20 results on '"Bohlooly‐Y, Mohammad"'
Search Results
2. The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120.
- Author
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Bjursell M, Xu X, Admyre T, Böttcher G, Lundin S, Nilsson R, Stone VM, Morgan NG, Lam YY, Storlien LH, Lindén D, Smith DM, Bohlooly-Y M, and Oscarsson J
- Subjects
- Animals, Body Composition, Body Weight, Diet, High-Fat methods, Energy Metabolism, Intestinal Mucosa metabolism, Lung metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Obesity etiology, Obesity genetics, Fatty Acids administration & dosage, Fatty Acids, Omega-3 administration & dosage, Glucose metabolism, Obesity metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism
- Abstract
GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.
- Published
- 2014
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3. Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms.
- Author
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Lelliott CJ, Ahnmark A, Admyre T, Ahlstedt I, Irving L, Keyes F, Patterson L, Mumphrey MB, Bjursell M, Gorman T, Bohlooly-Y M, Buchanan A, Harrison P, Vaughan T, Berthoud HR, and Lindén D
- Subjects
- Animals, Arcuate Nucleus of Hypothalamus metabolism, Arcuate Nucleus of Hypothalamus physiopathology, Chemokine CCL2 agonists, Chemokine CCL2 genetics, Chemokine CCL2 metabolism, Chemokine CCL7 agonists, Chemokine CCL7 genetics, Chemokine CCL7 metabolism, Circumventricular Organs metabolism, Circumventricular Organs physiopathology, Eating drug effects, Energy Metabolism, Female, Gene Expression Regulation, Glucose Intolerance genetics, Glucose Intolerance metabolism, Glucose Intolerance physiopathology, Humans, Hypothalamus metabolism, Hypothalamus physiopathology, Leptin deficiency, Leptin genetics, Mice, Mice, Knockout, Mice, Obese, Mitogen-Activated Protein Kinases genetics, Mitogen-Activated Protein Kinases metabolism, Obesity genetics, Obesity metabolism, Obesity physiopathology, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Melanocortin, Type 4 deficiency, Receptor, Melanocortin, Type 4 genetics, Receptors, Somatostatin deficiency, Receptors, Somatostatin genetics, Ribosomal Protein S6 Kinases, 70-kDa genetics, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Serum Response Factor agonists, Serum Response Factor genetics, Serum Response Factor metabolism, Signal Transduction, Antibodies, Monoclonal pharmacology, Arcuate Nucleus of Hypothalamus drug effects, Circumventricular Organs drug effects, Glucose Intolerance drug therapy, Hypothalamus drug effects, Obesity drug therapy, Receptor, Fibroblast Growth Factor, Type 1 antagonists & inhibitors
- Abstract
We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
- Published
- 2014
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4. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.
- Author
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Carobbio S, Hagen RM, Lelliott CJ, Slawik M, Medina-Gomez G, Tan CY, Sicard A, Atherton HJ, Barbarroja N, Bjursell M, Bohlooly-Y M, Virtue S, Tuthill A, Lefai E, Laville M, Wu T, Considine RV, Vidal H, Langin D, Oresic M, Tinahones FJ, Fernandez-Real JM, Griffin JL, Sethi JK, López M, and Vidal-Puig A
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- 3T3-L1 Cells, Animals, Down-Regulation, Humans, Insulin Resistance, Lipid Metabolism, Membrane Proteins metabolism, Mice, Mice, Knockout, Obesity, Morbid metabolism, RNA, Messenger metabolism, Stearoyl-CoA Desaturase metabolism, Adaptation, Physiological, Adipose Tissue, White metabolism, Membrane Proteins biosynthesis, Obesity physiopathology, Sterol Regulatory Element Binding Protein 1 metabolism
- Abstract
The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
- Published
- 2013
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5. Growth hormone is necessary for the p53-mediated, obesity-induced insulin resistance in male C57BL/6J x CBA mice.
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Bogazzi F, Raggi F, Russo D, Bohlooly-Y M, Sardella C, Urbani C, Lombardi M, Manetti L, Lupi I, Tornell J, and Martino E
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- Acromegaly, Adipose Tissue metabolism, Animals, Growth Hormone genetics, Insulin Resistance, Male, Mice, Mice, Transgenic, Tumor Suppressor Protein p53 genetics, Growth Hormone metabolism, Obesity metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1-3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.
