Orphan Receptor GPR146 in Fat Tissue Drives Fatty Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 25% of adults worldwide, yet approved treatments remain scarce. This study by Shi, Cheng, and colleagues identifies the orphan G protein-coupled receptor GPR146 as a previously unrecognized regulator of the fat–liver axis, offering a mechanistic explanation for how dysfunctional adipose tissue drives hepatic lipid overload.

The team first mined human genomic databases and found that the GPR146 risk SNP rs1997243-G is associated with higher plasma LDL-C, C-reactive protein, and multiple liver enzymes (GGT, AST, ALT, ALP), and with increased GPR146 expression in blood and subcutaneous adipose tissue via eQTL data from GTEx. This epidemiological signal motivated a deep mechanistic investigation in mice.

Using whole-body Gpr146 knockout mice fed a high-fat diet (HFD), the researchers observed markedly reduced hepatic triglyceride content, lower plasma ALT, and protection from diet-induced obesity in both sexes. Untargeted lipidomics confirmed broad reductions in hepatic mono-, di-, and triacylglycerols as well as free fatty acids. Transcriptomic analysis via GSEA showed that knockout livers had suppressed fatty acid metabolism, oxidative phosphorylation, and inflammatory gene sets. Importantly, AAV8-mediated acute knockdown of GPR146 in adult mice recapitulated these protective effects, ruling out developmental compensation.

Tissue-specific knockouts were decisive: adipose-specific deletion (Adiponectin-Cre) phenocopied the whole-body knockout — reducing body weight, adiposity, circulating free fatty acids, and hepatic steatosis — while liver-specific deletion had no significant effect on these parameters. This demonstrated that the hepatoprotective benefit originates entirely from adipose tissue GPR146. Mechanistically, in preadipocytes GPR146 couples to Gαq to activate PKC and downstream AKT, enhancing differentiation and lipid storage capacity. In fully differentiated adipocytes, GPR146 promotes lipolysis via ERK signaling, increasing free fatty acid release. Together these two complementary actions expand adipose lipid turnover and elevate the circulating FFA pool delivered to the liver for triglyceride synthesis.

Energy expenditure was elevated in both sexes of knockout mice, with female knockouts showing pronounced UCP1-mediated thermogenesis in brown and beige adipose tissue, while the male mechanism remained less clearly defined. The findings collectively establish GPR146 as a pleiotropic regulator of adipose biology — governing both adipogenesis and lipolysis — and as an upstream driver of hepatic steatosis through inter-organ lipid flux rather than direct hepatic action.