2721-LB: Obesity Switches Hepatic CB1 Signaling from Gi/oa-Mediated Lipolysis to Gsa-Driven Lipogenesis via the CREB-PPAR?-CD36-AMPK Axis

Introduction and Objective: Hepatocyte CB1 receptor (hCB1R) is implicated in obesity-induced steatotic liver disease (SLD), yet the molecular basis for its transition from homeostatic regulator to pathogenic driver remains unclear. Objective: To investigate the functional reprogramming of hCB1R signaling in response to diet-induced obesity (DIO). Methods: Using hCB1R knockout (hCB1Rko) mice and floxed controls, we evaluated the metabolic response to the peripheral CB1R antagonist JD5037. Transcriptomic profiling (RNA-Seq) and Western blotting were employed to map signaling pathways and protein expression profiles in lean versus steatotic liver environments. Results: While chronic JD5037 treatment of DIO mice reduced body weight and hyperleptinemia in both genotypes, it reversed hepatic steatosis in control but not in hCB1Rko mice, demonstrating a weight-independent requirement for hCB1R in lipid metabolism. In lean mice, hCB1R couples to Gi/oα to suppress the CREB-PPARγ-CD36 axis that inhibits lipogenesis and desinhibits AMPK-induced fatty acid oxidation; however, in the steatotic liver, protein expression shifts, forcing CB1R to couple to Gsα. This signaling bifurcation activates the CREB-mediated transcriptional program, robustly upregulating Pparg and Cd36 and driving hepatic fatty acid accumulation. Conclusion: Our data reveal that obesity reprograms hCB1R from a lipolytic Gi/oα-coupled receptor that protects from steatosis to a lipogenic Gsα-coupled driver of steatosis. Targeting this signaling switch may provide a more precise therapeutic strategy for the treatment of SLD. Disclosure J. Liu: None. G. Kunos: None. Funding Intramural funds of the National Institute on Alcohol Abuse and Alcoholism to George Kunos