-metabolism, Polyunsaturated fatty acid
Abstract: Non-alcoholic fatty liver disease (NAFLD) accompanies obesity and insulin resistance. Recent meta-analysis suggested omega-3 polyunsaturated fatty acids DHA and EPA to decrease liver fat in NAFLD patients. Anti-inflammatory, hypolipidemic, and insulin-sensitizing effects of DHA/EPA depend on their lipid form, with marine phospholipids showing better efficacy than fish oils. We characterized the mechanisms underlying beneficial effects of DHA/EPA phospholipids, alone or combined with an antidiabetic drug, on hepatosteatosis. C57BL/6N mice were fed for 7 weeks an obesogenic high-fat diet (cHF) or cHF-based interventions: (i) cHF supplemented with phosphatidylcholine-rich concentrate from herring (replacing 10% of dietary lipids; PC), (ii) cHF containing rosiglitazone (10 mg/kg diet; R), or (iii) PC + R. Metabolic analyses, hepatic gene expression and lipidome profiling were performed. Results showed that PC and PC + R prevented cHF-induced weight gain and glucose intolerance, while all interventions reduced abdominal fat and plasma triacylglycerols. PC and PC + R also lowered hepatic and plasma cholesterol and reduced hepatosteatosis. Microarray analysis revealed integrated down-regulation of hepatic lipogenic and cholesterol biosynthesis pathways by PC, while R-induced lipogenesis was fully counteracted in PC + R. Gene expression changes in PC and PC + R were associated with preferential enrichment of hepatic phosphatidylcholine and phosphatidylethanolamine fractions by DHA/EPA. The complex down-regulation of hepatic lipogenic and cholesterol biosynthesis genes and the antisteatotic effects were unique to DHA/EPA-containing phospholipids, since they were absent in mice fed soy-derived phosphatidylcholine. Thus, inhibition of lipid and cholesterol biosynthesis associated with potent antisteatotic effects in the liver in response to DHA/EPA-containing phospholipids support their use in NAFLD prevention and treatment.
Published: 2014
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8. Anti-Obesity Effect of n-3 Polyunsaturated Fatty Acids in Mice Fed High-Fat Diet Is Independent of Cold-Induced Thermogenesis

Author: Pavel Flachs, Ludmila Kazdova, Jan Kopecký, and Petra Janovska
Subjects: Male, medicine.medical_specialty, Physiology, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, Fatty Acids, Nonesterified, Biology, Diet, High-Fat, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Homeostasis, Glucose homeostasis, Obesity, Triglycerides, 030304 developmental biology, 2. Zero hunger, chemistry.chemical_classification, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, Body Weight, Fatty acid, Calorimetry, Indirect, Thermogenesis, General Medicine, Glucose Tolerance Test, Thermogenin, Cold Temperature, Mice, Inbred C57BL, Endocrinology, Adipose Tissue, chemistry, Anti-Obesity Agents, Polyunsaturated fatty acid
Abstract: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) exert beneficial effects on health and they could help to prevent development of obesity and associated metabolic disorders. In our previous studies in mice fed high-fat (cHF; ~60 % calories as fat) diet and maintained at 20 °C, dietary LC n-3 PUFA could counteract accretion of body fat, without inducing mitochondrial uncoupling protein 1 (UCP1) in adipose tissue, suggesting that the anti-obesity effect was not linked to adaptive (UCP1-mediated) thermogenesis. To exclude a possible dependence of the anti-obesity effect on any mechanism inducible by cold, experiments were repeated in mice maintained at thermoneutrality (30 °C). Male C57BL/6J mice were fed either cHF diet, or cHF diet supplemented with LC n-3 PUFA, or standard diet for 7 months. Similarly as at 20 °C, the LC n-3 PUFA supplementation reduced accumulation of body fat, preserved lipid and glucose homeostasis, and induced fatty acid re-esterification in epididymal white adipose tissue. Food consumption was not affected by LC n-3 PUFA intake. Our results demonstrated anti-obesity metabolic effect of LC n-3 PUFA, independent of cold-induced thermogenesis and they suggested that induction of fatty acid re-esterification creating a substrate cycle in white fat, which results in energy expenditure, could contribute to the anti-obesity effect.
Published: 2013
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9. Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: A key to lean phenotype

Author: Ondrej Kuda, Jan Kopecky, Martin Rossmeisl, and Pavel Flachs
Subjects: medicine.medical_specialty, PPARγ, Adipose Tissue, White, Calorie restriction, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, Biology, Ion Channels, Oxidative Phosphorylation, Mitochondrial Proteins, Futile substrate cycle, Mice, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Brown adipose tissue, Adipocytes, medicine, Animals, Humans, Lipolysis, Obesity, Molecular Biology, Uncoupling Protein 1, 030304 developmental biology, 0303 health sciences, Lipid metabolism, Cell Biology, Lipid Metabolism, Thermogenin, Mitochondria, Rats, Oxidative Stress, Phenotype, Endocrinology, medicine.anatomical_structure, Lipid mediator, Fatty acid re-esterification, lipids (amino acids, peptides, and proteins), Energy Metabolism, Thermogenesis, Signal Transduction
Abstract: We are facing a revival of the strategy to counteract obesity and associated metabolic disorders by inducing thermogenesis mediated by mitochondrial uncoupling protein-1 (UCP1). Thus, the main focus is on the adaptive non-shivering thermogenesis occurring both in the typical depots of brown adipose tissue (BAT) and in UCP1-containing cells that could be induced in white adipose tissue (WAT). Because contribution of WAT to resting metabolic rate is relatively small, the possibility to reduce adiposity by enhancing energy expenditure in classical white adipocytes is largely neglected. However, several pieces of evidence support a notion that induction of energy expenditure based on oxidation of fatty acids (FA) in WAT may be beneficial for health, namely: (i) studies in both humans and rodents document negative association between oxidative capacity of mitochondria in WAT and obesity; (ii) pharmacological activation of AMPK in rats as well as cold-acclimation of UCP1-ablated mice results in obesity resistance associated with increased oxidative capacity in WAT; and (iii) combined intervention using long-chain n-3 polyunsaturated FA (omega 3) and mild calorie restriction exerted synergism in the prevention of obesity in mice fed a high-fat diet; this was associated with strong hypolipidemic and insulin-sensitizing effects, as well as prevention of inflammation, and synergistic induction of mitochondrial oxidative phosphorylation (OXPHOS) and FA oxidation, specifically in epididymal WAT. Importantly, these changes occurred without induction of UCP1 and suggested the involvement of: (i) futile substrate cycle in white adipocytes, which is based on lipolysis of intracellular triacylglycerols and re-esterification of FA, in association with the induction of mitochondrial OXPHOS capacity, β-oxidation, and energy expenditure; (ii) endogenous lipid mediators (namely endocannabinoids, eicosanoids, prostanoids, resolvins, and protectins) and their cognate receptors; and (iii) AMP-activated protein kinase in WAT. Quantitatively, the strong induction of FA oxidation in WAT in response to the combined intervention is similar to that observed in the transgenic mice rendered resistant to obesity by ectopic expression of UCP1 in WAT. The induction of UCP1-independent FA oxidation and energy expenditure in WAT in response to the above physiological stimuli could underlie the amelioration of obesity and low-grade WAT inflammation, and it could reduce the release of FA from adipose tissue and counteract harmful consequences of lipid accumulation in other tissues. In this respect, new combination treatments may be designed using naturally occurring micronutrients (e.g. omega 3), reduced calorie intake or pharmaceuticals, exerting synergism in the induction of the mitochondrial OXPHOS capacity and stimulation of lipid catabolism in white adipocytes, and improving metabolic flexibility of WAT. The role of mutual interactions between adipocytes and immune cells contained in WAT in tissue metabolism should be better characterised. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.
Published: 2013
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10. AMP-activated Protein Kinase α2 Subunit Is Required for the Preservation of Hepatic Insulin Sensitivity by n-3 Polyunsaturated Fatty Acids

Author: Thomas E. Jensen, Jan Kopecky, Martin Rossmeisl, Ivan Mikšík, Simon A. Hawley, Marcin Baranowski, Pavel Flachs, Vladimir Kus, Petra Janovska, Zuzana Macek Jilkova, Benoit Viollet, Ondrej Kuda, Dasa Medrikova, Sophie Hébrard, Jan Górski, Tomas Jelenik, and M Hensler
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Cell Culture Techniques, AMP-Activated Protein Kinases, Mice, Insulin resistance, AMP-activated protein kinase, Internal medicine, Hyperinsulinism, Fatty Acids, Omega-3, Internal Medicine, medicine, Animals, Diet, Fat-Restricted, chemistry.chemical_classification, Metabolic Syndrome, Mice, Knockout, Adiponectin, biology, Insulin, Fatty liver, Glucose clamp technique, medicine.disease, Dietary Fats, Protein Subunits, Endocrinology, Metabolism, chemistry, Liver, biology.protein, Fatty Acids, Unsaturated, Glucose Clamp Technique, Hepatocytes, Insulin Resistance, Dyslipidemia, Polyunsaturated fatty acid
Abstract: OBJECTIVE The induction of obesity, dyslipidemia, and insulin resistance by high-fat diet in rodents can be prevented by n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs. RESEARCH DESIGN AND METHODS Mice with a whole-body deletion of the α2 catalytic subunit of AMPK (AMPKα2−/−) and their wild-type littermates were fed on either a low-fat chow, or a corn oil-based high-fat diet (cHF), or a cHF diet with 15% lipids replaced by n-3 LC-PUFA concentrate (cHF+F). RESULTS Feeding a cHF diet induced obesity, dyslipidemia, hepatic steatosis, and whole-body insulin resistance in mice of both genotypes. Although cHF+F feeding increased hepatic AMPKα2 activity, the body weight gain, dyslipidemia, and the accumulation of hepatic triglycerides were prevented by the cHF+F diet to a similar degree in both AMPKα2−/− and wild-type mice in ad libitum-fed state. However, preservation of hepatic insulin sensitivity by n-3 LC-PUFAs required functional AMPKα2 and correlated with the induction of adiponectin and reduction in liver diacylglycerol content. Under hyperinsulinemic-euglycemic conditions, AMPKα2 was essential for preserving low levels of both hepatic and plasma triglycerides, as well as plasma free fatty acids, in response to the n-3 LC-PUFA treatment. CONCLUSIONS Our results show that n-3 LC-PUFAs prevent hepatic insulin resistance in an AMPKα2-dependent manner and support the role of adiponectin and hepatic diacylglycerols in the regulation of insulin sensitivity. AMPKα2 is also essential for hypolipidemic and antisteatotic effects of n-3 LC-PUFA under insulin-stimulated conditions.
Published: 2010

11. n-3 PUFA: bioavailability and modulation of adipose tissue function

Author: Martin Rossmeisl, Eva Tvrzická, Barbora Stankova, Pavel Flachs, Jan Kopecky, Petr Brauner, Zuzana Macek Jilkova, Morten Bryhn, and Ondrej Kuda
Subjects: medicine.medical_specialty, Nutrition and Dietetics, Adiponectin, Insulin, medicine.medical_treatment, Medicine (miscellaneous), Adipose tissue, Adipokine, Lipid metabolism, Biology, medicine.disease, Endocrinology, Insulin resistance, Internal medicine, Lipogenesis, medicine, lipids (amino acids, peptides, and proteins), Metabolic syndrome
Abstract: Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. Then-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus,n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodentsn-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects ofn-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms.n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation ofn-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects ofn-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation byn-3 LC PUFA.
Published: 2009
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12. Low-dose acetylsalicylic acid inhibits the secretion of interleukin-6 from white adipose tissue