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- 2013
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6. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet.
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Bjursell M, Admyre T, Göransson M, Marley AE, Smith DM, Oscarsson J, and Bohlooly-Y M
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- Adipose Tissue, Brown pathology, Adipose Tissue, White pathology, Animals, Body Composition, Body Temperature Regulation, Diet, Dyslipidemias blood, Dyslipidemias prevention & control, Energy Metabolism, Fatty Liver metabolism, Fatty Liver prevention & control, Homeostasis, Insulin Resistance, Macrophages metabolism, Male, Mice, Mice, 129 Strain, Mice, Knockout, Obesity blood, Obesity genetics, Obesity pathology, Receptors, G-Protein-Coupled genetics, Dietary Fats administration & dosage, Hyperglycemia prevention & control, Hypoglycemia prevention & control, Obesity prevention & control, Receptors, G-Protein-Coupled physiology
- Abstract
Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short-chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient mice (Ffar2-KO) were given a high-fat diet (HFD) or chow diet and studied with respect to lipid and energy metabolism. On a HFD, Ffar2-KO mice had lower body fat mass and increased lean body mass. The changed body composition was accompanied by improved glucose control and lower HOMA index, indicating improved insulin sensitivity in Ffar2-KO mice. Moreover, the Ffar2-KO mice had higher energy expenditure accompanied by higher core body temperature and increased food intake. The liver weight and content of triglycerides as well as plasma levels of cholesterol were lower in the Ffar2-KO mice fed a HFD. A histological examination unveiled decreased lipid interspersed in brown adipose tissue of the Ffar2-KO mice. Interestingly, no significant differences in white adipose tissue (WAT) cell size were observed, but significantly lower macrophage content was detected in WAT from HFD-fed Ffar2-KO compared with wild-type mice. In conclusion, Ffar2 deficiency protects from HFD-induced obesity and dyslipidemia at least partly via increased energy expenditure.
- Published
- 2011
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7. The role of mitochondrial glycerol-3-phosphate acyltransferase-1 in regulating lipid and glucose homeostasis in high-fat diet fed mice.
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Yazdi M, Ahnmark A, William-Olsson L, Snaith M, Turner N, Osla F, Wedin M, Asztély AK, Elmgren A, Bohlooly-Y M, Schreyer S, and Lindén D
- Subjects
- Animals, Cholesterol blood, Diet, Dietary Fats administration & dosage, Disease Models, Animal, Energy Metabolism, Fatty Liver genetics, Female, Glucose Intolerance genetics, Glycerol-3-Phosphate O-Acyltransferase genetics, Homeostasis, Male, Mice, Mice, Mutant Strains, Mitochondria enzymology, Obesity genetics, Triglycerides analysis, Weight Gain, Dietary Fats adverse effects, Fatty Liver etiology, Glucose metabolism, Glucose Intolerance etiology, Glycerol-3-Phosphate O-Acyltransferase physiology, Obesity etiology, Triglycerides metabolism
- Abstract
Glycerol-3-phosphate acyltransferase (GPAT) is involved in triacylglycerol (TAG) and phospholipid synthesis, catalyzing the first committed step. In order to further investigate the in vivo importance of the dominating mitochondrial variant, GPAT1, a novel GPAT1(-/-) mouse model was generated and studied. Female GPAT1(-/-) mice had reduced body weight-gain and adiposity when fed chow diet compared with littermate wild-type controls. Furthermore, GPAT1(-/-) females on chow diet showed decreased liver TAG content, plasma cholesterol and TAG levels and increased ex vivo liver fatty acid oxidation and plasma ketone bodies. However, these beneficial effects were abolished and the glucose tolerance tended to be impaired when GPAT1(-/-) females were fed a long-term high-fat diet (HFD). GPAT1-deficiency was not associated with altered whole body energy expenditure or respiratory exchange ratio. In addition, there were no changes in male GPAT1(-/-) mice fed either diet except for increased plasma ketone bodies on chow diet, indicating a gender-specific phenotype. Thus, GPAT1-deficiency does not protect against HFD-induced obesity, hepatic steatosis or whole body glucose intolerance.
