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1. Natriuretic peptides promote glucose uptake in a cGMP-dependent manner in human adipocytes

Author

Marine Coué, Valentin Barquissau, Pauline Morigny, Katie Louche, Corinne Lefort, Aline Mairal, Christian Carpéné, Nathalie Viguerie, Peter Arner, Dominique Langin, Mikael Rydén, and Cedric Moro

Subjects
Medicine, Science
Abstract

Abstract Robust associations between low plasma level of natriuretic peptides (NP) and increased risk of type 2 diabetes (T2D) have been recently reported in humans. Adipose tissue (AT) is a known target of NP. However it is unknown whether NP signalling in human AT relates to insulin sensitivity and modulates glucose metabolism. We here show in two European cohorts that the NP receptor guanylyl cyclase-A (GC-A) expression in subcutaneous AT was down-regulated as a function of obesity grade while adipose NP clearance receptor (NPRC) was up-regulated. Adipose GC-A mRNA level was down-regulated in prediabetes and T2D, and negatively correlated with HOMA-IR and fasting blood glucose. We show for the first time that NP promote glucose uptake in a dose-dependent manner. This effect is reduced in adipocytes of obese individuals. NP activate mammalian target of rapamycin complex 1/2 (mTORC1/2) and Akt signalling. These effects were totally abrogated by inhibition of cGMP-dependent protein kinase and mTORC1/2 by rapamycin. We further show that NP treatment favoured glucose oxidation and de novo lipogenesis independently of significant gene regulation. Collectively, our data support a role for NP in blood glucose control and insulin sensitivity by increasing glucose uptake in human adipocytes. This effect is partly blunted in obesity.

Published
2018
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2. Effects of Physiological Doses of Resveratrol and Quercetin on Glucose Metabolism in Primary Myotubes

Author

Itziar Eseberri, Claire Laurens, Jonatan Miranda, Katie Louche, Arrate Lasa, Cedric Moro, and Maria P. Portillo

Subjects
resveratrol, quercetin, glucose, human primary myotubes, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Phenolic compounds have emerged in recent years as an option to face insulin resistance and diabetes. The central aim of this study was: (1) to demonstrate that physiological doses of resveratrol (RSV) or quercetin (Q) can influence glucose metabolism in human myotubes, (2) to establish whether AMP-activated protein kinase (AMPK) and protein kinase B –PKB- (Akt) pathways are involved in this effect. In addition, the effects of these polyphenols on mitochondrial biogenesis and fatty acid oxidation were analysed. Myotubes from healthy donors were cultured for 24 h with either 0.1 μM of RSV or with 10 μM of Q. Glucose metabolism, such as glycogen synthesis, glucose oxidation, and lactate production, were measured with D[U-14C]glucose. β-oxidation using [1–14C]palmitate as well as the expression of key metabolic genes and proteins by Real Time PCR and Western blot were also assessed. Although RSV and Q increased pgc1α expression, they did not significantly change either glucose oxidation or β-oxidation. Q increased AMPK, insulin receptor substrate 1 (IRS-1), and AS160 phosphorylation in basal conditions and glycogen synthase kinase 3 (GSK3β) in insulin-stimulated conditions. RSV tended to increase the phosphorylation rates of AMPK and GSK3β. Both of the polyphenols increased insulin-stimulated glycogen synthesis and reduced lactate production in human myotubes. Thus, physiological doses of RSV or Q may exhibit anti-diabetic actions in human myotubes.

Published
2021
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3. G0/G1 Switch Gene 2 controls adipose triglyceride lipase activity and lipid metabolism in skeletal muscle

Author

Claire Laurens, Pierre-Marie Badin, Katie Louche, Aline Mairal, Geneviève Tavernier, André Marette, Angelo Tremblay, S. John Weisnagel, Denis R. Joanisse, Dominique Langin, Virginie Bourlier, and Cedric Moro