Author: Kalypso Karastergiou, Mohammad Javad Hosseinzadeh-Attar, Pavel Flachs, Jan Kopecky, R Madani, Rahul Bhome, Vidya Mohamed-Ali, M Hensler, NC Ogston, Derek W. Gilroy, and Melanie Stables
Subjects: Male, medicine.medical_specialty, Adipose Tissue, White, Endocrinology, Diabetes and Metabolism, Receptors, Prostaglandin, Subcutaneous Fat, Mice, Obese, Medicine (miscellaneous), Adipose tissue, Prostaglandin, Prostacyclin, White adipose tissue, 030204 cardiovascular system & hematology, Prostacyclin synthase, Proinflammatory cytokine, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Adipocytes, medicine, Animals, Humans, Cyclooxygenase Inhibitors, Obesity, Gonads, Prostacyclin receptor, Aged, 030304 developmental biology, 0303 health sciences, Nutrition and Dietetics, Aspirin, biology, Interleukin-6, Tumor Necrosis Factor-alpha, Chemistry, Middle Aged, Endocrinology, Prostaglandin-Endoperoxide Synthases, Case-Control Studies, biology.protein, Female, lipids (amino acids, peptides, and proteins), Cyclooxygenase, medicine.drug
Abstract: Chronically elevated interleukin-6 (IL-6) is implicated in obesity-associated pathologies, where a proportion of this cytokine is derived from adipose tissue. Proinflammatory prostaglandins, which regulate this cytokine elsewhere, are also produced by this tissue.To investigate whether constitutively active cyclooxygenase (COX)/prostaglandin (PG) pathway in white adipose tissue (WAT) is responsible for basal IL-6 production.The effect of acetylsalicylic acid (ASA), an inhibitor of COX, on IL-6 was assessed in human subjects and mice. COX, downstream PG synthase (PGS) activity and PG receptor signalling were determined in subcutaneous (SC), gonadal (GN) WAT and adipocytes.In obese humans, low-dose ASA (150 mg day(-1) for 10 days) inhibited systemic IL-6 and reduced IL-6 release from SC WAT ex vivo (0.2 mM). Similarly, in mice, ASA (0.2 and 2.0 mg kg(-1)) suppressed SC WAT 6-keto-PGF(1alpha) (a stable metabolite of prostacyclin) and IL-6 release. Although both COX isoforms are comparably expressed, prostacyclin synthase expression is higher in GN WAT, with levels of activity correlating directly with IL-6. Both ASA (5 mM) and NS-398 (COX-2 selective inhibitoror=1 microM), but not SC-560 (COX-1 selective inhibitoror=1 microM), attenuated IL-6 release from murine WAT in vitro and abolished its depot differences. Prostacyclin receptor (IP) and, to a lesser extent, PGE(2) (EP2 and EP4) receptor agonists elevated the release of IL-6 from adipocytes.In adipose tissue, constitutive COX-2-coupled prostacyclin triggers the release of basal IL-6, which in obese subjects is significantly dampened by ASA ingestion, thus offering a novel, modifiable pathway to regulate the potentially pathological component of this cytokine.
Published: 2008
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13. Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance

Author: Pavel Flachs, Ondrej Kuda, Dasa Medrikova, Josef Houstek, Martin Rossmeisl, Eva Pastalkova, Petr Brauner, M Hensler, Zdenek Drahota, Jan Kopecky, Petra Janovska, Tomas Prazak, Vladimir Kus, Bohumir Stefl, and Zuzana Macek Jilkova
Subjects: Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, Stimulation, AMP-Activated Protein Kinases, Fatty Acids, Nonesterified, Protein Serine-Threonine Kinases, Body Temperature, Mice, Random Allocation, Oxygen Consumption, AMP-activated protein kinase, Lipid oxidation, Multienzyme Complexes, Physiology (medical), Internal medicine, medicine, Animals, Obesity, Muscle, Skeletal, Triglycerides, Meal, biology, Leptin, Body Weight, Calorimetry, Indirect, Thermogenesis, Ribonucleotides, Aminoimidazole Carboxamide, medicine.disease, Dietary Fats, Mice, Inbred C57BL, Endocrinology, Animals, Newborn, Basal metabolic rate, biology.protein, Basal Metabolism
Abstract: The obesogenic effect of a high-fat (HF) diet is counterbalanced by stimulation of energy expenditure and lipid oxidation in response to a meal. The aim of this study was to reveal whether muscle nonshivering thermogenesis could be stimulated by a HF diet, especially in obesity-resistant A/J compared with obesity-prone C57BL/6J (B/6J) mice. Experiments were performed on male mice born and maintained at 30 degrees C. Four-week-old mice were randomly weaned onto a low-fat (LF) or HF diet for 2 wk. In the A/J LF mice, cold exposure (4 degrees C) resulted in hypothermia, whereas the A/J HF, B/6J LF, and B/6J HF mice were cold tolerant. Cold sensitivity of the A/J LF mice was associated with a relatively low whole body energy expenditure under resting conditions, which was normalized by the HF diet. In both strains, the HF diet induced uncoupling protein-1-mediated thermogenesis, with a stronger induction in A/J mice. Only in A/J mice: 1) the HF diet augmented activation of whole body lipid oxidation by cold; and 2) at 30 degrees C, oxygen consumption, total content, and phosphorylation of AMP-activated protein kinase (AMPK), and AICAR-stimulated palmitate oxidation in soleus muscle was increased by the HF diet in parallel with significantly increased leptinemia. Gene expression data in soleus muscle of the A/J HF mice indicated a shift from carbohydrate to fatty acid oxidation. Our results suggest a role for muscle nonshivering thermogenesis and lipid oxidation in the obesity-resistant phenotype of A/J mice and indicate that a HF diet could induce thermogenesis in oxidative muscle, possibly via the leptin-AMPK axis.
Published: 2008
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14. Cell type-specific modulation of lipid mediator's formation in murine adipose tissue by omega-3 fatty acids

Author: Petra Janovska, Ondrej Kuda, Martina Rombaldova, Jan Kopecky, and Pavel Flachs
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Adipose tissue macrophages, Adipose Tissue, White, Biophysics, Anti-Inflammatory Agents, Adipose tissue, Administration, Oral, White adipose tissue, Protectin D1, Biology, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Mice, Internal medicine, Lipid droplet, Fatty Acids, Omega-3, medicine, Adipocytes, Animals, Immunologic Factors, Molecular Biology, Cells, Cultured, Macrophages, Lipid metabolism, Cell Biology, Lipid signaling, Stromal vascular fraction, Lipid Metabolism, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Dietary Supplements, lipids (amino acids, peptides, and proteins), Stromal Cells
Abstract: Mutual interactions between adipocytes and immune cells in white adipose tissue (WAT) are involved in modulation of lipid metabolism in the tissue and also in response to omega-3 polyunsaturated fatty acids (PUFA), which counteract adverse effects of obesity. This complex interplay depends in part on in situ formed anti- as well as pro-inflammatory lipid mediators, but cell types engaged in the synthesis of the specific mediators need to be better characterized. We used tissue fractionation and metabolipidomic analysis to identify cells producing lipid mediators in epididymal WAT of mice fed for 5 weeks obesogenic high-fat diet (lipid content 35% wt/wt), which was supplemented or not by omega-3 PUFA (4.3 mg eicosapentaenoic acid and 14.7 mg docosahexaenoic acid per g of diet). Our results demonstrate selective increase in levels of anti-inflammatory lipid mediators in WAT in response to omega-3, reflecting either their association with adipocytes (endocannabinoid-related N-docosahexaenoylethanolamine) or with stromal vascular cells (pro-resolving lipid mediator protectin D1). In parallel, tissue levels of obesity-associated pro-inflammatory endocannabinoids were suppressed. Moreover, we show that adipose tissue macrophages (ATMs), which could be isolated using magnetic force from the stromal vascular fraction, are not the major producers of protectin D1 and that omega-3 PUFA lowered lipid load in ATMs while promoting their less-inflammatory phenotype. Taken together, these results further document specific roles of various cell types in WAT in control of WAT inflammation and metabolism and they suggest that also other cells but ATMs are engaged in production of pro-resolving lipid mediators in response to omega-3 PUFA.
Published: 2015

15. Combined intervention with pioglitazone and n-3 fatty acids in metformin-treated type 2 diabetic patients: improvement of lipid metabolism

Author: Eva Fišerová, Alzbeta Gardlo, Ondrej Kuda, Morten Bryhn, Philip C. Calder, Jørgen Arendt Jensen, Jiri Veleba, Josune Olza, Ludmila Kazdova, Petra Janovska, Vojtech Skop, Martin Rossmeisl, Olga Horakova, Pavel Flachs, Hana Malinska, Olena Oliyarnyk, Jan Kopecky, Kristina Bardova, Terezie Pelikanova, Antonin Skoch, Jaroslava Trnovska, Gabriela Salim de Castro, and Milan Hájek
Subjects: medicine.medical_specialty, Eicosapentaenoic acid, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Indirect calorimetry, chemistry.chemical_compound, Internal medicine, medicine, Humans, chemistry.chemical_classification, Nutrition and Dietetics, Adiponectin, business.industry, Research, Meal test, Fatty acid, Metformin, Docosahexaenoic acid, Endocrinology, Postprandial, chemistry, Hyperinsulinemic-euglycemic clamp, lipids (amino acids, peptides, and proteins), Glycated hemoglobin, business, Pioglitazone, medicine.drug
Abstract: Background The marine n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert numerous beneficial effects on health, but their potency to improve treatment of type 2 diabetic (T2D) patients remains poorly characterized. We aimed to evaluate the effect of a combination intervention using EPA + DHA and the insulin-sensitizing drug pioglitazone in overweight/obese T2D patients already treated with metformin. Methods In a parallel-group, four-arm, randomized trial, 69 patients (66 % men) were assigned to 24-week-intervention using: (i) corn oil (5 g/day; Placebo), (ii) pioglitazone (15 mg/day; Pio), (iii) EPA + DHA concentrate (5 g/day, containing ~2.8 g EPA + DHA; Omega-3), or (iv) pioglitazone and EPA + DHA concentrate (Pio& Omega-3). Data from 60 patients were used for the final evaluation. At baseline and after intervention, various metabolic markers, adiponectin and cytokines were evaluated in serum using standard procedures, EPA + DHA content in serum phospholipids was evaluated using shotgun lipidomics and mass spectrometry, and hyperinsulinemic-euglycemic clamp and meal test were also performed. Indirect calorimetry was conducted after the intervention. Primary endpoints were changes from baseline in insulin sensitivity evaluated using hyperinsulinemic-euglycemic clamp and in serum triacylglycerol concentrations in fasting state. Secondary endpoints included changes in fasting glycemia and glycated hemoglobin (HbA1c), changes in postprandial glucose, free fatty acid and triacylglycerol concentrations, metabolic flexibility assessed by indirect calorimetry, and inflammatory markers. Results Omega-3 and Pio& Omega-3 increased EPA + DHA content in serum phospholipids. Pio and Pio& Omega-3 increased body weight and adiponectin levels. Both fasting glycemia and HbA1c were increased by Omega-3, but were unchanged by Pio& Omega-3. Insulin sensitivity was not affected by Omega-3, while it was improved by Pio& Omega-3. Fasting triacylglycerol concentrations and inflammatory markers were not significantly affected by any of the interventions. Lipid metabolism in the meal test and metabolic flexibility were additively improved by Pio& Omega-3. Conclusion Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA + DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy. Trial registration EudraCT number 2009-011106-42. Electronic supplementary material The online version of this article (doi:10.1186/s12986-015-0047-9) contains supplementary material, which is available to authorized users.
Published: 2015
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16. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet

Author: M Hensler, Pavel Flachs, Jana Ruzickova, Olga Horakova, Martin Rossmeisl, Jan Kopecky, Vidya Mohamed-Ali, and Mohammad Javad Hosseinzadeh-Attar
Subjects: Leptin, Male, medicine.medical_specialty, Docosahexaenoic Acids, Endocrinology, Diabetes and Metabolism, Adipokine, Adipose tissue, Biology, Eating, Mice, Insulin resistance, AMP-Activated Protein Kinase Kinases, Internal medicine, Adipocytes, Internal Medicine, medicine, Animals, Insulin, Obesity, Triglycerides, Caloric Restriction, chemistry.chemical_classification, Adiponectin, Reverse Transcriptase Polymerase Chain Reaction, nutritional and metabolic diseases, food and beverages, Fish oil, medicine.disease, Dietary Fats, Eicosapentaenoic acid, Enzyme Activation, Mice, Inbred C57BL, Glucose, Endocrinology, Adipose Tissue, Eicosapentaenoic Acid, Gene Expression Regulation, chemistry, Docosahexaenoic acid, Body Composition, lipids (amino acids, peptides, and proteins), Insulin Resistance, Protein Kinases, hormones, hormone substitutes, and hormone antagonists, Polyunsaturated fatty acid
Abstract: Aims/hypothesis: Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin. Methods: We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated. Results: In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA. Conclusions/interpretation: Intake of diets rich in EPA and DHA leads to elevated systemic concentrations of adiponectin, largely independent of food intake or adiposity and explain, to some extent, their anti-diabetic effects.
Published: 2006
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17. Involvement of AMP-activated protein kinase in fat depot-specific metabolic changes during starvation

Author: Jan Kopecky, Jana Sponarova, Martin Rossmeisl, Michaela Thomason-Hughes, Kirsty J. Mustard, Kristina Bardova, D. Grahame Hardie, Pavel Flachs, Petra Janovska, Radka Braunerova, Petr Brauner, and Olga Horakova
Subjects: AMPK, Male, medicine.medical_specialty, Biophysics, Acetyl-CoA carboxylase, 030209 endocrinology & metabolism, White adipose tissue, AMP-Activated Protein Kinases, Fatty Acids, Nonesterified, Protein Serine-Threonine Kinases, Biochemistry, Ion Channels, Mitochondrial Proteins, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, AMP-activated protein kinase, Lipid oxidation, Multienzyme Complexes, Structural Biology, Internal medicine, Adipocyte, Genetics, medicine, Animals, Uncoupling protein, Uncoupling Protein 2, Protein kinase A, Molecular Biology, 030304 developmental biology, Epididymis, 2. Zero hunger, 0303 health sciences, biology, Lipogenesis, Body Weight, Membrane Transport Proteins, Cell Biology, Lipid Metabolism, Endocrinology, Adipose Tissue, Gene Expression Regulation, chemistry, Starvation, biology.protein, Phosphoenolpyruvate carboxykinase
Abstract: The mechanisms controlling fat depot-specific metabolism are poorly understood. During starvation of mice, downregulation of lipogenic genes, suppression of fatty acid synthesis, and increases in lipid oxidation were all more pronounced in epididymal than in subcutaneous fat. In epididymal fat, relatively strong upregulation of uncoupling protein 2 and phosphoenolpyruvate carboxykinase genes was found. In mice maintained both at 20 and 30°C, AMP-activated protein kinase was activated in epididymal but did not change in subcutaneous fat. Our results suggest that AMPK may have a role in the different response of various fat depots to starvation.
Published: 2005
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18. Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue

Author: Marek Vecka, Eva Tvrzická, Morten Bryhn, Jana Ruzickova, Jan Kopecky, Pavel Flachs, Tomas Prazak, Jana Sponarova, and Martin Rossmeisl
Subjects: medicine.medical_specialty, Adipose tissue, Context (language use), Carbohydrate metabolism, Biochemistry, Muscle hypertrophy, Mice, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Obesity, chemistry.chemical_classification, Chemistry, Organic Chemistry, food and beverages, Cell Biology, Hyperplasia, medicine.disease, Diet, Endocrinology, Adipose Tissue, Fatty Acids, Unsaturated, lipids (amino acids, peptides, and proteins), medicine.symptom, Weight gain, Polyunsaturated fatty acid
Abstract: Omega-3 PUFA of marine origin reduce adiposity in animals fed a high-fat diet. Our aim was to learn whether EPA and DHA could limit development of obesity and reduce cellularity of adipose tissue and whether other dietary FA could influence the effect of EPA/DHA. Weight gain induced by composite high-fat diet in C57BL/6J mice was limited when the content of EPA/DHA was increased from 1 to 12% (wt/wt) of dietary lipids. Accumulation of adipose tissue was reduced, especially of the epididymal fat. Low ratio of EPA to DHA promoted the effect. A higher dose of EPA/DHA was required to reduce adiposity when admixed to diets that did not promote obesity, the semisynthetic high-fat diets rich in EFA, either alpha-linolenic acid (ALA, 18:3 n-3, the precursor of EPA and DHA) or linoleic (18:2 n-6) acid. Quantification of adipose tissue DNA revealed that except for the diet rich in ALA the reduction of epididymal fat was associated with 34-50% depression of tissue cellularity, similar to the 30% caloric restriction in the case of the high-fat composite diet. Changes in plasma markers and adipose gene expression indicated improvement of lipid and glucose metabolism due to EPA/DHA even in the context of the diet rich in ALA. Our results document augmentation of the antiadipogenic effect of EPA/DHA during development of obesity and suggest that EPA/DHA could reduce accumulation of body fat by limiting both hypertrophy and hyperplasia of fat cells. Increased dietary intake of EPA/DHA may be beneficial regardless of the ALA intake.
Published: 2004
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19. Cold-induced changes in white adipose tissue of A/J and C57BL/6J mice

Author: Jan Kopecky, Pavel Flachs, Kristina Bardova, Katerina Adamcova, and Michaela Svobodova
Subjects: medicine.medical_specialty, Endocrinology, Chemistry, Internal medicine, medicine, Adipose tissue, White adipose tissue, Cardiology and Cardiovascular Medicine, C57bl 6j
Published: 2016
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20. Inducibility of triglyceride turnover in white fat – A marker of lean phenotype

Author: Jan Kopecky, Katerina Adamcova, Karsten Kristiansen, Kristina Bardova, Lise Madsen, John G. Jones, Michaela Svobodova, Petra Janovska, Pavel Flachs, A. Keenan, and Petr Zouhar
Subjects: medicine.medical_specialty, chemistry.chemical_compound, Endocrinology, Triglyceride, chemistry, Internal medicine, medicine, White adipose tissue, Biology, Cardiology and Cardiovascular Medicine, Phenotype
Published: 2016
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21. Induction of Uncoupling Protein 3 Gene Expression in Skeletal Muscle of Preterm Newborns

Author: Richard Plavka, Josef Ruffer, Václav Sebroň, Petr Brauner, Jaroslav Vorlíček, Pavel Flachs, Pavel Kopecký, Jan Kopecký, and Ivana Vitkova
Subjects: Male, medicine.medical_specialty, Gestational Age, Oxidative phosphorylation, Mitochondrion, Biology, Ion Channels, Oxidative Phosphorylation, Mitochondrial Proteins, Fetus, Lipid oxidation, Internal medicine, Gene expression, medicine, Humans, Uncoupling Protein 3, Uncoupling protein, Myocyte, Uncoupling Protein 2, Muscle, Skeletal, UCP3, Myocardium, Infant, Newborn, Gene Expression Regulation, Developmental, Membrane Transport Proteins, Proteins, Skeletal muscle, Heart, Endocrinology, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Female, Carrier Proteins, Energy Metabolism, Infant, Premature
Abstract: Prematurity is associated with delayed postnatal activation of mitochondrial oxidative phosphorylation and impaired switch from glycolytic to oxidative metabolism. Fatty acids (FA), which represent a major energy substrate in mature muscle cells, are engaged in the postnatal activation of genes of energy metabolism and lipid oxidation. To understand the mechanism activating mitochondria in human newborns, expression of the genes for mitochondrial uncoupling proteins (UCP) was characterized in autopsy samples of skeletal (n = 28) and cardiac (n = 13) muscles of preterm neonates, who mostly died during the first postnatal month, and two aborted fetuses. Transcripts levels for UCP2, UCP3, and also for genes engaged in the transport of FA between cytoplasm and mitochondria were measured using real-time reverse transcriptase PCR. In accordance with studies in mice, our results document postnatal induction of UCP3 gene expression in skeletal muscle, involvement of nutritional FA in the induction, and a role of UCP3 in mitochondrial FA oxidation. They suggest impaired postnatal activation of UCP3 gene in neonates delivered before approximately 26 wk of gestation. Mean levels of the UCP3 transcript in skeletal muscle were by two orders of magnitude higher than in the heart. In contrast to UCP3, the UCP2 gene was active in fetuses, and its expression was not affected by nutrition. Our results support a role of UCP3 in postnatal activation of lipid oxidation in skeletal muscle and suggest the involvement of UCP3 in the delayed activation of mitochondrial energy conversion in very immature preterm neonates.
Published: 2003
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22. Impaired noradrenaline-induced lipolysis in white fat of aP2-Ucp1 transgenic mice is associated with changes in G-protein levels

Author: Kristina Bardova, Filip Baumruk, Jan Kopecký, Petr Svoboda, Jirí Novotný, Pavel Flachs, Ivan Mikšík, Jana Sponarova, and Lenka Bourova
Subjects: Male, medicine.medical_specialty, Genotype, G protein, Lipolysis, Alpha (ethology), Adipose tissue, Mice, Transgenic, Stimulation, White adipose tissue, Biology, Biochemistry, Gene Expression Regulation, Enzymologic, Ion Channels, Mitochondrial Proteins, Mice, Norepinephrine, Adenosine Triphosphate, GTP-Binding Proteins, In vivo, Internal medicine, Cyclic AMP, medicine, Animals, Molecular Biology, Uncoupling Protein 1, DNA Primers, G alpha subunit, Base Sequence, Membrane Proteins, Lipase, Cell Biology, Adenosine Diphosphate, Mice, Inbred C57BL, Endocrinology, Adipose Tissue, Hepatocytes, Carrier Proteins, Research Article
Abstract: In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein α subunit was increased while that of the inhibitory G-protein α subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.
Published: 2002
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23. Expression of the uncoupling protein 1 from theaP2gene promoter stimulates mitochondrial biogenesis in unilocular adipocytesin vivo

Author: Pavel Flachs, Martin Rossmeisl, Saverio Cinti, Milada Horáková, Petra Janovska, Jan Kopecký, Giorgio Barbatelli, Maria Cristina Zingaretti, Mariella Marelli, Ivo Syrový, and Petr Brauner
Subjects: medicine.medical_specialty, Oxidase test, Protein subunit, White adipose tissue, Mitochondrion, Biology, Biochemistry, Thermogenin, Endocrinology, Mitochondrial biogenesis, Internal medicine, Lipogenesis, medicine, Biogenesis
Abstract: Mitochondrial uncoupling protein 1 (UCP1) is a specific marker of multilocular brown adipocytes. Ectopic UCP1 in white fat of aP2-Ucp1 mice mitigates development of obesity by both, increasing energy expenditure and decreasing in situ lipogenesis. In order to further analyse consequences of respiratory uncoupling in white fat, the effects of the ectopic UCP1 on the morphology of adipocytes and biogenesis of mitochondria in these cells were studied. In subcutaneous white fat of both aP2-Ucp1 and young control (5-week-old) mice, numerous multilocular adipocytes were found, while they were absent in adult (7- to 9-month-old) animals. Only unilocular cells were present in epididymal fat of both genotypes. In both fat depots of aP2-Ucp1 mice, the levels of the UCP1 transcript and UCP1 antigen declined during ageing, and they were higher in subcutaneous than in epididymal fat. Under no circumstances could ectopic UCP1 induce the conversion of unilocular into multilocular adipocytes. Presence of ectopic UCP1 in unilocular adipocytes was associated with the elevation of the transcripts for UCP2 and for subunit IV of mitochondrial cytochrome oxidase (COX IV), and increased content of mitochondrial cytochromes. Electron microscopy indicated changes of mitochondrial morphology and increased mitochondrial content due to ectopic UCP1 in unilocular adipocytes. In 3T3-L1 adipocytes, 2,4-dinitrophenol increased the levels of the transcripts for both COX IV and for nuclear respiratory factor-1. Our results indicate that respiratory uncoupling in unilocular adipocytes of white fat is capable of both inducing mitochondrial biogenesis and reducing development of obesity.
Published: 2002
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24. Erratum: Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype

Author: Kristina Bardova, Michaela Svobodova, Martin Rossmeisl, Jana Hansikova, Ulrike Liisberg, John G. Jones, Petra Janovska, P Zouhar, Jan Kopecky, A G Borkowska, Karsten Kristiansen, Katerina Adamcova, Ondrej Kuda, Lise Madsen, Cátia Marques, Ivan Viegas, and Pavel Flachs
Subjects: 0301 basic medicine, medicine.medical_specialty, Nutrition and Dietetics, FGF21, Chemistry, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), White adipose tissue, Thermogenin, 03 medical and health sciences, 030104 developmental biology, Endocrinology, Mitochondrial biogenesis, Internal medicine, Lipogenesis, medicine, Glyceroneogenesis, Lipolysis, Thermogenesis
Abstract: Futile substrate cycling based on lipolytic release of fatty acids (FA) from intracellular triacylglycerols (TAG) and their re-esterification (TAG/FA cycling), as well as de novo FA synthesis (de novo lipogenesis (DNL)), represent the core energy-consuming biochemical activities of white adipose tissue (WAT). We aimed to characterize their roles in cold-induced thermogenesis and energy homeostasis. Male obesity-resistant A/J and obesity-prone C57BL/6J mice maintained at 30 °C were exposed to 6 °C for 2 or 7 days. In epididymal WAT (eWAT), TAG synthesis and DNL were determined using in vivo 2H incorporation from 2H2O into tissue TAG and nuclear magnetic resonance spectroscopy. Quantitative real-time-PCR and/or immunohistochemistry and western blotting were used to determine the expression of selected genes and proteins in WAT and liver. The mass of WAT depots declined during cold exposure (CE). Plasma levels of TAG and non-esterified FA were decreased by day 2 but tended to normalize by day 7 of CE. TAG synthesis (reflecting TAG/FA cycle activity) gradually increased during CE. DNL decreased by day 2 of CE but increased several fold over the control values by day 7. Expression of genes involved in lipolysis, glyceroneogenesis, FA re-esterification, FA oxidation and mitochondrial biogenesis in eWAT was induced during CE. All these changes were more pronounced in obesity-resistant A/J than in B6 mice and occurred in the absence of uncoupling protein 1 in eWAT. Expression of markers of glyceroneogenesis in eWAT correlated negatively with hepatic FA synthesis by day 7 in both strains. Leptin and fibroblast growth factor 21 plasma levels were differentially affected by CE in the two mouse strains. Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype.
Published: 2017
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25. Lipid signaling in adipose tissue: Connecting inflammationmetabolism

Author: Pavel Flachs, Ondrej Kuda, Mojgan Masoodi, Jan Kopecky, and Martin Rossmeisl
Subjects: medicine.medical_specialty, Adipose tissue macrophages, Adipose Tissue, White, Macrophage polarization, Adipose tissue, White adipose tissue, Cell Communication, Biology, Proinflammatory cytokine, chemistry.chemical_compound, Internal medicine, Adipocyte, medicine, Adipocytes, Lipolysis, Animals, Humans, Obesity, Molecular Biology, Inflammation, Macrophages, Cell Biology, Lipid signaling, Lipid Metabolism, Endocrinology, chemistry, lipids (amino acids, peptides, and proteins), Inflammation Mediators, Energy Metabolism, Signal Transduction
Abstract: Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n-6 and n-3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the formation of "healthy" adipocytes. This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance."
Published: 2014