- Published
- 2008
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8. Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice.
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Bjursell M, Gerdin AK, Lelliott CJ, Egecioglu E, Elmgren A, Törnell J, Oscarsson J, and Bohlooly-Y M
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- Animals, Arachidonic Acids blood, Body Composition physiology, Body Temperature physiology, Body Weight physiology, Calorimetry, Indirect, Cholesterol, Dietary adverse effects, DNA, Complementary biosynthesis, DNA, Complementary genetics, Dietary Fats, Unsaturated adverse effects, Dopamine metabolism, Endocannabinoids, Energy Intake physiology, Energy Metabolism physiology, Fatty Acids adverse effects, Feces chemistry, Homeostasis physiology, Hormones blood, Hypothalamus metabolism, Male, Mice, Mice, Inbred C57BL, Obesity physiopathology, Polyunsaturated Alkamides blood, RNA biosynthesis, RNA genetics, Reverse Transcriptase Polymerase Chain Reaction, Diet adverse effects, Motor Activity physiology, Obesity etiology
- Abstract
The aim of the present study was to investigate the short- and long-term effects of a high-fat Western diet (WD) on intake, storage, expenditure, and fecal loss of energy as well as effects on locomotor activity and thermogenesis. WD for only 24 h resulted in a marked physiological shift in energy homeostasis, including increased body weight gain, body fat, and energy expenditure (EE) but an acutely lowered locomotor activity. The acute reduction in locomotor activity was observed after only 3-5 h on WD. The energy intake and energy absorption were increased during the first 24 h, lower after 72 h, and normalized between 7 and 14 days on WD compared with mice given chow diet. Core body temperature and EE was increased between 48 and 72 h but normalized after 21 days on WD. These changes paralleled plasma T(3) levels and uncoupling protein-1 expression in brown adipose tissue. After 21 days of WD, energy intake and absorption, EE, and body temperature were normalized. In contrast, the locomotor activity was reduced and body weight gain was increased over the entire 21-day study period on WD. Calculations based on the correlation between locomotor activity and EE in 2-h intervals at days 21-23 indicated that a large portion of the higher body weight gain in the WD group could be attributed to the reduced locomotor activity. In summary, an acute and persisting decrease in locomotor activity is most important for the effect of WD on body weight gain and obesity in mice.
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- 2008
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9. GPR10 deficiency in mice results in altered energy expenditure and obesity.
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Bjursell M, Lennerås M, Göransson M, Elmgren A, and Bohlooly-Y M
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- Adipose Tissue metabolism, Animals, Blood Glucose metabolism, Body Temperature, Body Weight genetics, Body Weight physiology, Calorimetry methods, Eating genetics, Eating physiology, Energy Metabolism genetics, Feces chemistry, Female, Genotype, Lipoproteins, HDL blood, Lipoproteins, LDL blood, Male, Mice, Mice, Knockout, Obesity genetics, Receptors, G-Protein-Coupled deficiency, Receptors, G-Protein-Coupled genetics, Sex Factors, Time Factors, Energy Metabolism physiology, Obesity physiopathology, Receptors, G-Protein-Coupled physiology
- Abstract
In this study, mice carrying a disrupted gene encoding GPR10 (GPR10 KO) were studied to elucidate the function and importance of this receptor regarding metabolism. Female and male GPR10 KO mice had higher body weight after 11 and 15 weeks of age, respectively. The increased body weight was a result of increased fat mass. The obesity was much more pronounced in female mice, which also had a significant decrease in energy expenditure. In correlation to obesity, higher plasma levels of leptin, total cholesterol, and fractions of LDL and HDL were found in GPR10 KO compared to WT mice. Interestingly, GPR10 KO female mice had decreased relative food intake in correlation to higher hypothalamic expression levels of the anorexic signals CRH and POMC. In conclusion, female mice deficient of the gene encoding GPR10 develop higher body weight and obesity due to lower energy expenditure.
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- 2007
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10. G protein-coupled receptor 12 deficiency results in dyslipidemia and obesity in mice.