Subjects
Internal medicine, RC31-1245
Abstract

Objective: Recent data suggest that adipose triglyceride lipase (ATGL) plays a key role in providing energy substrate from triglyceride pools and that alterations of its expression/activity relate to metabolic disturbances in skeletal muscle. Yet little is known about its regulation. We here investigated the role of the protein G0/G1 Switch Gene 2 (G0S2), recently described as an inhibitor of ATGL in white adipose tissue, in the regulation of lipolysis and oxidative metabolism in skeletal muscle. Methods: We first examined G0S2 protein expression in relation to metabolic status and muscle characteristics in humans. We next overexpressed and knocked down G0S2 in human primary myotubes to assess its impact on ATGL activity, lipid turnover and oxidative metabolism, and further knocked down G0S2 in vivo in mouse skeletal muscle. Results: G0S2 protein is increased in skeletal muscle of endurance-trained individuals and correlates with markers of oxidative capacity and lipid content. Recombinant G0S2 protein inhibits ATGL activity by about 40% in lysates of mouse and human skeletal muscle. G0S2 overexpression augments (+49%, p

Published
2016
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4. Immune Cell Toll-like Receptor 4 Mediates the Development of Obesity- and Endotoxemia-Associated Adipose Tissue Fibrosis

Author

Isabelle K. Vila, Pierre-Marie Badin, Marie-Adeline Marques, Laurent Monbrun, Corinne Lefort, Lucile Mir, Katie Louche, Virginie Bourlier, Balbine Roussel, Philippe Gui, Jacques Grober, Vladimír Štich, Lenka Rossmeislová, Alexia Zakaroff-Girard, Anne Bouloumié, Nathalie Viguerie, Cedric Moro, Geneviève Tavernier, and Dominique Langin

Subjects
Biology (General), QH301-705.5
Abstract

Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.

Published
2014
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5. Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58

Author

Pierre-Marie Badin, Camille Loubière, Maarten Coonen, Katie Louche, Geneviève Tavernier, Virginie Bourlier, Aline Mairal, Arild C. Rustan, Steven R. Smith, Dominique Langin, and Cedric Moro

Subjects
comparative gene identification 58, fatty acid, substrate oxidation, intramyocellular triacylglycerol, peroxisome proliferator-activated receptor, mitochondria, Biochemistry, QD415-436
Abstract

We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (−77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-δ (PPARδ) by lipolysis products. Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.

Published
2012
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6. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

Author

Amandine Girousse, Geneviève Tavernier, Carine Valle, Cedric Moro, Niklas Mejhert, Anne-Laure Dinel, Marianne Houssier, Balbine Roussel, Aurèle Besse-Patin, Marion Combes, Lucile Mir, Laurent Monbrun, Véronic Bézaire, Bénédicte Prunet-Marcassus, Aurélie Waget, Isabelle Vila, Sylvie Caspar-Bauguil, Katie Louche, Marie-Adeline Marques, Aline Mairal, Marie-Laure Renoud, Jean Galitzky, Cecilia Holm, Etienne Mouisel, Claire Thalamas, Nathalie Viguerie, Thierry Sulpice, Rémy Burcelin, Peter Arner, and Dominique Langin

Subjects
Biology (General), QH301-705.5
Abstract

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

Published
2013
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7. Chronic apelin treatment improves hepatic lipid metabolism in obese and insulin-resistant mice by an indirect mechanism

Author

Sophie Le Gonidec, Philippe Valet, Nancy Geoffre, Jean-Philippe Pradere, Jean Personnaz, Cedric Moro, Isabelle Castan-Laurell, C. Bertrand, Aurélie Batut, Katie Louche, Simon Deleruyelle, Bernard Masri, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Hormones, facteurs de croissance et physiopathologie vasculaire, Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mice, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Internal medicine, Diabetes mellitus, Animals, Medicine, Obesity, Triglycerides, ComputingMilieux_MISCELLANEOUS, Apelin receptor, business.industry, Fatty liver, Lipid metabolism, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipid Metabolism, medicine.disease, 3. Good health, Apelin, Fatty Liver, 030104 developmental biology, Liver, 030220 oncology & carcinogenesis, Hepatocytes, Insulin Resistance, Steatosis, Energy Metabolism, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.

