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henolic 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. This research has been supported by Instituto de Salud Carlos III (CIBERObn) under Grant CB12/03/30007 (01/2013) and by the University of the Basque Country under Grant GIU18-173 (07/2018).

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.

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

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.

Dissecting exercise-mimicking pathways that can replicate the benefits of exercise in obesity and diabetes may lead to promising treatments for metabolic disorders. Muscle estrogen-related receptor gamma (ERRγ) is induced by exercise, and when over-expressed in the skeletal muscle mimics exercise by stimulating glycolytic-to-oxidative myofiber switch, mitochondrial biogenesis and angiogenesis in lean mice. The objective of this study was to test whether muscle ERRγ in obese mice mitigates weight gain and insulin resistance. To do so, ERRγ was selectively over-expressed in the skeletal muscle of obese and diabetic db/db mice. Muscle ERRγ over-expression successfully triggered glycolytic-to-oxidative myofiber switch, increased functional mitochondrial content and boosted vascular supply in the db/db mice. Despite aerobic remodeling, ERRγ surprisingly failed to improve whole-body energy expenditure, block muscle accumulation of triglycerides, toxic diacylglycerols (DAG) and ceramides or suppress muscle PKCε sarcolemmal translocation in db/db mice. Consequently, muscle ERRγ did not mitigate impaired muscle insulin signaling or insulin resistance in these mice. In conclusion, obesity and diabetes in db/db mice are not amenable to selective ERRγ-directed programming of classic exercise-like effects in the skeletal muscle. Other biochemical pathways or integrated whole-body effects of exercise may be critical for resisting diabetes and obesity.

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.

Circulating natriuretic peptide (NP) levels are reduced in obesity and predict the risk of type 2 diabetes (T2D). Since skeletal muscle was recently shown as a key target tissue of NP, we aimed to investigate muscle NP receptor (NPR) expression in the context of obesity and T2D. Muscle NPRA correlated positively with whole-body insulin sensitivity in humans and was strikingly downregulated in obese subjects and recovered in response to diet-induced weight loss. In addition, muscle NP clearance receptor (NPRC) increased in individuals with impaired glucose tolerance and T2D. Similar results were found in obese diabetic mice. Although no acute effect of brain NP (BNP) on insulin sensitivity was observed in lean mice, chronic BNP infusion improved blood glucose control and insulin sensitivity in skeletal muscle of obese and diabetic mice. This occurred in parallel with a reduced lipotoxic pressure in skeletal muscle due to an upregulation of lipid oxidative capacity. In addition, chronic NP treatment in human primary myotubes increased lipid oxidation in a PGC1α-dependent manner and reduced palmitate-induced lipotoxicity. Collectively, our data show that activation of NPRA signaling in skeletal muscle is important for the maintenance of long-term insulin sensitivity and has the potential to treat obesity-related metabolic disorders.

Introduction Bien qu'une association robuste entre une diminution des niveaux circulants de peptides natriuretiques (PN) et un risque accru de diabete de type 2 a ete rapportee chez l'homme, il n'y a, a ce jour, aucune evidence directe d'une effet des PN sur la sensibilite a l'insuline globale ou dans un tissu cible. Materiels et Methodes L'expression genique des recepteurs aux PN a ete mesuree par RT-qPCR dans des biopsies de tissu adipeux sous-cutane de deux cohortes europeennes independantes. Le transport de glucose a ete mesure sur des adipocytes humains isoles et sur des adipocytes hMADS ( human multipotent adipose-derived stem cell ) en culture. Les experiences de flux metaboliques et de signalisation ont ete effectuees sur hMADS en culture. Resultats Nous demontrons ici que l'expression du recepteur biologiquement actif aux PN de type A (NPRA) diminue tandis que celle du recepteur de clairance de type C (NPRC) augmente avec le degre d'obesite. L'expression du NPRA correle negativement avec la glycemie a jeun et est diminue chez des individus pre-diabetiques et diabetiques de type 2. L'expression du NPRA correle aussi negativement avec l'insulino-resistance (r=− 0,65, p Conclusions Collectivement, nos donnees supportent un role des PN dans la regulation du metabolisme du glucose et de la sensibilite a l'insuline en stimulant le transport de glucose dans l'adipocyte humain. La signalisation aux PN pourrait constituer une cible potentielle pour ameliorer l'insulinoresistance associee a l'obesite.

