Peripheral cannabinoid-1 receptor (CB1R) antagonism improves insulin sensitivity in mice with diet-induced obesity (DIO) by reversing the increase in de novo ceramide synthesis in the liver.

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIAAA	PHARM/PHYS-1

Authors

• R. Cinar
• G. Godlewski
• J. Tam
• J. Liu
• T. Jourdan
• B. Mukhopadhyay
• J. Harvey-White
• J.F. McElroy
• R. Chorvat
• G. Kunos

Abstract

Obesity-related insulin resistance is associated with increased signalling by lipid mediators: endocannabinoids (ECs) and ceramides. Brain-penetrant CB1R antagonists reduce the metabolic complications of obesity but have neuropsychiatric side effects, whereas peripherally restricted CB1R antagonists/inverse agonists offer similar metabolic benefits without causing behavioral effects. Here we analyzed the effects of the peripheral CB1R inverse agonist JD-5037 on metabolic functions and on the biosynthesis of ceramides in C57Bl6/J mice with DIO. Oral treatment with JD-5037 at 3 mg/kg/day for 28 days reversed the diet-induced increase in C16:0, C18:0 and C20:0, but not other, ceramide species in the liver by inhibiting serine palmitoyltransferase (SPT) activity through inhibition of the gene expression of the SPT3 subunit that catalyzes the rate-limiting step of de novo ceramide synthesis. In primary mouse hepatocytes, the EC anandamide increases ceramide synthesis and inhibits insulin-induced akt phosphorylation via CB1R, and these effects are abrogated by the SPT inhibitor myriocin. Chronic treatments of DIO mice with either myriocin or JD-5037 reversed hepatic insulin resistance, as verified using euglycemic/hyperinsulinemic clamp. We conclude that ECs induce CB1R-mediated hepatic insulin resistance via increased synthesis of specific ceramide subspecies in the liver, and that this mechanism plays a role in diet-induced insulin resistance.

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