Published
2018

8. Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity

Author

Katie Louche, Cedric Moro, Olivier Le Bacquer, Carla Domingues-Faria, Christophe Giraudet, Stéphane Walrand, Nahum Sonenberg, Kristell Combe, Christophe Montaurier, Véronique Patrac, Christelle Guillet, Jérôme Salles, Yves Boirie, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service Nutrition Clinique, CHU Clermont-Ferrand, Department of Biochemistry, Hôpital Lapeyronie, Region Auvergne, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Clermont-Ferrand, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)

Subjects
Male, 0301 basic medicine, obesity, Anabolism, CD36, Cell Cycle Proteins, environment and public health, Mice, Eukaryotic Initiation Factors, Mice, Knockout, 2. Zero hunger, protein homeostasis, Mice, Inbred BALB C, biology, lipid accumulation, muscle squelettique, lipotoxicity, insulino- résistance, 3. Good health, obésité, medicine.anatomical_structure, Lipotoxicity, protéine, mTOR, biological phenomena, cell phenomena, and immunity, Biotechnology, medicine.medical_specialty, accumulation de lipides, Mechanistic Target of Rapamycin Complex 1, Diet, High-Fat, 03 medical and health sciences, ATGL, Insulin resistance, Internal medicine, medicine, Animals, Muscle, Skeletal, PI3K/AKT/mTOR pathway, Adaptor Proteins, Signal Transducing, Diacylglycerol kinase, fungi, Skeletal muscle, Lipid metabolism, Lipid Metabolism, Phosphoproteins, medicine.disease, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Endocrinology, voluntary muscle, Proteostasis, biology.protein, Insulin Resistance, Carrier Proteins, protein, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science
Abstract

cope In recent years, several studies reported the role of eIF4E-binding proteins (4E-BPs) on the development of diet-induced obesity and insulin resistance. Our aim was to investigate the effect of 4E-BP protein deletion on lipid accumulation and metabolism in skeletal muscle in response to a high fat diet-induced obesity in 4E-BP1/2 DKO mice. Methods and results Diet-induced obesity engendered increased ectopic accumulation of lipotoxic species in skeletal muscle of 4E-BP1 and 4E-BP2 double-knockout mice (4E-BP1/2 DKO), namely diacylglycerols and ceramides. Increased lipid accumulation was associated with alterations in the expression of genes involved in fatty acid transport (FATP, CD36), diacylglycerol/triacylglycerol biosynthesis (GPAT1, AGPAT1, DGAT1) and β-oxidation (CPT1b, MCAD). Diet-induced obesity resulted in increased lean mass and muscle in 4E-BP1/2 DKO mice despite the development of a more severe systemic insulin resistance. Since increased expression of genes of several proteolytic systems (MuRF1, Atrogin/MAFbx and Cathepsin-L) in 4EBP1/2 DKO skeletal muscle was reported, the increased of skeletal muscle mass in 4E-BP1/2 DKO mice suggests that ablation of 4E-BPs compensate with activation of muscle anabolism. Conclusions These findings indicate that 4E-BP proteins may prevent excess lipid accumulation in skeletal muscle and suggest that 4E-BPs are key regulators of muscle homeostasis regardless of insulin sensitivity. This article is protected by copyright. All rights reserved

Published
2017

9. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle

Author

Cedric Moro, Virginie Bourlier, Angelo Tremblay, Katie Louche, Alexandra Montagner, Pierre-Marie Badin, Etienne Mouisel, Dominique Langin, John Weisnagel, Claire Laurens, André Marette, Denis R. Joanisse, Hervé Guillou, Aline Mairal, ProdInra, Archive Ouverte, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Medicine, Imperial College London, Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Department of Kinesiology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), CHU-CHUQ, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Department of Clinical Biochemistry, This work was supported by grants from the National Research Agency ANR-12-JSV1-0010-01 (CM), Societe Francophone du Diabete (CM), Canadian Institutes of Health Research grant CIHR MOP-68846 (DRJ) and a Pfizer/CIHR research Chair on the pathogenesis of insulin resistance and cardiovascular diseases (AM), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institute of Metabolic and Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Université Laval, and Moro, Cédric

