Researchers at National University of Singapore identified the orphan receptor GPR146 as a critical driver of fatty liver disease (MASLD) through adipose-liver crosstalk. Human genetic data linked the GPR146 locus to elevated liver enzymes and inflammation markers. In mice, deleting GPR146 whole-body or specifically in fat tissue — but not in the liver — protected against diet-induced obesity and hepatic fat accumulation. Mechanistically, GPR146 promotes fat cell formation via Gαq-PKC-AKT signaling and boosts fat breakdown in mature adipocytes through ERK activation, together raising circulating free fatty acids that flood the liver. These findings position adipose GPR146 as a pleiotropic therapeutic target for obesity-related liver disease.