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Bjursell M, Gerdin AK, Jönsson M, Surve VV, Svensson L, Huang XF, Törnell J, and Bohlooly-Y M
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- Animals, Blood Glucose metabolism, Body Composition, Body Weight, Carrier Proteins biosynthesis, Cholesterol blood, Dyslipidemias genetics, Eating, Energy Metabolism, Female, Ion Channels, Male, Membrane Proteins biosynthesis, Mice, Mice, Knockout, Mitochondrial Proteins, Triglycerides metabolism, Uncoupling Protein 1, Dyslipidemias etiology, Obesity genetics, Receptors, G-Protein-Coupled deficiency
- Abstract
Obesity has been proposed to be a result of an imbalance in the physiological system that controls and maintains the body energy homeostasis. Several G-protein coupled receptors (GPCRs) are involved in the regulation of energy homeostasis. To investigate the importance of GPCR12, mice deficient of this receptor (GPCR12 KO) were studied regarding metabolism. Expression of GPCR12 was found primarily in the limbic and sensory systems, indicating its possible involvement in motivation, emotion together with various autonomic functions, and sensory information processing. GPCR12 KO mice were found to have higher body weight, body fat mass, lower respiratory exchange ratio (RER), hepatic steatosis, and were dyslipidemic. Neither food intake nor energy in faeces was affected in the GPCR12 KO mice. However, lower energy expenditure was found in the GPCR12 KO mice, which may explain the obesity. In conclusion, GPCR12 is considered important for the energy balance since GPCR12 KO mice develop obesity and have lower energy expenditure. This may be important for future drugs that target this receptor.
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- 2006
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11. Melanin-concentrating hormone receptor 1 deficiency increases insulin sensitivity in obese leptin-deficient mice without affecting body weight.
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Bjursell M, Gerdin AK, Ploj K, Svensson D, Svensson L, Oscarsson J, Snaith M, Törnell J, and Bohlooly-Y M
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- Animals, Body Composition, Body Temperature Regulation, Corticotropin-Releasing Hormone analysis, Eating, Glucose metabolism, Mice, Mice, Obese, Motor Activity, RNA, Messenger analysis, Receptors, Leptin, Receptors, Somatostatin deficiency, Stearoyl-CoA Desaturase genetics, Body Weight, Insulin Resistance, Leptin deficiency, Obesity metabolism, Receptors, Somatostatin physiology
- Abstract
The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin (ob/ob) double-null mice (MCHr1 knockout ob/ob) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight.
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- 2006
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12. Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice.
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Egecioglu E, Bjursell M, Ljungberg A, Dickson SL, Kopchick JJ, Bergström G, Svensson L, Oscarsson J, Törnell J, and Bohlooly-Y M
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- Animals, Body Weight drug effects, Female, Ghrelin, Injections, Male, Mice, Mice, Knockout, Feeding Behavior drug effects, Hypolipoproteinemias chemically induced, Hypolipoproteinemias physiopathology, Obesity chemically induced, Obesity physiopathology, Peptide Hormones administration & dosage, Receptors, Somatotropin deficiency
- Abstract
We have previously shown that growth hormone (GH) overexpression in the brain increased food intake, accompanied with increased hypothalamic agouti-related protein (AgRP) expression. Ghrelin, which stimulates both appetite and GH secretion, was injected intracerebroventricularly to GHR-/- and littermate control (+/+) mice to determine whether ghrelin's acute effects on appetite are dependent on GHR signaling. GHR-/- mice were also analyzed with respect to serum levels of lipoproteins, apolipoprotein (apo)B, leptin, glucose, and insulin as well as body composition. Central injection of ghrelin into the third dorsal ventricle increased food consumption in +/+ mice, whereas no change was observed in GHR-/- mice. After ghrelin injection, AgRP mRNA expression in the hypothalamus was higher in +/+ littermates than in GHR-/- mice, indicating a possible importance of AgRP in the GHR-mediated effect of ghrelin. Compared with controls, GHR-/- mice had increased food intake, leptin levels, and total and intra-abdominal fat mass per body weight and deceased lean mass. Moreover, serum levels of triglycerides, LDL and HDL cholesterol, and apoB, as well as glucose and insulin levels were lower in the GHR-/- mice. In summary, ghrelin's acute central action to increase food intake requires functionally intact GHR signaling. Long-term GHR deficiency in mice is associated with high plasma leptin levels, obesity, and increased food intake but a marked decrease in all lipoprotein fractions.