Subjects
0301 basic medicine, Male, obesity, Glucose uptake, [SDV]Life Sciences [q-bio], Gene Expression, human health, Mice, Lipid droplet, Myocyte, Multidisciplinary, acide gras, muscle squelettique, santé humaine, Mitochondria, [SDV] Life Sciences [q-bio], obésité, medicine.anatomical_structure, Lipotoxicity, Oxidation-Reduction, medicine.medical_specialty, diabète de type 2, Satellite Cells, Skeletal Muscle, Lipolysis, Primary Cell Culture, Biology, Perilipin-5, Article, Diglycerides, 03 medical and health sciences, Insulin resistance, Lipid oxidation, Internal medicine, medicine, homéostasie lipidique, Animals, Humans, Muscle, Skeletal, métabolisme, Triglycerides, 030102 biochemistry & molecular biology, Body Weight, Skeletal muscle, Lipid Droplets, medicine.disease, type ii diabetes, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, voluntary muscle, Perilipin, Physical Endurance, fatty acid, Insulin Resistance, Sedentary Behavior, Oleic Acid
Abstract

Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

Published
2016

10. Central chronic apelin infusion decreases energy expenditure and thermogenesis in mice

Author

Anne Abot, Philippe Valet, Alexandre Lucas, Claude Knauf, Anne Drougard, Tereza Bautzova, Xavier Fioramonti, Audren Fournel, Alysson Marlin, Thibaut Duparc, Cedric Moro, Sophie Le-Gonidec, Patrice D. Cani, Etienne Meunier, Aurélie Batut, Jean Lesage, Katie Louche, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Hôpital de Rangueil-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Max Planck Institute of Immunobiology and Epigenetics, Institut de Recherche en Santé Digestive - IRSD [Purpan, Toulouse], Institut National de la Recherche Agronomique ( INRA ) -Université Paul Sabatier - Toulouse 3 ( UPS ) -Ecole Nationale Vétérinaire de Toulouse-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse, Focal Area Infection Biology, Biozentrum, University of Basel ( Unibas ), Environnement périnatal et croissance, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Walloon Excellence in Life sciences and BIOtechnology ( WELBIO ), Université Catholique de Louvain ( UCL ), Microbiota, Université Catholique de Louvain ( UCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Société Francaise de Nutrition (SFN), the Fondation Recherche Médicale (FRM) (Grant ING20150532586)the Societe Francophone du Diabète (Allocations Exceptionnelles 2016), ANR-12-JSV1-0010,DYNAMISE,Impact de la dynamique des gouttelettes lipidiques dans le muscle squelettique sur le métabolisme oxydatif et la sensibilité à l’insuline ( 2012 ), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Basel (Unibas), Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-12-JSV1-0010,DYNAMISE,Impact de la dynamique des gouttelettes lipidiques dans le muscle squelettique sur le métabolisme oxydatif et la sensibilité à l'insuline(2012), UCL - SSS/LDRI - Louvain Drug Research Institute, université de Bourgogne, CSGA, Jeunes Chercheuses et Jeunes Chercheurs - Impact de la dynamique des gouttelettes lipidiques dans le muscle squelettique sur le métabolisme oxydatif et la sensibilité à l'insuline - - DYNAMISE2012 - ANR-12-JSV1-0010 - JC - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-12-JSV1-0010,DYNAMISE,Impact de la dynamique des gouttelettes lipidiques dans le muscle squelettique sur le métabolisme oxydatif et la sensibilité à l’insuline(2012), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cani, Patrice D., and Knauf, Claude