26. Mitochondrial uncoupling and lipid metabolism in adipocytes

Author: Pavel Flachs, Kristina Bardova, Jan Kopecký, Petr Brauner, and Martin Rossmeisl
Subjects: medicine.medical_specialty, White adipose tissue, Biology, Models, Biological, Biochemistry, Ion Channels, Mitochondrial Proteins, Mice, chemistry.chemical_compound, Internal medicine, Adipocytes, medicine, Animals, Humans, Uncoupling Protein 1, Fatty acid synthesis, UCP3, ATP synthase, Membrane Proteins, Lipid metabolism, Lipid Metabolism, Thermogenin, Mitochondria, Endocrinology, Adipose Tissue, chemistry, Lipogenesis, biology.protein, Ectopic expression, Carrier Proteins
Abstract: Metabolism of white adipose tissue is involved in the control of body fat content. In vitro experiments indicated a dependence of lipogenesis on mitochondrial ATP production, as well as a reciprocal link between hormonal effects on metabolism and energetics of adipocytes. Therefore, mitochondrial uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to control of lipid metabolism and adiposity. This is supported by the expression of protonophoric proteins in adipocytes, e.g. uncoupling proteins (UCPs) 2 and 5, and some anion transporters, and induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. Negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by mitochondrial uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white but not in brown fat. Probably due to depression of ATP/ADP ratio in white fat of transgenic mice, both fatty acid synthesis and lipolytic action of noradrenaline in adipocytes were relatively low. These results support the role of protonophoric proteins in adipocytes in the control of adiposity. The main function of these proteins in white fat may be modulation of lipogenesis and intracellular hormone signalling. Augmentation of energy expenditure may be of relatively small importance, in accordance with the low oxidative capacity of white adipocytes.
Published: 2001
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27. Decreased fatty acid synthesis due to mitochondrial uncoupling in adipose tissue

Author: Petra Janovska, Jan Kopecký, Ivo Syrový, Pavel Flachs, Filip Baumruk, and Martin Rossmeisl
Subjects: Male, Gene Expression, Adipose tissue, Mice, Transgenic, White adipose tissue, Mitochondrion, Biochemistry, Ion Channels, Mitochondrial Proteins, Mice, chemistry.chemical_compound, Genetics, Animals, Molecular Biology, Uncoupling Protein 1, Fatty acid synthesis, chemistry.chemical_classification, Chemistry, Fatty Acids, Membrane Proteins, Fatty acid, 3T3-L1, 3T3 Cells, Thermogenin, Mitochondria, Mice, Inbred C57BL, Adipose Tissue, Lipogenesis, Carrier Proteins, Energy Metabolism, Biotechnology
Abstract: Synthesis of fatty acid (FA) in adipose tissue requires cooperation of mitochondrial and cytoplasmic enzymes. Mitochondria are required for the production of ATP and they also support the formation of acetyl-CoA and NADPH in cytoplasm. Since cellular levels of all these metabolites depend on the efficiency of mitochondrial energy conversion, mitochondrial proton leak via uncoupling proteins (UCPs) could modulate FA synthesis. In 3T3-L1 adipocytes, 2,4-dinitrophenol depressed the synthesis of FA 4-fold while increasing FA oxidation 1. 5-fold and the production of lactate 14-fold. Inhibition of FA synthesis in 3T3-L1 adipocytes was proportional to the decrease in mitochondrial membrane potential. FA synthesis from D-[U-(14)C] glucose was reduced up to fourfold by ectopic UCP1 in the white fat of transgenic aP2-Ucp1 mice, reflecting the magnitude of UCP1 expression in different fat depots and the reduction of adiposity. Transcript levels for lipogenic enzymes were lower in the white fat of the transgenic mice than in the control animals. Our results show that uncoupling of oxidative phosphorylation depresses FA synthesis in white fat. Reduction of adiposity via mitochondrial uncoupling in white fat not only reflects increased energy expenditure, but also decreased in situ lipogenesis.
Published: 2000
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28. Oleuropein as an inhibitor of peroxisome proliferator-activated receptor gamma

Author: Michaela Svobodova, Jan Kopecky, Pavel Flachs, Ioanna Andreadou, and Alexios-Leandros Skaltsounis
Subjects: chemistry.chemical_classification, biology, Endocrinology, Diabetes and Metabolism, Peroxisome proliferator-activated receptor, Peroxisome, Cell biology, chemistry.chemical_compound, Fatty acid synthase, chemistry, Biochemistry, Oleuropein, Adipogenesis, Adipocyte, Genetics, biology.protein, Receptor, Transcription factor, Research Paper
Abstract: Oleuropein, the major phenolic compound found in olive leaves and oil, exerts antioxidant, anti-inflammatory and anti-atherogenic effects and suppresses the adipocyte differentiation in vitro. Herein, we characterized molecular mechanisms underlying the anti-adipogenic effects of oleuropein on 3T3-L1 cells and adipocytes derived from stromal-vascular fraction of dorsolumbar and gonadal fat dissected from mice. We found that oleuropein (>100 μM) decreased viability of preadipocytes proliferating in vitro and did not exerted any cytotoxic effects in post-confluent cells after induction of differentiation. Oleuropein (>100 μM) inhibited adipocyte differentiation, suppressed gene expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-/enhancer-binding protein α, sterol regulatory element-binding transcription factor 1c and fatty acid synthase. Furthermore, we tested ability of oleuropein to regulate of PPARγ-, PPARα- or PPARβ-/PPARδ-mediated β-lactamase expression in appropriate reporter gene assays. Oleuropein between 10 and 400 μM concentrations did not affect activity of PPARα or PPARβ/δ. Contrary, PPARγ activity, either basal or rosiglitazone activated, was inhibited by oleuropein. Our data suggest that oleuropein exerts anti-adipogenic effect through direct inhibition of PPARγ transcriptional activity.
Published: 2013

29. Fibroblast growth factor-21 and the beneficial effects of long-chain n-3 polyunsaturated fatty acids

Author: Jan Kopecky, Ibon Redondo-Angulo, Anna Planavila, Joan Villarroya, Dasa Medrikova, Pavel Flachs, Francesc Villarroya, and Marta Giralt
Subjects: Male, medicine.medical_specialty, FGF21, Time Factors, Clinical chemistry, Peroxisome proliferator-activated receptor, Gene Expression, Biology, Diet, High-Fat, Weight Gain, Biochemistry, Ion Channels, Mitochondrial Proteins, Insulin resistance, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Insulin, PPAR alpha, Receptor, Triglycerides, Uncoupling Protein 1, chemistry.chemical_classification, Adiponectin, Reverse Transcriptase Polymerase Chain Reaction, Organic Chemistry, Body Weight, Cell Biology, medicine.disease, Up-Regulation, Fibroblast Growth Factors, Mice, Inbred C57BL, Endocrinology, chemistry, Adipose Tissue, Liver, Corn Oil, human activities, Corn oil, Polyunsaturated fatty acid
Abstract: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) in the diet protect against insulin resistance and obesity. Fibroblast growth factor-21 (Fgf21) is a hormonal factor released mainly by the liver that has powerful anti-diabetic effects. Here, we tested whether the beneficial metabolic effects of LC n-3 PUFA involve the induction of Fgf21. C57BL/6 J mice were exposed to an obesogenic, corn-oil-based, high-fat diet (cHF), or a diet in which corn oil was replaced with a fish-derived LC n-3 PUFA concentrate (cHF + F) using two experimental settings: short-term (3 weeks) and long-term treatment (8 weeks). CHF + F reduced body weight gain, insulinemia, and triglyceridemia compared to cHF. cHF increased plasma Fgf21 levels and hepatic Fgf21 gene expression compared with controls, but these effects were less pronounced or absent in cHF + F-fed mice. In contrast, hepatic expression of peroxisome proliferator-activated receptor (PPAR)-α target genes were more strongly induced by cHF + F than cHF, especially in the short-term treatment setting. The expression of genes encoding Fgf21, its receptors, and Fgf21 targets was unaltered by short-term LC n-3 PUFA treatment, with the exception of Ucp1 (uncoupling protein 1) and adiponectin genes, which were specifically up-regulated in white fat. In the long-term treatment setting, the expression of Fgf21 target genes and receptors was not differentially affected by LC n-3 PUFA. Collectively, our findings indicate that increased Fgf21 levels do not appear to be a major mechanism through which LC n-3 PUFA ameliorates high-fat-diet-associated metabolic disorders.
Published: 2013

30. Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue

Author: Elayne Hondares, José M. Gallego-Escuredo, Jessica Perugini, Pavel Kopecky, Pavel Flachs, Rubén Cereijo, Francesc Villarroya, Marta Giralt, Saverio Cinti, Andrea Frontini, Jan Kopecky, and Alberto Goday
Subjects: Adult, Male, medicine.medical_specialty, FGF21, Endocrinology, Diabetes and Metabolism, Adipose Tissue, White, Adrenal Gland Neoplasms, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, Pheochromocytoma, Biology, Marker gene, Ion Channels, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Adipose Tissue, Brown, Internal medicine, Brown adipose tissue, medicine, Humans, Fibroblast, Uncoupling Protein 1, 030304 developmental biology, Aged, 0303 health sciences, Infant, Newborn, Middle Aged, medicine.disease, Thermogenin, Fibroblast Growth Factors, medicine.anatomical_structure, 4-1BB Ligand, Adipocytes, Brown, Female, Transcriptome, Transcription Factors
Abstract: Objective In rodents, brown (BAT) and white (WAT) adipose tissues are targets and expression sites for fibroblast growth factor-21 (FGF21). In contrast, human WAT expresses negligible levels of FGF21. We examined FGF21 expression in human BAT samples, including the induced BAT found in adult patients with pheochromocytoma, and interscapular and visceral BAT from newborns. Methods The expression of FGF21 and uncoupling protein-1 (UCP1, a brown adipocyte marker), was determined by quantitative real-time-PCR and immunoblotting. The transcript levels of marker genes for developmentally-programmed BAT (zinc-finger-protein of the cerebellum-1, ZIC1) and inducible-BAT (cluster of differentiation-137, CD137) were also determined. Results FGF21 and UCP1 are significantly expressed in visceral adipose tissue from pheochromocytoma patients, but not in visceral fat from healthy individuals. In neonates, FGF21 and UCP1 are both expressed in visceral and interscapular fat, and their expression levels show a significant positive correlation. Marker gene expression profiles suggest that inducible BAT is present in visceral fat from pheochromocytoma patients and neonates, whereas developmentally-programmed BAT is present in neonatal interscapular fat. Conclusions Human BAT, but not WAT, expresses FGF21. The expression of FGF21 is especially high in inducible, also called beige/brite, neonatal BAT, but it is also found in the interscapular, developmentally-programmed, BAT of neonates.
Published: 2013

31. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice

Author: Petra Janovska, Anabela P. Rolo, Carlos M. Palmeira, Pavel Flachs, João S. Teodoro, Ana P. Gomes, Filipe V. Duarte, P Zouhar, Kristina Bardova, Jan Kopecký, and Ana T. Varela
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adipose Tissue, White, Blotting, Western, Medicine (miscellaneous), Adipose tissue, Mice, Obese, White adipose tissue, Chenodeoxycholic Acid, Diet, High-Fat, Real-Time Polymerase Chain Reaction, Ion Channels, Mitochondrial Proteins, chemistry.chemical_compound, Mice, Lipid oxidation, Adipose Tissue, Brown, Chenodeoxycholic acid, Internal medicine, Brown adipose tissue, Glucose Intolerance, medicine, Animals, Obesity, Uncoupling Protein 1, Nutrition and Dietetics, Cholic acid, Thermogenesis, Lipid Metabolism, Thermogenin, Mice, Inbred C57BL, Oxidative Stress, Endocrinology, medicine.anatomical_structure, chemistry, Energy Metabolism, Signal Transduction
Abstract: Besides their role in lipid absorption, bile acids (BAs) can act as signalling molecules. Cholic acid was shown to counteract obesity and associated metabolic disorders in high-fat-diet (cHF)-fed mice while enhancing energy expenditure through induction of mitochondrial uncoupling protein 1 (UCP1) and activation of non-shivering thermogenesis in brown adipose tissue (BAT). In this study, the effects of another natural BA, chenodeoxycholic acid (CDCA), on dietary obesity, UCP1 in both interscapular BAT and in white adipose tissue (brite cells in WAT), were characterized in dietary-obese mice.To induce obesity and associated metabolic disorders, male 2-month-old C57BL/6J mice were fed cHF (35% lipid wt wt(-1), mainly corn oil) for 4 months. Mice were then fed either (i) for 8 weeks with cHF or with cHF with two different doses (0.5%, 1%; wt wt(-1)) of CDCA (8-week reversion); or (ii) for 3 weeks with cHF or with cHF with 1% CDCA, or pair-fed (PF) to match calorie intake of the CDCA mice fed ad libitum; mice on standard chow diet were also used (3-week reversion).In the 8-week reversion, the CDCA intervention resulted in a dose-dependent reduction of obesity, dyslipidaemia and glucose intolerance, which could be largely explained by a transient decrease in food intake. The 3-week reversion revealed mild CDCA-dependent and food intake-independent induction of UCP1-mediated thermogenesis in interscapular BAT, negligible increase of UCP1 in subcutaneous WAT and a shift from carbohydrate to lipid oxidation.CDCA could reverse obesity in cHF-fed mice, mainly in response to the reduction in food intake, an effect probably occuring but neglected in previous studies using cholic acid. Nevertheless, CDCA-dependent and food intake-independent induction of UCP1 in BAT (but not in WAT) could contribute to the reduction in adiposity and to the stabilization of the lean phenotype.
Published: 2013

