Yu Shi, Kai Yan Cheng, Thi Tun Thi, Yifan Wang, Yang Yang, Xiaoyun Cao, Vanna Chhay, Yujia Shen, Yuchen He, Tianyun Zhao, Yan Ting Lim, Amy Deik, Courtney Dennis, Kerry Pierce, Kevin Bullock, Martin Wabitsch, Clary B. Clish, Alexander S. Banks, Radoslaw M. Sobota, Chad A. Cowan, Haojie Yu
The limited therapeutic options for metabolic dysfunction-associated steatotic liver disease (MASLD) underscore the need for deeper mechanistic insight and new treatment strategies. Here, we identify the orphan G protein-coupled receptor GPR146 as a regulator of hepatic steatosis through adipose-liver crosstalk. Human genetic analyses link the GPR146 locus to circulating markers of liver injury and inflammation. In mice, both constitutive and acute GPR146 depletion protect against diet-induced obesity and hepatic steatosis. Notably, adipose-specific, but not liver-specific, GPR146 deletion reduces hepatic lipid accumulation by limiting free fatty acid (FFA) influx. Mechanistically, GPR146 promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating FFA. Together, these coordinated actions increase FFA delivery to the liver, promoting triglyceride accumulation. Our findings establish GPR146 as a pleiotropic regulator of adipose tissue biology and a potential therapeutic target for MASLD.