Pharmacological inhibition of G protein-coupled receptor kinase 5 decreases high-fat diet-induced hepatic steatosis in mice.

G protein-coupled receptor kinase 5 (GRK5) is implicated in the pathogenesis of obesity in both humans and rodent models. Our previous work demonstrated that genetic deletion or pharmacological inhibition of GRK5 suppresses 3T3-L1 adipocyte differentiation. Here, we assessed the small-molecule GRK5 inhibitor, GRK5-IN-2, for its effects on metabolic tissues and therapeutic potential in a mouse model of diet-induced obesity. Mice were fed a high-fat diet for 8 weeks to induce obesity, followed by continued a high-fat diet with oral administration of GRK5-IN-2 (25 or 50 mg/kg) or water vehicle, five days per week for an additional 16 weeks. GRK5-IN-2 treatment had no effect on body weight, fat/lean mass, insulin tolerance, food intake, or energy expenditure but significantly reduced hepatic triglyceride accumulation and de novo lipogenesis. A follow-up study using 25 mg/kg of GRK5-IN-2 confirmed that the treatment did not alter adiposity but significantly reduced hepatic triglyceride levels. This effect was associated with decreased expression of the lipogenic gene Acc2, alongside increased expression of Tfam, a key regulator of mitochondrial biogenesis, and the lipid utilization proteins COXIV and ACSL1 in the liver, suggesting enhanced mitochondrial function and fatty acid oxidation as potential mechanisms. Together, these findings suggest that GRK5 inhibition selectively modulates hepatic lipid metabolism without altering systemic metabolic parameters, highlighting GRK5 as a potential therapeutic target for fatty liver disease.