32. Adipose tissue-related proteins locally associated with resolution of inflammation in obese mice

Author: Pavel Flachs, Martin Rossmeisl, Zuzana Macek Jilkova, Olga Horakova, Jürgen Eckel, Jan Kopecky, Petra Janovska, Dasa Medrikova, Henrike Sell, and M Hensler
Subjects: Male, medicine.medical_specialty, Docosahexaenoic Acids, Endocrinology, Diabetes and Metabolism, Adipose Tissue, White, Medicine (miscellaneous), Adipose tissue, Mice, Obese, 030209 endocrinology & metabolism, Inflammation, Enzyme-Linked Immunosorbent Assay, Diet, High-Fat, Real-Time Polymerase Chain Reaction, Rosiglitazone, 03 medical and health sciences, Mice, 0302 clinical medicine, Adipokines, Internal medicine, Fatty Acids, Omega-3, Adipocytes, Medicine, Animals, Obesity, 030304 developmental biology, Obese Mice, 0303 health sciences, Nutrition and Dietetics, business.industry, Resolution (electron density), Dietary Fats, Immunohistochemistry, Mice, Inbred C57BL, Endocrinology, Thiazolidinediones, medicine.symptom, business, Energy Metabolism
Abstract: Resolution of low-grade inflammation of white adipose tissue (WAT) is one of the keys for amelioration of obesity-associated metabolic dysfunctions. We focused on the identification of adipokines, which could be involved at the early stages of resolution of WAT inflammation.Male C57BL/6J mice with obesity induced in response to a 22-week feeding corn oil-based high-fat (cHF) diet were divided into four groups and were fed with, for 2 weeks, control cHF diet or cHF-based diets supplemented with: (i) concentrate of n-3 long-chain polyunsaturated fatty acids, mainly eicosapentaenoic and docosahexaenoic acids (cHF+F); (ii) thiazolidinedione drug rosiglitazone (cHF+TZD); and (iii) both compounds (cHF+F+TZD).The short-term combined intervention exerted additive effect in the amelioration of WAT inflammation in obese mice, namely in the epididymal fat, even in the absence of any changes in either adipocyte volume or fat mass. The combined intervention elicited hypolipidaemic effect and induced adiponectin, whereas the responses to single interventions (cHF+F, cHF+TZD) were less pronounced. In addition, analysis in WAT lysates using protein arrays revealed that the levels of a small set of adipose tissue-related proteins, namely macrophage inflammatory protein 1γ, endoglin, vascular cell adhesion molecule 1 and interleukin 1 receptor antagonist, changed in response to the anti-inflammatory interventions and were strongly reduced in the cHF+F+TZD mice. These results were verified using both the analysis of gene expression and enzyme-linked immunosorbent analysis in WAT lysates. In contrast with adiponectin, which showed changing plasma levels in response to dietary interventions, the levels of the above proteins were affected only in WAT.We identified several adipose tissue-related proteins, which are locally involved in resolution of low-grade inflammation and remodelling of WAT.
Published: 2012

33. Preservation of Metabolic Flexibility in Skeletal Muscle by a Combined Use of n-3 PUFA and Rosiglitazone in Dietary Obese Mice

Author: Kristina Bardova, Cornelia Prehn, Pavel Flachs, Jaap Keijer, Thomas Illig, Dasa Medrikova, Olga Horakova, Evert M. van Schothorst, Annelies Bunschoten, M Hensler, Jan Kopecky, Martin Rossmeisl, Ondrej Kuda, Rui Wang-Sattler, Petra Janovska, Jerzy Adamski, and Vladimir Kus
Subjects: Male, eicosapentaenoic acid, Mouse, medicine.medical_treatment, Muscle Fibers, Skeletal, Gene Expression, Type 2 diabetes, induced insulin-resistance, Biochemistry, Mice, 0302 clinical medicine, Drug Discovery, Molecular Cell Biology, Tissue Distribution, 0303 health sciences, Multidisciplinary, biology, Chemistry, Fatty Acids, Drug Synergism, Animal Models, Lipids, marine origin, Human and Animal Physiology, Carbohydrate Metabolism, Medicine, impaired glucose-tolerance, Metabolic Pathways, Rosiglitazone, Glycolysis, Oxidation-Reduction, Research Article, medicine.drug, weight-loss, medicine.medical_specialty, fish-oil, Science, Blood sugar, 030209 endocrinology & metabolism, Carbohydrate metabolism, Diet, High-Fat, Lipid Mediators, 03 medical and health sciences, Model Organisms, Insulin resistance, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Metabolomics, Obesity, Muscle, Skeletal, Biology, Nutrition, 030304 developmental biology, Sphingolipids, Insulin, activated-receptor-alpha, ceramidase activity, Lipid Metabolism, medicine.disease, Mice, Inbred C57BL, Insulin receptor, Metabolism, Endocrinology, Gene Expression Regulation, Ceramidase activity, biology.protein, WIAS, Fysiologie van Mens en Dier, Thiazolidinediones, type-2 diabetes-mellitus, polyunsaturated fatty-acids
Abstract: Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.
Published: 2012
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34. The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice

Author: Pierre Chambon, Daniel Meztger, Jan Kopecky, M Hensler, Pavel Flachs, Zuzana Macek Jilkova, Walter Wahli, and Kristina Bardova
Subjects: Male, DHA and EPA, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Drug Evaluation, Preclinical, Adipose tissue, Fat cell proliferation, Gene Expression, fish oil, chemistry.chemical_compound, Gene Knockout Techniques, Mice, 0302 clinical medicine, Endocrinology, Weight loss, Adipocyte, Adipocytes, lcsh:RC620-627, chemistry.chemical_classification, Epididymis, 0303 health sciences, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, lcsh:Nutritional diseases. Deficiency diseases, medicine.symptom, Stearoyl-CoA Desaturase, Polyunsaturated fatty acid, Lipidology, medicine.medical_specialty, Peroxisome proliferator-activated receptor gamma, fat cell turnover, Short Report, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, 03 medical and health sciences, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, PPAR alpha, Obesity, 030304 developmental biology, Cell Proliferation, Biochemistry, medical, Biochemistry (medical), Proteins, PPAR gamma, chemistry, Prostaglandin-Endoperoxide Synthases, Trans-Activators, Corn Oil, Adipocytes/drug effects, Adipocytes/pathology, Cell Proliferation/drug effects, Corn Oil/adverse effects, Epididymis/metabolism, Epididymis/pathology, Fatty Acids, Omega-3/pharmacology, Obesity/chemically induced, Obesity/prevention & control, PPAR alpha/genetics, PPAR alpha/metabolism, PPAR gamma/genetics, Prostaglandin-Endoperoxide Synthases/genetics, Prostaglandin-Endoperoxide Synthases/metabolism, Proteins/genetics, Proteins/metabolism, Stearoyl-CoA Desaturase/genetics, Stearoyl-CoA Desaturase/metabolism, Trans-Activators/genetics, Trans-Activators/metabolism, Corn oil, Transcription Factors
Abstract: Background Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice. Methods A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARγL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor γ in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42. Results Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice. Conclusion Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.
Published: 2011

35. Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

Author: Petra Janovska, Z. Macek Jilkova, Grygoriy Tsenov, Pavel Flachs, Michaela Svobodova, Ralph Rühl, E. Papp, Martin Rossmeisl, Ondrej Kuda, P Zouhar, Vladimir Kus, M Hensler, Jan Kopecky, and Vidya Mohamed-Ali
Subjects: Male, medicine.medical_specialty, Docosahexaenoic Acids, Endocrinology, Diabetes and Metabolism, Adipose Tissue, White, Calorie restriction, Adipose tissue, Mice, Obese, White adipose tissue, Fish oil, Biology, Diet, High-Fat, Real-Time Polymerase Chain Reaction, 15-Deoxy-Delta(12,15)-prostaglandin J(2), DHA, EPA, Metabolic syndrome, 15)-prostaglandin J(2), Mice, Insulin resistance, Internal medicine, Fatty Acids, Omega-3, Internal Medicine, medicine, Animals, Caloric Restriction, chemistry.chemical_classification, 15-Deoxy-Delta(12, Prostaglandin D2, medicine.disease, Lipid Metabolism, Obesity, Dietary Fats, Immunohistochemistry, Endocrinology, chemistry, Docosahexaenoic acid, Energy Metabolism, Polyunsaturated fatty acid
Abstract: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice.Male mice (C57BL/6J) were habituated to a corn-oil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF + F), ad libitum; (3) cHF with calorie restriction (CR; cHF + CR); and (4) cHF + F + CR. Mice fed a chow diet were also studied.We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ(12,15)-prostaglandin J(2) and protectin D1.White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.
Published: 2011

36. Unmasking differential effects of rosiglitazone and pioglitazone in the combination treatment with n-3 fatty acids in mice fed a high-fat diet

Author: Zuzana Macek Jilkova, Martin Rossmeisl, Thomas Illig, Rui Wang-Sattler, Michaela Svobodova, Vladimir Kus, Pavel Flachs, Jan Kopecky, Zhonghao Yu, Kristina Bardova, Petra Janovska, and Ondrej Kuda
Subjects: Blood Glucose, Male, Anatomy and Physiology, Biochemistry, Mice, Endocrinology, 0302 clinical medicine, Homeostasis, Glucose homeostasis, Drug Interactions, Thiazolidinedione, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, Fatty Acids, Lipids, 3. Good health, Medicine, Rosiglitazone, Research Article, medicine.drug, Polyunsaturated fatty acid, Drugs and Devices, medicine.medical_specialty, medicine.drug_class, Science, Endocrine System, 030209 endocrinology & metabolism, 03 medical and health sciences, Insulin resistance, Adverse Reactions, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, Hypoglycemic Agents, Metabolomics, Obesity, Biology, Nutrition, 030304 developmental biology, Diabetic Endocrinology, Pioglitazone, Adiponectin, business.industry, Diabetes Mellitus Type 2, medicine.disease, Dietary Fats, Mice, Inbred C57BL, chemistry, Metabolic Disorders, Thiazolidinediones, Metabolic syndrome, business
Abstract: Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy.
Published: 2011

37. Modulation of type I iodothyronine 5'-deiodinase activity in white adipose tissue by nutrition: possible involvement of leptin

Author: Jan Kopecký, Stanislav Pavelka, Pavel Flachs, Z. Macek Jilkova, M Hensler, and V Kůs
Subjects: Leptin, medicine.medical_specialty, Thyroid Hormones, Physiology, Adipose tissue macrophages, Adipose Tissue, White, Injections, Subcutaneous, Adipose tissue, Adipokine, White adipose tissue, Iodide Peroxidase, Gene Expression Regulation, Enzymologic, Mice, Adipose Tissue, Brown, Internal medicine, Brown adipose tissue, medicine, Animals, Obesity, RNA, Messenger, Caloric Restriction, PRDM16, Leptin receptor, Chemistry, General Medicine, Recombinant Proteins, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Animal Nutritional Physiological Phenomena, Stearoyl-CoA Desaturase
Abstract: Adipose tissue is an important target for thyroid hormones (TH). However, the metabolism of TH in white adipose tissue is poorly characterized. Our objective was to describe possible changes in activities of TH-metabolizing enzymes in white adipose tissue, and the role of TH metabolism in the tissue during obesogenic treatment, caloric restriction and in response to leptin in mice. Activity of type I iodothyronine 5’-deiodinase (D1) in white fat was stimulated by a high-fat diet, which also increased plasma leptin levels, while brown adipose tissue D1 activity did not change. Caloric restriction decreased the activity of D1 in white fat (but not in the liver), reduced leptin levels, and increased the expression of stearoyl CoA desaturase 1 (SCD-1), a marker and mediator of the effect of leptin on tissue metabolism. Leptin injections increased D1 activity and down-regulated SCD-1 in white fat. Our results demonstrate changes in D1 activity in white adipose tissue under the conditions of changing adiposity, and a stimulatory effect of leptin on D1 activity in the tissue. These results suggest a functional role for D1 in white adipose tissue, with D1 possibly being involved in the control of adipose tissue metabolism and/or accumulation of the tissue.
Published: 2009