Subjects
0301 basic medicine, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Interleukin-1beta, Gene Expression, Nitric Oxide Synthase Type II, Adipose tissue, adipose-tissue, Mice, 0302 clinical medicine, Adipose Tissue, Brown, Brown adipose tissue, circadian clock, Glucose homeostasis, Uncoupling Protein 1, PRDM16, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Multidisciplinary, brown fat, Thermogenesis, Type 2 diabetes, food-intake, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Thermogenin, 3. Good health, Apelin, DNA-Binding Proteins, Infusions, Intraventricular, medicine.anatomical_structure, Hypothalamus, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Alimentation et Nutrition, medicine.medical_specialty, Biology, diabetic mice, signaling controls, Article, 03 medical and health sciences, Internal medicine, medicine, Animals, Food and Nutrition, gut microbiota, insulin-resistant mice, Neurosciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ddc:616.8, metabolic-disorders, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Neurons and Cognition, glucose-homeostasis, Energy Metabolism, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Apelin is a bioactive peptide involved in the control of energy metabolism. In the hypothalamus, chronic exposure to high levels of apelin is associated with an increase in hepatic glucose production, and then contributes to the onset of type 2 diabetes. However, the molecular mechanisms behind deleterious effects of chronic apelin in the brain and consequences on energy expenditure and thermogenesis are currently unknown. We aimed to evaluate the effects of chronic intracerebroventricular (icv) infusion of apelin in normal mice on hypothalamic inflammatory gene expression, energy expenditure, thermogenesis and brown adipose tissue functions. We have shown that chronic icv infusion of apelin increases the expression of pro-inflammatory factors in the hypothalamus associated with an increase in plasma interleukin-1 beta. In parallel, mice infused with icv apelin exhibit a significant lower energy expenditure coupled to a decrease in PGC1alpha, PRDM16 and UCP1 expression in brown adipose tissue which could explain the alteration of thermogenesis in these mice. These data provide compelling evidence that central apelin contributes to the development of type 2 diabetes by altering energy expenditure, thermogenesis and fat browning.

Published
2016

11. Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58

Author

Cedric Moro, Steven R. Smith, Camille Loubière, Aline Mairal, Dominique Langin, Virginie Bourlier, Pierre-Marie Badin, Katie Louche, Arild C. Rustan, Geneviève Tavernier, Maarten Coonen, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmaceutical Biosciences, University of Oslo (UiO), Translational Research Institute for Metabolism and Diabetes and the Burnham Institute, Florida Hospital, and Simon, Marie Francoise

Subjects
MESH: Oxidation-Reduction, Hydrolases, Muscle Fibers, Skeletal, Peroxisome proliferator-activated receptor, Mitochondrion, Biochemistry, MESH: Lipase, Mice, 0302 clinical medicine, Endocrinology, substrate oxidation, MESH: Animals, PPAR delta, Research Articles, Cells, Cultured, chemistry.chemical_classification, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Muscle Fibers, Skeletal, Myogenesis, MESH: Gene Expression Regulation, Enzymologic, Fatty Acids, MESH: Energy Metabolism, 1-Acylglycerol-3-Phosphate O-Acyltransferase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, humanities, MESH: Hydrolases, MESH: Fatty Acids, MESH: Glucose, mitochondria, medicine.anatomical_structure, MESH: Young Adult, Gene Knockdown Techniques, Peroxisome proliferator-activated receptor delta, Oxidation-Reduction, MESH: Cells, Cultured, MESH: Triglycerides, Adolescent, MESH: 1-Acylglycerol-3-Phosphate O-Acyltransferase, MESH: Mitochondria, Lipolysis, 030209 endocrinology & metabolism, Oxidative phosphorylation, QD415-436, Biology, Gene Expression Regulation, Enzymologic, Young Adult, 03 medical and health sciences, health services administration, mental disorders, medicine, Animals, Humans, MESH: Lipolysis, MESH: PPAR delta, Muscle, Skeletal, Glycogen synthase, MESH: Mice, Triglycerides, 030304 developmental biology, MESH: Adolescent, MESH: Humans, comparative gene identification 58, peroxisome proliferator-activated receptor, intramyocellular triacylglycerol, Skeletal muscle, Lipase, Cell Biology, MESH: Gene Knockdown Techniques, Glucose, chemistry, biology.protein, fatty acid, Energy Metabolism
Abstract