Introduction L'apeline est une adipokine dont les effets benefiques sur le metabolisme energetique ont ete decrits notamment chez les souris obeses et resistantes a l'insuline. Elle permet, entre autre, d'augmenter l'utilisation des lipides et la biogenese mitochondriale dans le muscle. Par contre, les effets de l'apeline sur le metabolisme hepatique ne sont pas connus. Il est vrai que le foie exprime tres faiblement le recepteur APJ en situation physiologique. Le but de cette etude a donc ete de determiner quels sont les effets d'un traitement a l'apeline chez des souris obeses et insulino-resistantes sur le metabolisme lipidique hepatique. Materiels et Methodes Des souris mâles adultes ont ete nourries soit avec un regime standard soit hyperlipidique (HFD) pendant 10 semaines puis traitees pendant 28 jours avec une injection ip d'apeline (0,1 μmol/kg/j) ou de PBS. L'etat d'insulino-resistance a ete evalue. Au sacrifice, le foie a ete preleve afin de mesurer differentes fonctions metaboliques. En parallele, des hepatocytes isoles de souris standard ont ete traites au palmitate (250 μm) et a l'apeline (10 – 7M) a court (20 min) et moyen terme (7 h). Resultats Le traitement apeline chez les souris HFD reduit le gain de masse grasse et l'hyperinsulinemie comme precedemment montre. Dans le foie, le contenu en TG est diminue ainsi que l'expression de genes impliques dans la lipogenese de novo (SREBP-1c, FAS…). L'augmentation de la β-oxydation observee chez les souris HFD est reduite apres le traitement apeline ainsi que la secretion de VLDL. Sur les hepatocytes isoles traites au palmitate, l'apeline n'a pas d'effet sur l'expression des genes de la lipogenese de novo. En aigu l'apeline n'a pas d'effet sur la phosphorylation d'Akt decrite auparavant dans d'autres tissus. Conclusions La steatose hepatique est attenuee chez les souris insulino-resistantes traitees a l'apeline. Cependant il semblerait que les effets de l'apeline sur le metabolisme hepatique soient indirects et une consequence de l'amelioration globale de la sensibilite a l'insuline.

Introduction L'obesite et le diabete de type 2 (DT2) se caracterisent par une diminution des niveaux circulants de peptides natriuretiques (PN) chez l'homme. Nous avons recemment demontre une signalisation fonctionnelle des PN dans le muscle squelettique. L'objectif de ce travail est d'etudier l'influence de l'obesite et du DT2 sur la signalisation aux PN chez l'homme et la souris. Materiels et methodes Nous avons mesure l'expression proteique des recepteurs aux PN, biologiquement actif (NPRA) et de clairance (NPRC) dans des biopsies musculaires issues de patients normoponderes ou obeses et dans un modele murin d'obesite/diabete (souris db/db et db/+). Nous avons ensuite etudie l'influence d'une perfusion continue de Brain-NP (BNP) par mini-pompe osmotique pendant 4 semaines chez des souris engraissees pendant 16 semaines. Des mesures de poids, composition corporelle et tolerance au glucose ont ete realisees. Resultats Nos resultats demontrent une correlation positive entre l'expression proteique du NPRA musculaire et la sensibilite a l'insuline ( r =0,51, p p Conclusion Nous demontrons pour la premiere fois que la signalisation musculaire aux PN est associee a la sensibilite a l'insuline et que l'obesite et le DT2 se caracterisent par une diminution de la signalisation musculaire aux PN chez l'homme et la souris. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Introduction Les triglycerides intramusculares constituent une source d'energie importante pour le muscle squelettique, notamment au cours d'un exercice physique. Des travaux precedents chez le rongeur indiquent que la perilipine 5 (PLIN5), proteine localisee a la surface de gouttelettes lipidiques de triglycerides, pourrait jouer un role dans le metabolisme lipidique musculaire. L'objec-tif de ce travail etait de caracteriser et d'etudier le role de PLIN5 dans la regulation de la lipolyse et du metabolisme oxydatif musculaire. Materiels et methodes Nous avons caracterise l'expression proteique de PLIN5 dans differents muscles de souris et chez des individus de poids normal sedentaires, entraines en endurance, et obeses intolerants au glucose (IGT). Nous avons egalement surexprime PLIN5 par une approche adenovirale dans des cultures primaires de cellules musculaires squelettiques humaines pour etudier son role fonctionnel dans la regulation du metabolisme energetique. Resultats Nos resultats montrent que PLIN5 est fortement exprime dans les muscles oxydatifs par rapport aux muscles glycolytiques. Nous montrons egalement une forte correlation positive de PLIN5 avec la sensibilite a l'insuline (r 2 = 0,42, p p = 0,0025), ainsi que la mobilisation et l'utilisation des acides gras issus de la lipolyse des triglycerides (− 46 %, p = 0,0035). Ceci s'accompagne d'une augmentation de l'oxydation du glucose et de la synthese de glycogene, concomitante avec une diminution de l'expression genique de PDK4 (Pyruvate Dehydrogenase Kinase 4). Conclusion Ces resultats indiquent que PLIN5 joue un role important dans la regulation de la lipolyse et du metabolisme oxydatif musculaire. PLIN5 pour-rait en partie determiner la sensibilite a l'insuline en modulant le flux d'acides gras dans le muscle squelettique. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.