38. n-3 PUFA: bioavailability and modulation of adipose tissue function

Author: Jan, Kopecky, Martin, Rossmeisl, Pavel, Flachs, Ondrej, Kuda, Petr, Brauner, Zuzana, Jilkova, Barbora, Stankova, Eva, Tvrzicka, and Morten, Bryhn
Subjects: Inflammation, Metabolic Syndrome, Lipid Metabolism, Dietary Fats, Mitochondria, Rats, Mice, Adipose Tissue, Fatty Acids, Omega-3, Animals, Humans, Adiponectin, Insulin Resistance, Signal Transduction
Abstract: Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. The n-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus, n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodents n-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects of n-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms. n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation of n-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects of n-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation by n-3 LC PUFA.
Published: 2009

39. Prevention and reversal of obesity and glucose intolerance in mice by DHA derivatives

Author: M Hensler, Kjetil Berge, Vidya Mohamed-Ali, Jan Kopecky, Zuzana Macek Jilkova, Morten Bryhn, Pavel Flachs, Anne Kristin Holmeide, Vladimir Kus, Dasa Medrikova, Ctibor Povysil, Kristyna Slamova, Tomas Jelenik, and Martin Rossmeisl
Subjects: Male, medicine.medical_specialty, Docosahexaenoic Acids, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Blood sugar, Blood lipids, Weight Gain, Polymerase Chain Reaction, Mice, Endocrinology, Insulin resistance, Internal medicine, Glucose Intolerance, medicine, Glucose homeostasis, Animals, Obesity, Triglycerides, Hypolipidemic Agents, chemistry.chemical_classification, Glucose tolerance test, Nutrition and Dietetics, medicine.diagnostic_test, Glucose Tolerance Test, medicine.disease, Eicosapentaenoic acid, Dietary Fats, Mice, Inbred C57BL, Disease Models, Animal, Glucose, chemistry, Docosahexaenoic acid, RNA, lipids (amino acids, peptides, and proteins), Energy Intake, Polyunsaturated fatty acid
Abstract: The n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert hypolipidemic effects and prevent development of obesity and insulin resistance in animals fed high-fat diets. We sought to determine the efficacy of alpha-substituted DHA derivatives as lipid-lowering, antiobesity, and antidiabetic agents. C57BL/6 mice were given a corn oil-based high-fat (35% weight/weight) diet (cHF), or cHF with 1.5% of lipids replaced with alpha-methyl DHA ethyl ester (Substance 1), alpha-ethyl DHA ethyl ester (Substance 2), alpha,alpha-di-methyl DHA ethyl ester (Substance 3), or alpha-thioethyl DHA ethyl ester (Substance 4) for 4 months. Plasma markers of glucose and lipid metabolism, glucose tolerance, morphology, tissue lipid content, and gene regulation were characterized. The cHF induced obesity, hyperlipidemia, impairment of glucose homeostasis, and adipose tissue inflammation. Except for Substance 3, all other substances prevented weight gain and Substance 2 exerted the strongest effect (63% of cHF-controls). Glucose intolerance was significantly prevented (~67% of cHF) by both Substance 1 and Substance 2. Moreover, Substance 2 lowered fasting glycemia, plasma insulin, triacylglycerols, and nonesterified fatty acids (73, 9, 47, and 81% of cHF-controls, respectively). Substance 2 reduced accumulation of lipids in liver and skeletal muscle, as well as adipose tissue inflammation associated with obesity. Substance 2 also induced weight loss in dietary obese mice. In contrast to DHA administered either alone or as a component of the EPA/DHA concentrate (replacing 15% of dietary lipids), Substance 2 also reversed established glucose intolerance in obese mice. Thus, Substance 2 represents a novel compound with a promising potential in the treatment of obesity and associated metabolic disturbances.
Published: 2009

40. Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet

Author: Annelies Bunschoten, Jan Kopecky, Carolien Vink, Evert M. van Schothorst, Jaap Keijer, Nicole L.W. Franssen-van Hal, Guido J. E. J. Hooiveld, Ondrej Kuda, Jos Molthoff, and Pavel Flachs
Subjects: Male, omega-3 fats, RIKILT - Business Unit Veiligheid & Gezondheid, adipose-tissue, c57bl/6j mice, Voeding, Metabolisme en Genomica, Mice, Intestine, Small, Promoter Regions, Genetic, Beta oxidation, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, Peroxisome, Fish oil, Eicosapentaenoic acid, Metabolism and Genomics, PRI Bioscience, Phenotype, Biochemistry, Eicosapentaenoic Acid, Docosahexaenoic acid, Metabolisme en Genomica, Human and Animal Physiology, Nutrition, Metabolism and Genomics, lipids (amino acids, peptides, and proteins), obesity-resistance, Oxidation-Reduction, body-weight gain, Polyunsaturated fatty acid, Biotechnology, Research Article, fish-oil, Docosahexaenoic Acids, lcsh:QH426-470, Colon, lcsh:Biotechnology, Biology, beta-oxidation, Voeding, Lipid oxidation, lcsh:TP248.13-248.65, Genetics, Animals, Nutrition, Gene Expression Profiling, Fatty acid, Lipid Metabolism, gene-expression, Mice, Inbred C57BL, lcsh:Genetics, chemistry, Gene Expression Regulation, WIAS, RIKILT - Business Unit Safety & Health, Fysiologie van Mens en Dier, RNA, inflammatory processes, metabolism, Transcription Factors
Abstract: Background Dietary polyunsaturated fatty acids (PUFA), in particular the long chain marine fatty acids docosahexaenoic (DHA) and eicosapentaenoic (EPA), are linked to many health benefits in humans and in animal models. Little is known of the molecular response to DHA and EPA of the small intestine, and the potential contribution of this organ to the beneficial effects of these fatty acids. Here, we assessed gene expression changes induced by DHA and EPA in the wildtype C57BL/6J murine small intestine using whole genome microarrays and functionally characterized the most prominent biological process. Results The main biological process affected based on gene expression analysis was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR, and -in a second animal experiment- intestinal fatty acid oxidation measurements confirmed significant gene expression differences and showed in a dose-dependent manner significant changes at biological functional level. Furthermore, no major changes in the expression of lipid metabolism genes were observed in the colon. Conclusion We show that marine n-3 fatty acids regulate small intestinal gene expression and increase fatty acid oxidation. Since this organ contributes significantly to whole organism energy use, this effect on the small intestine may well contribute to the beneficial physiological effects of marine PUFAs under conditions that will normally lead to development of obesity, insulin resistance and diabetes.
Published: 2009

41. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism

Author: Martin Rossmeisl, Pavel Flachs, Jan Kopecky, and Morten Bryhn
Subjects: medicine.medical_specialty, Adipokine, Adipose tissue, White adipose tissue, Biology, Adipokines, Internal medicine, Fatty Acids, Omega-3, medicine, Adipocytes, Animals, Humans, Cell Proliferation, chemistry.chemical_classification, Metabolic Syndrome, Adiponectin, Lipid metabolism, General Medicine, Endocrinology, chemistry, Mitochondrial biogenesis, Adipose Tissue, Docosahexaenoic acid, lipids (amino acids, peptides, and proteins), Metabolic Networks and Pathways, Polyunsaturated fatty acid
Abstract: Adipose tissue and its secreted products, adipokines, have a major role in the development of obesity-associated metabolic derangements including Type 2 diabetes. Conversely, obesity and its metabolic sequelae may be counteracted by modulating metabolism and secretory functions of adipose tissue. LC-PUFAs (long-chain polyunsaturated fatty acids) of the n-3 series, namely DHA (docosahexaenoic acid; C(22:6n-3)) and EPA (eicosapentaenoic acid; C(20:5n-3)), exert numerous beneficial effects, such as improvements in lipid metabolism and prevention of obesity and diabetes, which partially result from the metabolic action of n-3 LC-PUFAs in adipose tissue. Recent studies highlight the importance of mitochondria in adipose tissue for the maintenance of systemic insulin sensitivity. For instance, both n-3 LC-PUFAs and the antidiabetic drugs TZDs (thiazolidinediones) induce mitochondrial biogenesis and beta-oxidation. The activation of this 'metabolic switch' in adipocytes leads to a decrease in adiposity. Both n-3 LC-PUFAs and TZDs ameliorate a low-grade inflammation of adipose tissue associated with obesity and induce changes in the pattern of secreted adipokines, resulting in improved systemic insulin sensitivity. In contrast with TZDs, which act as agonists of PPARgamma (peroxisome-proliferator-activated receptor-gamma) and promote differentiation of adipocytes and adipose tissue growth, n-3 LC-PUFAs affect fat cells by different mechanisms, including the transcription factors PPARalpha and PPARdelta. Some of the effects of n-3 LC-PUFAs on adipose tissue depend on their active metabolites, especially eicosanoids. Thus treatments affecting adipose tissue by multiple mechanisms, such as combining n-3 LC-PUFAs with either caloric restriction or antidiabetic/anti-obesity drugs, should be explored.
Published: 2008

42. Triglyceride-lowering effect of respiratory uncoupling in white adipose tissue

Author: Martin Rossmeisl, Frantisek Kolar, Dagmar Bobkova, Pavel Flachs, Rudolf Poledne, Jan Kopecky, Jan Kovar, and Ivo Syrovy
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Lipoproteins, Medicine (miscellaneous), Adipose tissue, Gene Expression, Mice, Transgenic, White adipose tissue, Ketone Bodies, Fatty Acids, Nonesterified, Ion Channels, Mitochondrial Proteins, chemistry.chemical_compound, Mice, Endocrinology, Internal medicine, medicine, Uncoupling protein, Animals, Triglycerides, Uncoupling Protein 1, Epididymis, Lipoprotein lipase, Bezafibrate, Triglyceride, Catabolism, Reverse Transcriptase Polymerase Chain Reaction, Fatty Acids, Homozygote, Public Health, Environmental and Occupational Health, Membrane Proteins, Dietary Fats, Mitochondria, DNA-Binding Proteins, Lipoprotein Lipase, chemistry, Adipose Tissue, Liver, Transcription Factor AP-2, Phosphoenolpyruvate Carboxykinase (GTP), Carrier Proteins, Oxidation-Reduction, Food Science, Lipoprotein, medicine.drug, Transcription Factors
Abstract: Objective: Hypolipidemic drugs such as bezafibrate and thiazolidinediones are known to induce the expression of mitochondrial uncoupling proteins (UCPs) in white adipose tissue. To analyze the potential triglyceride (TG)-lowering effect of respiratory uncoupling in white fat, we evaluated systemic lipid metabolism in aP2-Ucp1 transgenic mice with ectopic expression of UCP1 in adipose tissue. Research Methods and Procedures: Hemizygous and homozygous transgenic mice and their nontransgenic littermates were fed chow or a high-fat diet for up to 3 months. Total TGs, nonesterified fatty acids, and the composition of plasma lipoproteins were analyzed. Hepatic TG production was measured in mice injected with Triton WR1339. Uptake and the use of fatty acids were estimated by measuring adipose tissue lipoprotein lipase activity and fatty acid oxidation, respectively. Adipose tissue gene expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. Results: Transgene dosage and the high-fat diet interacted to markedly reduce plasma TGs. This was reflected by decreased concentrations of very-low-density lipoprotein particles in the transgenic mice. Despite normal hepatic TG secretion, the activity of lipoprotein lipase in epididymal fat was enhanced by the high-fat diet in the transgenic mice in a setting of decreased re-esterification and increased in situ fatty acid oxidation. Discussion: Respiratory uncoupling in white fat may lower plasma lipids by enhancing their in situ clearance and catabolism.
Published: 2005

43. Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce-beta oxidation in white fat

Author: Martin Rossmeisl, N. Franssen van Hal, Josef Houstek, Zdeněk Drahota, Petr Pecina, Jana Ruzickova, Pavel Flachs, Olga Horakova, Jan Kopecky, C. Vlcek, Jana Sponarova, Jaap Keijer, and Petr Brauner
Subjects: Male, obesity, Endocrinology, Diabetes and Metabolism, RIKILT - Business Unit Veiligheid & Gezondheid, Adipose tissue, activated protein-kinase, White adipose tissue, adipose-tissue, cpt-i, Mice, Adipocytes, Beta oxidation, Cells, Cultured, Epididymis, chemistry.chemical_classification, alpha-Linolenic Acid, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Mitochondria, Adipose Tissue, Eicosapentaenoic Acid, Biochemistry, messenger-rna, Lipogenesis, Fatty Acids, Unsaturated, lipids (amino acids, peptides, and proteins), PPARGC1A, Oxidation-Reduction, Polyunsaturated fatty acid, linolenic acid, medicine.medical_specialty, Docosahexaenoic Acids, coactivator pgc-1-alpha, NF-E2-Related Factor 1, Subcutaneous Fat, Biology, Mitochondrial Proteins, Fish Oils, Carnitine palmitoyltransferase 1, Internal medicine, Internal Medicine, medicine, Animals, dietary fish-oil, Carnitine O-Palmitoyltransferase, gene-expression, Mice, Inbred C57BL, Endocrinology, Gene Expression Regulation, chemistry, Mitochondrial biogenesis, Trans-Activators, RIKILT - Business Unit Safety & Health, metabolism, Transcription Factors
Abstract: Aims/hypothesis Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor -linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. Methods The effects of EPA/DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. Results Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in -linolenic acid. This was associated with a three-fold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite high-fat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. Conclusions/interpretation The anti-adipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of -oxidation and upregulation of mitochondrial biogenesis
Published: 2005

44. Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores

Author: O. Matejkova, Jana Sponarova, Jana Ruzickova, Jan Kopecky, Martin Rossmeisl, Petr Brauner, Kristina Bardova, Tomas Prazak, Ondrej Kuda, and Pavel Flachs
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, Mice, Transgenic, White adipose tissue, AMP-Activated Protein Kinases, Choristoma, Protein Serine-Threonine Kinases, Models, Biological, Ion Channels, Mitochondrial Proteins, Mice, AMP-activated protein kinase, Multienzyme Complexes, Internal medicine, medicine, Adipocytes, Uncoupling protein, Animals, Humans, Obesity, Uncoupling Protein 1, Nutrition and Dietetics, Adiponectin, biology, Chemistry, AMPK, Membrane Proteins, Thermogenin, Mitochondria, Endocrinology, Adipose Tissue, Lipogenesis, biology.protein, Carrier Proteins, Energy Metabolism
Abstract: As indicated by in vitro studies, both lipogenesis and lipolysis in adipocytes depend on the cellular ATP levels. Ectopic expression of mitochondrial uncoupling protein 1 (UCP1) in the white adipose tissue of the aP2-Ucp1 transgenic mice reduced obesity induced by genetic or dietary manipulations. Furthermore, respiratory uncoupling lowered the cellular energy charge in adipocytes, while the synthesis of fatty acids (FA) was inhibited and their oxidation increased. Importantly, the complex metabolic changes triggered by ectopic UCP1 were associated with the activation of AMP-activated protein kinase (AMPK), a metabolic master switch, in adipocytes. Effects of several typical treatments that reduce adiposity, such as administration of leptin, beta-adrenoceptor agonists, bezafibrate, dietary n-3 polyunsaturated FA or fasting, can be compared with a phenotype of the aP2-Ucp1 mice. These situations generally lead to the upregulation of mitochondrial UCPs and suppression of the cellular energy charge and FA synthesis in adipocytes. On the other hand, FA oxidation is increased. Moreover, it has been shown that AMPK in adipocytes can be activated by adipocyte-derived hormones leptin and adiponectin, and also by insulin-sensitizes thiazolidinediones. Thus, it is evident that metabolism of adipose tissue itself is important for the control of body fat content and that the cellular energy charge and AMPK are involved in the control of lipid metabolism in adipocytes. The reciprocal link between synthesis and oxidation of FA in adipocytes represents a prospective target for the new treatment strategies aimed at reducing obesity.
Published: 2004

45. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author: S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. 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Chipchase, S, Treece, K, Pound, N, Hill, N, Cyganek, K, Mirkiewicz sieradzka, B, Malecki, M, Wolkow, P, Skupien, J, Naskalska, A, Sieradzki, J, Tapp, R, Tonkin, A, Harper, A, Mccarty, D, Söderberg, S, Taylor, H, Chitson, P, Alberti, G, Sheetz, M, Aiello, L, Davis, M, Milton, R, Arora, V, Hu, K, Girach, A, Vignati, L, Tyrberg, M, Melander, A, Lindblad, U, Giannarelli, R, Coppelli, A, Sartini, M, Aragona, M, Fletcher, E, Ninkovic, S, Foster, L, Jones, D, De Gooyer, T, Stitt, A, Vingrys, A, Wilkinson berka, J, Lewandowska, A, Randeva, H, Komorowski, J, Lewandowski, K, Jurowski, P, Sankar, S, Gos, R, Kowluru, R, Odenbach, S, Shinn, S, Agardh, C, Hultberg, B, Segura, R, Fonollosa, A, Berrone, E, Beltramo, E, Solimine, C, Ubertalli, A, Islam, N, Esteve, E, Fernandez, M, Recas, I, Mauri, S, Biarnes, F, Junca, E, Fernádez real, J, Rössner, S, Stenlof, K, Levy, B, Perry, B, Fitchet, M, Chrysos, G, Kamaratos, A, Lepeniotis, G, Kokkoris, S, Varytimiadis, K, Stasini, F, Mikros, S, Gianneli, D, 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S, Choi, D, Kim, N, Matsumoto, S, Suetsugu, M, Matsutomo, R, Pisarczyk wiza, D, Banaszak, A, Wysocki, H, Usui, H, Shikata, K, Okada, S, Ogawa, D, Yozai, K, Kido, Y, Nagase, R, Ohga, S, Tone, A, Sasaki, M, Wada, J, Unno, Y, Horiuchi, S, Mclennan, S, Kamarinos, M, Waltham, M, Dy, V, Yue, D, Zdychova, J, Komers, R, Cresci, B, Giannini, S, Manuelli, C, Giunti, S, Pinach, S, Ianni Palarchio, A, Arnaldi, L, Vittone, F, Camussi, G, Cavallo Perin, P, Gruden, G, Marshall, S, Jones, S, White, K, Brizzi, M, Dentelli, P, Rosso, A, Calvi, C, Gambino, R, Cassader, M, Salvidio, G, Deferrari, G, Pegoraro, L, Pagano, G, Cavallo perin, P, Oates, R, Ellery, C, Beebe, D, Coutcher, J, Qian, Y, Lowe, V, Appleton, T, Raunig, D, O'Neil, S, Mylari, B, Amazonas, R, Fujita, A, Doi, A, Matsuno, S, Okamoto, K, Matsumoto, E, Furuta, H, Nishi, M, Tsuno, T, Taniguchi, H, Bessho, H, Wasén, E, Isoaho, R, Mattila, K, Vahlberg, T, Kivelä, S, Irjala, K, Rigalleau, V, Lasseur, C, Perlemoine, C, Barthes, N, Raffaitin, C, Chauveau, P, Combe, C, Baillet blanco, L, Beauvieux, M, Gin, H, Heinrich, S, Steiner, T, Ott, U, Holdass, H, Fellström, B, Jardine, A, Staffler, B, Logan, J, Gimpelewicz, C, Stanciu, C, Pena, C, Serafinceanu, C, González posada, J, Hernández, D, Pérez tamajó, L, Ló, A, Herná Alarcó, M, Meneses, M, Barsotti, M, Rizzo, G, Schmauss, S, Havrdova, T, Saudek, F, Boucek, P, Adamec, M, Invitti, C, Gilardini, L, Parati, G, Mazzilli, G, Pontiggia, B, Sartorio, A, Lutgers, H, Groenier, K, Zasadzinska, G, Saryusz wolska, M, Kurktschiev, D, Majdrakova, I, Varbanova, T, Todorova, B, Bajo martinez, A, Bernal, E, Sanchez, O, Ugalde canitrot, A, Sanchez largo, E, Coca robinot, D, Fabregate, R, Calbacho, M, Marquez, J, Saban ruiz, J, Penesova, A, Cizmarova, E, Blazicek, P, De Jongh, R, Serné, E, Ijzerman, R, De Vries, G, Andersen, N, Knudsen, S, Helleberg, K, Mogensen, C, Waluś, M, Idzior waluś, B, Sztefko, K, Cieślik, G, Fedak, D, Wozniakiewicz, E, Lin, S, Guo, M, Lin, C, Liu, X, Francisco, M, Rodriguez rosas, H, Peiró martinez, I, Macías batista, A, Harte, A, Rodriguez cuenca, S, Valsamakis, G, Chetty, R, Anderson, L, Roca, P, Matyka, K, Lasalle, J, Hershon, K, Berman, L, Gibson, E, Gillen, D, Maroni, J, Simmons, D, Hiukka, A, Forder, P, Leinonen, E, Hilden, H, Fruchart, J, Keech, A, Farnier, M, Freeman, M, Macdonell, G, Perevozskaya, I, Mitchel, Y, Gumbiner, B, Didangelos, T, Athyros, V, Mikhailidis, D, Papageorgiou, A, Bouloukos, V, Pehlivanidis, A, Symeonidis, A, Elisaf, M, Mckenney, J, Insull, W, Lewin, A, Maccubbin, D, Kush, D, Schuster, H, Barter, P, Stender, S, Bonnet, J, Morrell, J, Watkins, C, Kallend, D, Stalenhoef, A, Ballantyne, C, Murin, J, Tonstad, S, Rose, H, Wilpshaar, W, Jenkins, A, Karschimkus, C, Dragicevic, G, Rowley, K, Wolthers, T, Best, J, Voet, B, Murdoch, S, Marcovina, S, Brunzell, J, Caparevic, Z, Kostic, N, Ilic, S, Sartore, G, Piarulli, F, Cantaro, S, Reitano, R, Fiore, C, Marin, R, Bassan, S, Manzato, E, Fedele, D, Solini, A, Santini, E, Thornalley, P, Babaei jadidi, R, Karachalias, N, Kupich, C, Ahmed, N, Fowler, A, Baker, A, Starczynski, J, O'Hare, P, Szepietowska, B, Szelachowska, M, Puch, U, Glebocka, A, Quinn, D, Mcternan, C, Bonser, R, Idzior walus, B, Woźniakiewicz, E, Dimitriou, K, Apostolou, O, Kontela, E, Devangelio, E, Gould, E, Serri, O, Roussin, A, Buithieu, J, Mamputu, J, Renier, G, Giordanetti, S, De Amici, E, Poggi, G, Turpini, C, Fratino, P, Garzaniti, A, Banu, I, Paries, J, Roman, G, Negrean, M, Bala, C, Nita, C, Kistorp, C, Gustafsson, F, Chong, A, Lip, G, Galatius, S, Ari, N, Sahilli, M, Ceylan isık, A, Ozansoy, G, Karasu yilmaz, C, Matteucci, E, Rosada, J, Pallini, M, Evangelista, I, Cassetti, G, Giusti, C, Giampietro, O, Capaldo, B, Galderisi, M, Cicala, S, Turco, A, Imbroinise, A, Nosso, G, D'Errico, A, De Divitiis, O, Klimontov, V, Korolyova, E, Jeltova, L, Bondar, I, Tarkun, I, Arslan, B, Canturk, Z, Tarkun, P, Agacdiken, A, Komsuoglu, B, Méneveau, N, Pierre justin, E, Alsayed, M, Sabbah, R, Paulin, S, Marcu, S, Tauveron, I, Zimmermann, C, Schiele, F, Seronde, M, Vautrin, P, Lusson, J, Thieblot, P, Bernard, Y, Mistry, A, Pye, M, Peovska, I, Maksimovic Pavlovic, J, Vavlukis, M, Pop Gorceva, D, Bosevski, M, Scognamiglio, R, Negut, C, De Kreutzenberg, S, Madonna, R, De Caterina, R, Willerson, J, Geng, Y, Vahsen, S, Ledwig, D, Ramrath, S, Frantz, S, Schmidt, I, Calvillo, L, Dienesch, C, Elbing, I, Bischoff, H, Ertl, G, Bauersachs, J, Davydov, A, Mkrtum'Yan, A, Baranova, L, Ikeda, Y, Suehiro, T, Osaki, F, Ota, K, Arii, K, Kumon, Y, Hashimoto, K, Doney, A, Morris, A, Palmer, C, Byun, S, Doo, H, Pagnin, E, Calo, L, Fadini, G, Kubaszek, A, Chai, S, Chai, Q, Rasmussen, L, Ledet, T, Wogensen, L, Lengyel, C, Varró, A, Virág, L, Magyar, J, Bíró, T, Jost, N, Skoumal, R, Nánási, P, Tóth, M, Horkay, F, Papp, J, Zacharopoulou, O, Athanaselis, S, Tsokos, N, Doupis, J, Psallas, M, Cokkinos, D, Pavlatos, S, Liatis, S, Akhobadze, T, Dzneladze, L, Samarguliani, I, Taskiran, M, Rasmussen, V, Jensen, G, Fisher, A, Petrovsky, N, Srikusalanukul, W, Budge, M, Trifunovic zamaklar, D, Zivkovic, M, Jelic, V, Vukomanovic, G, Ristic, A, Seferovic, P, Costa, J, Duarte, S, Manley, S, Sailesh, S, Venkataraman, A, Haider, Y, Groza, I, Oprean, M, Ardelean, A, Morosanu, A, Darkow, T, Vanderplas, A, Mamas, M, Mcelduff, P, Burns, J, Edwards, R, Fitchet, A, Young, R, Gibson, J, Lichiardopol, R, Niculescu, N, Totora, A, Pencea, C, Tomescu, I, Cinteza, M, Manicardi, V, Coscelli, C, Navazio, A, Catellani, E, Michelini, M, Dall'Asta, D, Guberti, A, Piazza, A, Gasparini, E, Pantaleoni, M, Guiducci, U, Manari, A, Sejil, S, Janand delenne, B, Avierinos, J, Habib, G, Labastie, N, Vague, P, Lassmann vague, V, Luźniak, P, Tatoń, J, Wojciechowska Luźniak, A, Zairis, M, Lyras, A, Patsourakos, N, Tsirimbis, V, Foussas, S, Lupón, J, Urrutia, A, Herreros, J, González, B, Coll, R, Altimir, S, Prats, M, Valle, V, Abreu padí, C, Rábago, G, Ivanova, L, Brasacchio, D, Harno, E, Keenan, A, Li, H, Lu, Z, Ke, L, Liu, H, Jeong, I, Chae, M, Choi, M, Yoo, H, Kim, C, Yun, M, Na, M, Kang, Y, Kong, O, Son, S, Kim, I, Tanaka, N, Hosoi, M, Matsuyama, Y, Fukumoto, M, Yamakita, T, Yoshioka, K, Ishii, T, Sato, T, Fujii, S, Aoki, T, Shibata, T, Mizutani, N, Suzuki, J, Fowelin, J, Samuelsson, P, Brandrup wogsen, G, Okumura, K, Tokmakova, A, Staroverova, D, Antcieferov, M, Shutichina, I, Kuntchevich, G, Vriesendorp, T, Morélis, Q, Legemate, D, Schaper, F, Mainas, E, Gkioulmpasanis, I, Panagiotou, I, Vassilikos, G, Skorda, L, Sidira, M, Christoforidou, M, Alaveras, A, Artikis, V, Evdemon, E, Lechleitner, M, Koch, T, Ebenbichler, C, Sturm, W, Moretti, L, Moruzzo, D, Boldrini, E, Pandolfo, C, Kameyama, M, Iwasa, R, Cho, M, Nam, J, Huh, K, Kaplar, M, Paragh, G, Erdei, A, Csongradi, E, Garai, I, Varga, J, Galuska, L, Udvardy, M, Higa, M, Kaneko, Y, Hiroi, N, Koziarska, D, Nowacki, P, Majkowska, L, Luzniak, P, Wojciechowska luźniak, A, Tushuizen, M, Nieuwland, R, Snoeck, D, Sturk, A, Diamant, M, Aguiar, L, Bahia, L, Villela, N, Laflor, C, Conde, C, Bottino, D, Dorigo, D, Bouskela, E, Pu, S, Luo, Z, Lam, K, Dan, Q, Xu, A, Shen, J, Cheng, K, Xu, J, Thamer, C, Stefan, N, Haap, M, Heller, E, Tschritter, O, De Prado, A, Ortiz, A, Ybarra, J, Gich, I, Pou, J, Ehren, M, Roggenland, D, Reinsen, B, Klein, H, Rittig, K, Stock, J, Kocher, B, Balletshofer, B, Shon, H, Chung, D, Nakatani, Y, Matsuhisa, M, Kaneto, H, Hatazaki, M, Yoshiuchi, K, Katakami, N, Kawamori, D, Ohtoshi, K, Sakamoto, K, Matsuoka, T, Ozawa, K, Ogawa, S, Hori, M, Yamasaki, Y, Zitouni, K, Harry, D, Nourooz zadeh, J, Earle, K, Olesen, P, Franco, L, Corvaja, C, Semplicini, A, Ceylan işık, A, Arı, N, Rösen, P, Lee, I, Park, K, Jung, E, Shin, D, Jo, S, Obuobie, K, Prakash, P, Hanna, F, Lazarus, J, Varadhan, L, Gurushankar, J, James, D, Sheikh, S, Gaede, P, Zou, D, Vilarrasa, N, Perez maraver, M, Mena, E, Perez, D, Setti, G, Buckingham, R, Urbančič, V, Stefanovska, A, Bernjak, A, Ažman juvan, K, Kocijančič, A, Glowania, A, Filters, T, Fosmark, D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, EASD, Endocrinology, Diabetes and Metabolism, Human physiology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Family medicine, Internal Medicine, Medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2004