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- 2006
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13. Bovine growth hormone transgenic mice are resistant to diet-induced obesity but develop hyperphagia, dyslipidemia, and diabetes on a high-fat diet.
- Author
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Olsson B, Bohlooly-Y M, Fitzgerald SM, Frick F, Ljungberg A, Ahrén B, Törnell J, Bergström G, and Oscarsson J
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- Acromegaly metabolism, Acromegaly physiopathology, Animals, Body Composition, Body Temperature, Carrier Proteins genetics, Cattle, Diabetes Mellitus, Experimental metabolism, Dietary Fats pharmacology, Eating, Energy Metabolism physiology, Glucose Tolerance Test, Hyperlipidemias metabolism, Hyperphagia metabolism, Ion Channels, Lipids blood, Lipoproteins blood, Membrane Proteins genetics, Membrane Transport Proteins genetics, Mice, Mice, Transgenic, Mitochondrial Proteins genetics, Obesity metabolism, Oxygen Consumption physiology, Uncoupling Protein 1, Uncoupling Protein 2, Diabetes Mellitus, Experimental physiopathology, Growth Hormone genetics, Hyperlipidemias physiopathology, Hyperphagia physiopathology, Obesity physiopathology
- Abstract
It is known that bovine GH (bGH) transgenic mice have increased body mass, insulin resistance, and altered lipoprotein metabolism when fed a normal diet (ND). In this study, the effects of 8 wk of high-fat diet (HFD) were investigated in 6-month-old male bGH mice. Although littermate controls had unchanged energy intake, energy intake was higher in the bGH mice on a HFD than on a low-fat diet. Nevertheless, the bGH mice were resistant to diet-induced weight gain, and only in the bGH mice did the HFD result in increased energy expenditure. Glucose oxidation was higher in the bGH mice compared with littermate controls on both a HFD and ND. In addition, the bGH mice had 0.5 C higher body temperature throughout the day and increased hepatic uncoupling protein 2 expression; changes that were unaffected by the HFD. On a HFD, the effect of bGH overexpression on serum triglycerides and apolipoprotein B was opposite to that on a ND, resulting in higher serum concentrations of triglycerides and apolipoprotein B compared with littermate controls. Increased serum triglycerides were explained by decreased triglyceride clearance. The HFD led to diabetes only in the bGH mice. In conclusion, bGH transgenic mice were resistant to diet-induced obesity despite hyperphagia, possibly due to increased energy expenditure. On a HFD, bGH mice became dyslipidemic and diabetic and thereby more accurately reflect the metabolic situation in acromegalic patients.
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- 2005
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14. Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
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Bohlooly-Y M, Olsson B, Bruder CE, Lindén D, Sjögren K, Bjursell M, Egecioglu E, Svensson L, Brodin P, Waterton JC, Isaksson OG, Sundler F, Ahrén B, Ohlsson C, Oscarsson J, and Törnell J
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- Adipose Tissue anatomy & histology, Animals, Base Sequence, Blood Glucose metabolism, Body Weight, Calorimetry, Indirect, Cattle, DNA Probes, Energy Intake drug effects, Female, Gene Expression Regulation genetics, Gene Expression Regulation physiology, Genome, Growth Hormone administration & dosage, Growth Hormone pharmacology, Growth Hormone physiology, Hyperinsulinism chemically induced, Hyperphagia blood, Hyperphagia physiopathology, Hypothalamus physiology, Injections, Intraventricular, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Obesity blood, Growth Hormone genetics, Hyperlipidemias genetics, Hyperphagia genetics, Insulin Resistance genetics, Obesity etiology
- Abstract
It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
- Published
- 2005
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15. IDOL regulates systemic energy balance through control of neuronal VLDLR expression
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Lee, Stephen D, Priest, Christina, Bjursell, Mikael, Gao, Jie, Arneson, Douglas V, Ahn, In Sook, Diamante, Graciel, van Veen, J Edward, Massa, Megan G, Calkin, Anna C, Kim, Jason, Andersén, Harriet, Rajbhandari, Prashant, Porritt, Michelle, Carreras, Alba, Ahnmark, Andrea, Seeliger, Frank, Maxvall, Ingela, Eliasson, Pernilla, Althage, Magnus, Åkerblad, Peter, Lindén, Daniel, Cole, Tracy A, Lee, Richard, Boyd, Helen, Bohlooly-Y, Mohammad, Correa, Stephanie M, Yang, Xia, Tontonoz, Peter, and Hong, Cynthia
- Subjects
Medical Biochemistry and Metabolomics ,Medical Physiology ,Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Nutrition ,Genetics ,Digestive Diseases ,Liver Disease ,Obesity ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Oral and gastrointestinal ,Stroke ,Metabolic and endocrine ,Animals ,Blood Glucose ,Diet ,Energy Metabolism ,Hypothalamus ,Insulin Resistance ,Mice ,Mice ,Knockout ,Neurons ,Receptors ,LDL ,Ubiquitin-Protein Ligases ,Medical biochemistry and metabolomics ,Medical physiology ,Nutrition and dietetics - Abstract
Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.