International audience; We investigated here the specific role of CGI-58 in the regulation of energy metabolism in skeletal muscle. We first examined CGI-58 protein expression in various muscle types in mice, and next modulated CGI-58 expression during overexpression and knockdown studies in human primary myotubes and evaluated the consequences on oxidative metabolism. We observed a preferential expression of CGI-58 in oxidative muscles in mice consistent with triacylglycerol hydrolase activity. We next showed by pulse-chase that CGI-58 overexpression increased by more than 2-fold the rate of triacylglycerol (TAG) hydrolysis, as well as TAG-derived fatty acid (FA) release and oxidation. Oppositely, CGI-58 silencing reduced TAG hydrolysis and TAG-derived FA release and oxidation (-77%, P < 0.001), whereas it increased glucose oxidation and glycogen synthesis. Interestingly, modulations of CGI-58 expression and FA release are reflected by changes in pyruvate dehydrogenase kinase 4 gene expression. This regulation involves the activation of the peroxisome proliferator activating receptor-δ (PPARδ) by lipolysis products. Altogether, these data reveal that CGI-58 plays a limiting role in the control of oxidative metabolism by modulating FA availability and the expression of PPARδ-target genes, and highlight an important metabolic function of CGI-58 in skeletal muscle.

Published
2012

12. Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans

Author

Gerd Schmitz, Cedric Moro, Steven R. Smith, Gerhard Liebisch, Arild C. Rustan, Aline Mairal, Pierre-Marie Badin, Katie Louche, Dominique Langin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institute of Clinical Chemistry, Universität Regensburg (UR), Department of Pharmaceutical Biosciences, University of Oslo (UiO), Translational Research Institute for Metabolism and Diabetes and the Burnham Institute, Florida Hospital, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], This work was supported by grants from the National Research Agency (ANR-09-JCJC-0019-01) and the European Foundation for the Study of Diabetes/Novo Nordisk (to C.M.), the Commission of the European Communities (Integrated Project HEPADIP, and National Institutes of Health grants US-1P30-DK-072476 (Pennington Biomedical Research Center/Nutrition Obesity Research Center) and R01-AG-030226 (to S.R.S.). The Hormone Assay and Analytical Services Core, Vanderbilt Diabetes Research and Training Center, supported by National Institutes of Health Grant DK-20593, performed TAG and DAG analyses., European Project: 32591,HEPADIP, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, and Hepatic and adipose tissue and functions in the metabolic syndrome - HEPADIP - 32591 - OLD

Subjects
Male, Endocrinology, Diabetes and Metabolism, MESH: Glucose Clamp Technique, Mass Spectrometry, MESH: Lipase, 0302 clinical medicine, Tandem Mass Spectrometry, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, education.field_of_study, MESH: Muscle, Skeletal, MESH: Middle Aged, MESH: Sterol Esterase, biology, MESH: Chromatography, Gas, Glucose clamp technique, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, MESH: Insulin Resistance, medicine.anatomical_structure, MESH: Young Adult, lipids (amino acids, peptides, and proteins), Female, MESH: Triglycerides, Adult, medicine.medical_specialty, Spectrometry, Mass, Electrospray Ionization, Chromatography, Gas, Population, 030209 endocrinology & metabolism, MESH: Spectrometry, Mass, Electrospray Ionization, Pathophysiology, MESH: Diglycerides, Diglycerides, 03 medical and health sciences, Young Adult, Insulin resistance, Internal medicine, Internal Medicine, medicine, Humans, Glycogen synthase, education, Muscle, Skeletal, Protein kinase B, Triglycerides, 030304 developmental biology, MESH: Mass Spectrometry, MESH: Humans, Skeletal muscle, MESH: Tandem Mass Spectrometry, MESH: Adult, Lipase, Sterol Esterase, medicine.disease, MESH: Male, Insulin receptor, Endocrinology, Adipose triglyceride lipase, biology.protein, Glucose Clamp Technique, Insulin Resistance, MESH: Female
Abstract

OBJECTIVE Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance. RESEARCH DESIGN AND METHODS We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling. RESULTS Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance. CONCLUSIONS Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.