46. Expression of mitochondrial uncoupling protein 3 and adenine nucleotide translocase 1 genes in developing rat heart: putative involvement in control of mitochondrial membrane potential

Author: Kristina Bardova, Pavel Flachs, Jan Kopecký, Bohuslav Ostadal, Petr Brauner, Libor Skarka, and Daniela Jarkovská
Subjects: Male, Population, Peroxisome proliferator-activated receptor, Receptors, Cytoplasmic and Nuclear, Mitochondrion, Biology, Rhodamine 123, Ion Channels, Membrane Potentials, Mitochondrial Proteins, chemistry.chemical_compound, Uncoupling protein, Animals, Uncoupling Protein 3, Northern blot, Rats, Wistar, education, Molecular Biology, UCP3, chemistry.chemical_classification, education.field_of_study, Myocardium, Adenine Nucleotide Translocator 1, Adenine Nucleotide Translocator 2, Heart, Peroxisome, Molecular biology, Mitochondria, Rats, chemistry, Animals, Newborn, Cardiology and Cardiovascular Medicine, Carrier Proteins, Transcription Factors
Abstract: Postnatal maturation of the heart depends on the switch from glycolytic to oxidative metabolism and it is associated with decreasing tolerance to oxygen deprivation. Therefore, changes in composition and function of cardiac mitochondria during postnatal development require detailed characterization. Left-ventricular myocardium of prenatal, and 1-, 2-, 5-, 10-, 20-, 28-, 50-, 60-, and 90-d-old male Wistar rats was studied. The expression of uncoupling proteins (UCPs), adenine nucleotide translocase (ANT), and peroxisome proliferator-activated receptor alpha (PPARalpha) genes was characterized by northern blotting (UCP2), real-time quantitative RT-PCR (UCP2, UCP3, ANT1, ANT2, and PPARalpha), and by immunoblotting (UCP3). In isolated mitochondria, cytochromes a + a(3) were quantified by a spectrophotometry, and mitochondrial membrane potential (MMP) was measured using Rhodamine 123 (by spectrofluorimetry and flow cytometry). The specific content of cytochromes in mitochondria increased two-fold between birth and day 30, similarly, as the expression of ANT1 and PPARalpha genes. Postnatal activation in the expression of UCP2, UCP3, ANT1 and PPARalpha genes resulted in the expression maxima between days 20 and 30. The content/expression declined following day 20 (UCP2, UCP3, and PPARalpha) or 30 (cytochromes and ANT1), while expression of ANT2 declined continuously during the first month of life. In 1-d-old animals a single population of mitochondria with a relatively high MMP was observed; with increasing age, a second population of mitochondria with a significantly lower MMP appeared. The results support the view that mitochondrial energy conversion in heart changes during ontogeny and suggest the involvement of UCP3 and/or ANT1 in the control mechanism.
Published: 2003

47. Modulation of lipid metabolism by energy status of adipocytes: implications for insulin sensitivity

Author: Tomáš Pražák, Kristina Bardova, Jan Kopecký, Pavel Flachs, Jana Sponarova, and Petr Brauner
Subjects: medicine.medical_specialty, Adipose tissue, White adipose tissue, Carbohydrate metabolism, General Biochemistry, Genetics and Molecular Biology, Ion Channels, Mitochondrial Proteins, Mice, Insulin resistance, History and Philosophy of Science, Internal medicine, medicine, Adipocytes, Uncoupling protein, Animals, Humans, Obesity, Uncoupling Protein 1, biology, General Neuroscience, Membrane Proteins, Lipid metabolism, medicine.disease, Lipid Metabolism, Insulin receptor, Endocrinology, Lipogenesis, biology.protein, Insulin Resistance, Carrier Proteins, Energy Metabolism, Signal Transduction
Abstract: It is becoming evident that insulin resistance of white adipose tissue is a major factor underlying the cardiovascular risk of obesity. Impaired fat storage rather than altered glucose metabolism in adipocytes probably contributes to development of insulin resistance in muscle and other tissues, in particular via increased delivery of nonesterified fatty acids into circulation. Lipid metabolism of adipose tissue is affected by the energy status of fat cells. In vitro experiments indicated the dependence of both lipogenesis and lipolysis on ATP levels in adipocytes. Thus, respiratory uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to the control of lipid metabolism, adiposity, and insulin sensitivity. This notion is supported by the expression of UCPs in adipocytes, for example, UCP2, UCP5, as well as some protonophoric anion transporters, and by induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. A negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in the aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by respiratory uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white, but not brown fat. Probably due to depression of the ATP/ADP ratio, both fatty acid synthesis and lipolytic action of norepinephrine in adipocytes of transgenic mice were relatively low. Expression of regulatory G-proteins, which are essential for both catecholamine and insulin signaling in adipocytes, was also altered by ectopic UCP1. These results support the role of protonophoric proteins in adipocytes in the control of adiposity and insulin sensitivity. Antidiabetic effects of thiazolidinediones, fibrates, beta(3)-adrenoreceptor agonists, dietary n-3 PUFAs, and leptin may be explained at least partially by their effects on the energy and hence also the lipid metabolism of fat cells.
Published: 2002

48. Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo

Author: Martin, Rossmeisl, Giorgio, Barbatelli, Pavel, Flachs, Petr, Brauner, Maria Cristina, Zingaretti, Mariella, Marelli, Petra, Janovská, Milada, Horáková, Ivo, Syrový, Saverio, Cinti, and Jan, Kopecký
Subjects: Male, Aging, Membrane Proteins, Ion Channels, Mitochondria, Mice, Inbred C57BL, Mitochondrial Proteins, Mice, Adipocytes, Animals, Obesity, RNA, Messenger, Carrier Proteins, Promoter Regions, Genetic, Uncoupling Protein 1
Abstract: Mitochondrial uncoupling protein 1 (UCP1) is a specific marker of multilocular brown adipocytes. Ectopic UCP1 in white fat of aP2-Ucp1 mice mitigates development of obesity by both, increasing energy expenditure and decreasing in situ lipogenesis. In order to further analyse consequences of respiratory uncoupling in white fat, the effects of the ectopic UCP1 on the morphology of adipocytes and biogenesis of mitochondria in these cells were studied. In subcutaneous white fat of both aP2-Ucp1 and young control (5-week-old) mice, numerous multilocular adipocytes were found, while they were absent in adult (7- to 9-month-old) animals. Only unilocular cells were present in epididymal fat of both genotypes. In both fat depots of aP2-Ucp1 mice, the levels of the UCP1 transcript and UCP1 antigen declined during ageing, and they were higher in subcutaneous than in epididymal fat. Under no circumstances could ectopic UCP1 induce the conversion of unilocular into multilocular adipocytes. Presence of ectopic UCP1 in unilocular adipocytes was associated with the elevation of the transcripts for UCP2 and for subunit IV of mitochondrial cytochrome oxidase (COX IV), and increased content of mitochondrial cytochromes. Electron microscopy indicated changes of mitochondrial morphology and increased mitochondrial content due to ectopic UCP1 in unilocular adipocytes. In 3T3-L1 adipocytes, 2,4-dinitrophenol increased the levels of the transcripts for both COX IV and for nuclear respiratory factor-1. Our results indicate that respiratory uncoupling in unilocular adipocytes of white fat is capable of both inducing mitochondrial biogenesis and reducing development of obesity.
Published: 2002

49. Transgenic UCP1 in white adipocytes modulates mitochondrial membrane potential

Author: Pavel Flachs, Filip Baumruk, Milada Horáková, Daniel Floryk, and Jan Kopecký
Subjects: Genetically modified mouse, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, medicine.medical_specialty, Cell Membrane Permeability, Transgene, Biophysics, Respiratory chain, Endogeny, Mice, Transgenic, Oxidative phosphorylation, White adipose tissue, Biochemistry, Guanosine Diphosphate, Ion Channels, Membrane Potentials, Mitochondrial Proteins, Mice, Structural Biology, Tetramethylrhodamine methyl ester, Internal medicine, Genetics, medicine, Adipocytes, Animals, Uncoupling Protein 2, Obesity, Molecular Biology, Uncoupling Protein 1, Fluorescent Dyes, Membrane potential, Proton leak, Chemistry, Fatty Acids, Membrane Proteins, Membrane Transport Proteins, Proteins, Cell Biology, Energy metabolism, Flow Cytometry, Thermogenin, Mitochondria, Endocrinology, Female, Carrier Proteins
Abstract: To test if mitochondrial uncoupling in white adipocytes is responsible for obesity resistance of the aP2-Ucp transgenic mice expressing ectopic uncoupling protein 1 (UCPI) in white fat, mitochondrial membrane potential (delta psi(m)) was estimated by flow cytometry in adipocytes isolated from gonadal fat. Ectopic UCP1 (approximately 0.8 mol UCP1/mol respiratory chain) decreased the delta psi(m) and rendered the potential sensitive to GDP and fatty acids. These ligands of UCP1 had no effect on delta psi(m) in white adipocytes from non-transgenic mice, suggesting that the function of endogenous UCP2 in adipocytes was not affected. The results support the hypothesis that mitochondrial uncoupling in white fat may prevent development of obesity.
Published: 1999

50. Immunodetection of UCP1, UCP2, and UCP3 in human and mouse tissues

Author: Petr Brauner, Jan Kopecký, and Pavel Flachs
Subjects: Biology, Biochemistry, Molecular biology, UCP3
Published: 2000
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