CB1 Blockade Activates Sirt1 and AMPK Signaling to Improve Glycemic Control and Increase Energy Expenditure in the Liver

Presentation Number: SUN 607
Date of Presentation: April 2nd, 2017

Jie Liu*, Grzegorz Godlewski, Tony Jourdan, Keming Xiong, Ziyi Liu, Resat Cinar and George Kunos
National Institutes of Health, Rockville, MD


The endocannabinoid system reserves energy in homeostasis and is overactive in metabolic disorders associated with obese. CB1 blockade has shown promising therapeutic potential in reversing body weight gain, insulin and leptin resistance by increasing energy expenditure in obese object. The equivalent efficacy of peripheral restricted CB1R inverse agonist JD5037 indicates that catabolic process in the periphery tissues plays an important role in this antagonism. We investigated the molecular mechanism in the liver. Activation of CB1 inhibited Sirt1/mTORC2 signaling pathway, which can be reversed by CB1 blockade. In diet-induced obese mice, CB1 blockade normalized the HFD-induced reduction in hepatic Sirt1 activity and mTORC2 signaling. JD5037 improved hyperglycemia dependent on hepatic Sirt1/mTORC2, whereas reversed hyperinsulinemia, liver steatosis and fatty acid β-oxidation, electron transport chain (ETC) complex I and IV activities independent of hepatic Sirt1. The basal fatty acid β-oxidation rate was significant lower in liver-specific Sirt1 knockout (Sirt1-LKO) mice compare to their littermate controls, which reflected the major role of Sirt1/PPARα in the liver. However, the reversal of HFD-reduced fatty acid β-oxidation by JD5037 reached to the same extent in both strains, and this was mediated by a hepatic Sirt1-independent AMPK pathway. In conclusion, we demonstrated that the peripherally restricted CB1 antagonist/agonist activated hepatic Sirt1 and AMPK signaling pathways to improve glycemic control and increase energy expenditure in the liver.


Nothing to Disclose: JL, GG, TJ, KX, ZL, RC, GK