- Published
- 2019
16. Ghrelin increases intake of rewarding food in rodents
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Egecioglu, Emil, Jerlhag, Elisabet, Salome, Nicolas, Skibicka, Karolina P., Haage, David, Bohlooly-Y, Mohammad, Andersson, Daniel, Bjursell, Mikael, Perrissoud, Daniel, Engel, Jorgen A., and Dickson, Suzanne L.
- Subjects
obesity ,motivation ,Dopamine ,digestive, oral, and skin physiology ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,food anticipation ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,hormones, hormone substitutes, and hormone antagonists ,psychological phenomena and processes ,reward ,VTA - Abstract
We investigated whether ghrelin action at the level of the ventral tegmental area (VTA), a key node in the mesolimbic reward system, is important for the rewarding and motivational aspects of the consumption of rewarding/palatable food. Mice with a disrupted gene encoding the ghrelin receptor (GHS-R1A) and rats treated peripherally with a GHS-R1A antagonist both show suppressed intake of rewarding food in a free choice (chow/rewarding food) paradigm. Moreover, accumbal dopamine release induced by rewarding food was absent in GHS-R1A knockout mice. Acute bilateral intra-VTA administration of ghrelin increased 1-hour consumption of rewarding food but not standard chow. In comparison with sham rats, VTA-lesioned rats had normal intracerebroventricular ghrelin-induced chow intake, although both intake of and time spent exploring rewarding food was decreased. Finally, the ability of rewarding food to condition a place preference was suppressed by the GHS-R1A antagonist in rats. Our data support the hypothesis that central ghrelin signaling at the level of the VTA is important for the incentive value of rewarding food.
- Published
- 2010
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17. Central NMU signaling in body weight and energy balance regulation: evidence from NMUR2 deletion and chronic central NMU treatment in mice.
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Egecioglu, Emil, Ploj, Karolina, Xiufeng Xu, Bjursell, Mikael, Salomé, Nicolas, Andersson, Nikias, Ohlsson, Claes, Taube, Magdalena, Hansson, Caroline, Bohlooly-Y, Mohammad, Morgan, David G. A., and Dickson, Suzanne L.