Published
2011

13. Browning of White Adipose Cells by Intermediate Metabolites: An Adaptive Mechanism to Alleviate Redox Pressure

Author

Louis Casteilla, Brigitte Wdziekonski, Katie Louche, Corinne Barreau, Phi Villageois, Christian Dani, Francesc Villarroya, Anne Galinier, Sandra Berger-Müller, Audrey Carrière, Romy Walther, Emmanuelle Arnaud, Cedric Moro, Mireille André, Philippe Collas, Yannick Jeanson, Vanessa Chenouard, STROMALab, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lactate transport, 0303 health sciences, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Adipose tissue, Oxidative phosphorylation, White adipose tissue, Mitochondrion, Biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Biochemistry, Brown adipose tissue, Internal Medicine, medicine, Browning, Uncoupling protein, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1α and PPARα pathways but requires active PPARγ signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body β-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance.

Published
2014

14. High-fat diet-mediated lipotoxicity and insulin resistance is related to impaired lipase expression in mouse skeletal muscle

Author

Pierre Marie Badin, Aline Mairal, Marie Adeline Marques, Virginie Bourlier, Isabelle K. Vila, Cedric Moro, Katie Louche, Dominique Langin, Geneviève Tavernier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de biochimie clinique, CHU Toulouse [Toulouse], Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Simon, Marie Francoise

Subjects
medicine.medical_treatment, Glucose uptake, Muscle Proteins, Weight Gain, MESH: Mice, Knockout, MESH: Lipase, Mice, 0302 clinical medicine, Endocrinology, Insulin, MESH: Animals, Phosphorylation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Knockout, 0303 health sciences, Mice, Inbred C3H, MESH: Muscle, Skeletal, biology, Intracellular Signaling Peptides and Proteins, food and beverages, 1-Acylglycerol-3-Phosphate O-Acyltransferase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, MESH: Glucose, MESH: Insulin Resistance, medicine.anatomical_structure, Lipotoxicity, MESH: Weight Gain, MESH: Membrane Proteins, medicine.medical_specialty, MESH: 1-Acylglycerol-3-Phosphate O-Acyltransferase, MESH: Glucose Tolerance Test, 030209 endocrinology & metabolism, MESH: Carrier Proteins, MESH: Insulin, Diet, High-Fat, Perilipin-2, Perilipin-3, Diglycerides, MESH: Diglycerides, 03 medical and health sciences, MESH: Muscle Proteins, Insulin resistance, Internal medicine, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, Muscle, Skeletal, MESH: Mice, Inbred C3H, MESH: Mice, 030304 developmental biology, MESH: Phosphorylation, Skeletal muscle, Membrane Proteins, Lipase, Glucose Tolerance Test, medicine.disease, IRS1, Insulin receptor, MESH: Diet, High-Fat, Glucose, Adipose triglyceride lipase, biology.protein, Insulin Resistance, Carrier Proteins
Abstract

Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cϵ membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (−37%, P < .05) and AS160 Thr642 (−47%, P

Published
2013

15. Breaking down insulin resistance

Author

Dominique Langin, Aline Mairal, Cecilia Holm, Claire Thalamas, Isabelle K. Vila, Marianne Houssier, Bénédicte Prunet-Marcassus, Sylvie Caspar-Bauguil, Lucile Mir, Niklas Mejhert, Marie-Laure Renoud, Peter Arner, Geneviève Tavernier, Carine Valle, Aurélie Waget, Cedric Moro, Rémy Burcelin, Nathalie Viguerie, Balbine Roussel, Katie Louche, Aurèle Besse-Patin, Laurent Monbrun, Marion Combes, Veronic Bezaire, Marie Adeline Marques, Jean Galitzky, Amandine Girousse, Anne Laure Dinel, Etienne Mouisel, Thierry Sulpice, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Physiogenex, Facteurs de risque intestinaux, diabète et dyslipidémie (Equipe 2), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Equipe 1, Department of Experimental Medical Science, Lund University [Lund], CIC - Biotherapie - Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de biochimie clinique, and CHU Toulouse [Toulouse]

