SUN-665 Peripheral CB(1)R Blocker Improves Metabolism in Diet Induced Obese Mice Independent of Hepatic FGF21

Obesity is associated with an overactive endocannabinoid system, and selective blockade of CB(1)R in peripheral tissues, including the liver, reverses HFD-induced metabolic abnormalities by restoring normal lipid and glucose homeostasis. Fibroblast growth factor-21 (FGF21) has emerged as a major endocrine regulator derived from the liver that reduces adiposity and hepatic steatosis and improves glucose tolerance and insulin sensitivity, with changes similar to those induced by CB(1)R blockade. Here we investigated whether FGF21 mediate the metabolic effects of CB1R blockade in DIO mice. In C57BL/6J wild-type mice, HFD caused a robust increase in hepatic Fgf21 mRNA and serum FGF21 levels, which were reversed by chronic CB(1)R blockade to levels observed in STD or vehicle-treated hepatocyte-specific CB(1)R(-/-) (LCB1(-/-)) mice, indicating activation of CB(1)R in the liver is largely involved in HFD-induced “FGF21-resistant” state. In contrast, the expression of the FGF21 receptor Fgfr1 and co-receptor β-klotho (Klb) were dramatically reduced by HFD in both epididymal fat and brain tissue in wild-type mice, and these effects were reversed by peripheral CB(1)R antagonist JD5037 treatment. To address whether FGF21 mediated the metabolic effects of CB(1)R blockade, we repeated JD5037 treatment in liver-specific FGF21(-/-) (FGF21-LKO) mice. Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in FGF21-LKO mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB(1)R blockade in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21.