- Subjects
OBESITY in animals ,REGULATION of body weight ,INFUSION therapy ,ABNORMALITIES in mice ,VETERINARY diet therapy ,REGULATION of ingestion ,VETERINARY therapeutics - Abstract
To investigate the role of the central neuromedin U (NMU) signaling system in body weight and energy balance regulation, we examined the effects of long-term intracerebroventricular (icy) infusion of NMU in C57B 116 mice and in mice lacking the gene encoding NMU receptor 2. In diet-induced obese male and female C57BL/6 mice, icy infusion of NMU (8 μg∙day
-1 ∙mouse-1 ) for 7 days decreased body weight and total energy intake compared with vehicle treatment. However, these parameters were unaffected by NMU treatment in lean male and female C57BL/6 mice fed a standard diet. In addition, female (but not male) NMUR2-null mice had increased body weight and body fat mass when fed a high-fat diet but lacked a clear body weight phenotype when fed a standard diet compared with wild-type littermates. Furthermore, female (but not male) NMUR2-null mice fed a high-fat diet were protected from central NMU-induced body weight loss compared with littermate wild-type mice. Thus, we provide the first evidence that long-term central NMU treatment reduces body weight, food intake, and adiposity and that central NMUR2 signaling is required for these effects in female but not male mice. [ABSTRACT FROM AUTHOR]- Published
- 2009
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18. Allostatic hypermetabolic response in PGC1α/β heterozygote mouse despite mitochondrial defects
- Author
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Rodriguez-Cuenca, Sergio, Lelliot, Christopher J, Campbell, Mark, Peddinti, Gopal, Martinez-Uña, Maite, Ingvorsen, Camilla, Dias, Ana Rita, Relat, Joana, Mora, Silvia, Hyötyläinen, Tuulia, Zorzano, Antonio, Orešič, Matej, Bjursell, Mikael, Bohlooly-Y, Mohammad, Lindén, Daniel, and Vidal-Puig, Antonio
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Male ,Aging ,Heterozygote ,Nuclear Proteins ,Thermogenesis ,lipotoxicity ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,3. Good health ,PGC-1alpha ,adipose tissue ,Mitochondria ,Disease Models, Animal ,Mice ,mitochondrial dysfunction ,hepatic lipidome ,Animals ,Obesity ,Insulin Resistance ,Energy Metabolism ,Transcriptome ,Transcription Factors - Abstract
Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1β coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1β [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.
19. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity
- Author
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Carobbio, Stefania, Hagen, Rachel M, Lelliott, Christopher J, Slawik, Marc, Medina-Gomez, Gema, Tan, Chong-Yew, Sicard, Audrey, Atherton, Helen J, Barbarroja, Nuria, Bjursell, Mikael, Bohlooly-Y, Mohammad, Virtue, Sam, Tuthill, Antoinette, Lefai, Etienne, Laville, Martine, Wu, Tingting, Considine, Robert V, Vidal, Hubert, Langin, Dominique, Oresic, Matej, Tinahones, Francisco J, Fernandez-Real, Jose Manuel, Griffin, Julian L, Sethi, Jaswinder K, López, Miguel, and Vidal-Puig, Antonio
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Mice, Knockout ,Adipose Tissue, White ,Down-Regulation ,Membrane Proteins ,Lipid Metabolism ,Adaptation, Physiological ,3. Good health ,Obesity, Morbid ,Mice ,3T3-L1 Cells ,Animals ,Humans ,lipids (amino acids, peptides, and proteins) ,Obesity ,RNA, Messenger ,Insulin Resistance ,Sterol Regulatory Element Binding Protein 1 ,Stearoyl-CoA Desaturase - Abstract
The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
20. Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms
- Author
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Lelliott, Christopher J, Ahnmark, Andrea, Admyre, Therese, Ahlstedt, Ingela, Irving, Lorraine, Keyes, Feenagh, Patterson, Laurel, Mumphrey, Michael B, Bjursell, Mikael, Gorman, Tracy, Bohlooly-Y, Mohammad, Buchanan, Andrew, Harrison, Paula, Vaughan, Tristan, Berthoud, Hans-Rudolf, and Lindén, Daniel
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Leptin ,Serum Response Factor ,Hypothalamus ,Mice, Obese ,Eating ,Mice ,Glucose Intolerance ,Animals ,Humans ,Obesity ,Receptor, Fibroblast Growth Factor, Type 1 ,Receptors, Somatostatin ,Chemokine CCL7 ,Chemokine CCL2 ,2. Zero hunger ,Mice, Knockout ,digestive, oral, and skin physiology ,Arcuate Nucleus of Hypothalamus ,Antibodies, Monoclonal ,Ribosomal Protein S6 Kinases, 70-kDa ,3. Good health ,Gene Expression Regulation ,Circumventricular Organs ,Receptor, Melanocortin, Type 4 ,Female ,Mitogen-Activated Protein Kinases ,Energy Metabolism ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
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