Subjects
Male, Anatomy and Physiology, Mouse, Glucose uptake, medicine.medical_treatment, Gene Expression, Adipose tissue, White adipose tissue, Biochemistry, Mice, Endocrinology, 0302 clinical medicine, Integrative Physiology, Molecular Cell Biology, Insulin, Longitudinal Studies, Biology (General), [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, 0303 health sciences, General Neuroscience, Fatty Acids, food and beverages, Animal Models, Middle Aged, Biological Sciences, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipids, Adipose Tissue, Lipogenesis, Synopsis, Carbohydrate Metabolism, Medicine, Metabolic Pathways, General Agricultural and Biological Sciences, Research Article, Adult, medicine.medical_specialty, Adolescent, Clinical Research Design, QH301-705.5, Lipolysis, Adipose Tissue, White, 030209 endocrinology & metabolism, Carbohydrate metabolism, Biology, Niacin, General Biochemistry, Genetics and Molecular Biology, Glycerides, Young Adult, 03 medical and health sciences, Model Organisms, Insulin resistance, Internal medicine, medicine, Animals, Humans, Animal Models of Disease, Obesity, Aged, Nutrition, 030304 developmental biology, Diabetic Endocrinology, General Immunology and Microbiology, Sterol Esterase, Diabetes Mellitus Type 2, Lipid Metabolism, medicine.disease, Insulin receptor, Glucose, Metabolism, Cross-Sectional Studies, biology.protein
Abstract

Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis., When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity., Author Summary In periods of energy demand, mobilization of fat stores in mammals (i.e., adipose tissue lipolysis) is essential to provide energy in the form of fatty acids. In excess, however, fatty acids induce resistance to the action of insulin, which serves to regulate glucose metabolism in skeletal muscle and liver. Insulin resistance (or low insulin sensitivity) is believed to be a cornerstone of the complications of obesity such as type 2 diabetes and cardiovascular diseases. In this study, our clinical observation of natural variation in fat cell lipolysis in individuals reveals that a high lipolytic rate is associated with low insulin sensitivity. Furthermore, partial genetic and pharmacologic inhibition of hormone-sensitive lipase, one of the enzymes involved in the breakdown of white adipose tissue lipids, results in improvement of insulin sensitivity in mice without gain in body weight and fat mass. We undertake a series of mechanistic studies in mice and in human fat cells to show that blunted lipolytic capacity increases the synthesis of new fatty acids from glucose in fat cells, a pathway that has recently been shown by others to be a major determinant of whole body insulin sensitivity. In conclusion, partial inhibition of adipose tissue lipolysis is a plausible strategy in the treatment of obesity-related insulin resistance.

Published
2013

16. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle

Author

Pierre-Marie Badin, Emilie Montastier, Dominique Langin, Nathalie Viguerie, Isabelle de Glisezinski, Cedric Moro, Jens Jordan, Julia Reinke, Virginie Bourlier, Claire Thalamas, Stefan Engeli, Katie Louche, Stefanie Lieske, Andreas L. Birkenfeld, Bibiana Beckmann, Dominique Larrouy, and I. Harant

Subjects
Adult, Male, medicine.medical_specialty, Muscle Fibers, Skeletal, Primary Cell Culture, Oxidative phosphorylation, 030204 cardiovascular system & hematology, Biology, Mitochondrion, Oxidative Phosphorylation, 03 medical and health sciences, 0302 clinical medicine, Oxygen Consumption, Internal medicine, Natriuretic Peptide, Brain, medicine, Humans, Obesity, Muscle, Skeletal, Cells, Cultured, Heat-Shock Proteins, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Myogenesis, Brief Report, Skeletal muscle, Lipid metabolism, General Medicine, Lipid Metabolism, Adaptation, Physiological, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Mitochondria, Muscle, Up-Regulation, Endocrinology, medicine.anatomical_structure, Genes, Mitochondrial, Gene Expression Regulation, Signal transduction, Thermogenesis, Oxidation-Reduction, Receptors, Atrial Natriuretic Factor, Atrial Natriuretic Factor, Signal Transduction, Transcription Factors
Abstract

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP–dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training–induced improvement in skeletal muscle fat oxidative capacity in humans.

Published
2012

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