Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis

BACKGROUND: Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. METHODOLOGY: Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). PRINCIPAL FINDINGS: In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. CONCLUSION/SIGNIFICANCE: These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorder

Régulation de la glycéronéogenèse du tissu adipeux par les thiazolidinediones et les acides rétinoïques (implications dans le diabète de type 2)

L'obésité est le principal facteur de risque de l'insulino-résistance et du diabète de type 2. Le lien entre l'hypertrophie du tissu adipeux et ces pathologies serait les acides gras non-estérifiés (AGNE) provenant de la lipolyse adipocytaire. Une élévation chronique des AGNE sanguins induirait une résistance à l'insuline. Dans l'adipocyte, une fraction des AGNE issus de la lipolyse est ré-estérifiée en triglycérides. Cette ré-estérification requiert la synthèse de glycérol-3-phosphate qui provient, à jeun, du pyruvate et lactate circulants grâce à une voie métabolique appelée glycéronéogenèse et dont l'enzyme clé est la phosphoénolpyruvate carboxykinase cytosolique (PEPCK-C). Au cours de ce travail, nous avons monté que les thiazolidinediones et les rexinoïdes exercent leurs effets hypolipidémiants et antidiabétiques grâce à une induction rapide et sélective de la transcription du gène PEPCK-C qui conduit à une augmentation de l'activité PEPCK-C et de la glycéronéogenèse.Obesity is a major risk factor for insulin resistance and type 2 diabetes. The link between hypertrophied adipose tissue and this pathology is thought to be non-esterified fatty acids (NEFA) arising from adipocyte lipolysis. Sustained increase in plasma NEFA induces insulin resistance. In adipocytes, a significant part of lipolytic NEFA is re-esterified to triacylglycerol. Re-esterification requires glycerol-3-phosphate which, during fasting, is synthesized from lactate or pyruvate in metabolic pathway named glyceroneogenesis, whose key enzyme is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). In this study, we give evidence that thiazolidinediones and rexinoids exert their hypolipidemic and antidiabetic effects in adipose tissue at least in part through a rapid and selective induction of PECK-C gene transcription leading to increased PECK-C and glyceroneogenesis. Subsequent fatty acid re-esterification participates in the reduction in blood NEFA and insulin resistance.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Glycéronéogenèse et PEPCK-C

Un des liens entre obésité, résistance à l’insuline et diabète de type 2 incrimine les acides gras non estérifiés (AGNE) issus de l’hydrolyse des triglycérides dans le tissu adipeux. Une part importante de ces AGNE est ré-estérifiée immédiatement en triglycérides. La ré-estérification requiert la glycéronéogenèse ou synthèse de glycérol-3-phosphate qui, notamment à jeun, provient de substrats non glucidiques. Plus le recyclage des AGNE est important, moins ils sont libérés. La glycéronéogenèse et l’expression de son enzyme clé, la PEPCK-C, sont sélectivement induites par les thiazolidinediones hypolipidémiantes et antidiabétiques qui réduisent ainsi l’efflux des AGNE, leur taux circulant et l’insulinorésistance

Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration.

International audienceThe cannabinoid receptor 2 (CB2) plays a pleiotropic role in innate immunity and is a crucial mediator of liver disease. In this study, we investigated the impact of CB2 receptors on the regenerative process associated with liver injury. Following acute hepatitis induced by carbon tetrachloride (CCl(4)), CB2 was induced in the nonparenchymal cell fraction and remained undetectable in hepatocytes. Administration of CCl(4) to CB2(-/-) mice accelerated liver injury, as shown by increased alanine/aspartate aminotransferase levels and hepatocyte apoptosis, and delayed liver regeneration, as reflected by a retarded induction of hepatocyte proliferating cell nuclear antigen expression; proliferating cell nuclear antigen induction was also delayed in CB2(-/-) mice undergoing partial hepatectomy. Conversely, following treatment with the CB2 agonist JWH-133, CCl(4)-treated WT mice displayed reduced liver injury and accelerated liver regeneration. The CCl(4)-treated CB2(-/-) mice showed a decrease in inducible nitric oxide synthase and tumor necrosis factor-alpha expression, and administration of the nitric oxide donor moldomine (SIN-1) to these animals reduced hepatocyte apoptosis, without affecting liver regeneration. Impaired liver regeneration was consecutive to an interleukin-6 (IL-6)-mediated decrease in matrix metalloproteinase 2 (MMP-2) activity. Indeed, CCl(4)-treated CB2(-/-) mice displayed lower levels of hepatic IL-6 messenger RNA and increased MMP-2 activity. Administration of IL-6 to these mice decreased MMP-2 activity and improved liver regeneration, without affecting hepatocyte apoptosis. Accordingly, administration of the MMP inhibitor CTTHWGFTLC to CCl(4)-treated CB2(-/-) mice improved liver regeneration. Finally, in vitro studies demonstrated that incubation of hepatic myofibroblasts with JWH-133 increased tumor necrosis factor-alpha and IL-6 and decreased MMP-2 expressions. CONCLUSION: CB2 receptors reduce liver injury and promote liver regeneration following acute insult, via distinct paracrine mechanisms involving hepatic myofibroblasts. These results suggest that CB2 agonists display potent hepatoprotective properties, in addition to their antifibrogenic effects

Hypothalamic Apelin/Reactive oxygen species signaling controls hepatic glucose metabolism in the onset of diabetes

Aims: We have previously demonstrated that central apelin is implicated in the control of peripheral glycemia, and its action depends on nutritional (fast versus fed) and physiological (normal versus diabetic) states. An intracerebroventricular (icv) injection of a high dose of apelin, similar to that observed in obese/diabetic mice, increase fasted glycemia, suggesting (i) that apelin contributes to the establishment of a diabetic state, and (ii) the existence of a hypothalamic to liver axis. Using pharmacological, genetic, and nutritional approaches, we aim at unraveling this system of regulation by identifying the hypothalamic molecular actors that trigger the apelin effect on liver glucose metabolism and glycemia. Results: We show that icv apelin injection stimulates liver glycogenolysis and gluconeogenesis via an over-activation of the sympathetic nervous system (SNS), leading to fasted hyperglycemia. The effect of central apelin on liver function is dependent of an increased production of hypothalamic reactive oxygen species (ROS). These data are strengthened by experiments using lentiviral vector-mediated over-expression of apelin in hypothalamus of mice that present over-activation of SNS associated to an increase in hepatic glucose production. Finally, we report that mice fed a high-fat diet present major alterations of hypothalamic apelin/ROS signaling, leading to activation of glycogenolysis. Innovation/Conclusion: These data bring compelling evidence that hypothalamic apelin is one master switch that participates in the onset of diabetes by directly acting on liver function. Our data support the idea that hypothalamic apelin is a new potential therapeutic target to treat diabetes. © 2014 Mary Ann Liebert, Inc

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

International audienc