The GLP-1 Receptor Agonist Dulaglutide Attenuates Hepatic Steatosis in Obesity via a Weight-Independent Mechanism

Recent clinical trials testing glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated improved outcomes in obesity-associated complications, including cardiovascular events and hepatic steatosis. Despite their positive effects, whether the benefits of GLP-1 RAs are due to weight loss or are a direct therapeutic effect remains unclear. Therefore, we pair fed middle-aged low-density lipoprotein receptor knockout (Ldlr−/−) mice a western high-fat diet to model complex atherosclerosis and metabolic dysfunction–associated fatty liver disease (MAFLD) and then administered dulaglutide or placebo twice a week for 6 weeks. Older compared with younger Ldlr−/− mice develop accelerated atherosclerosis resembling human lesions, and advanced MAFLD. Dulaglutide improved glucose tolerance and MAFLD independent of weight but had no effects on insulin sensitivity or atherosclerosis compared with weight-matched placebo-treated mice. The diminished hepatic steatosis was attributed to both decreased de novo lipogenesis and reduced adipose tissue lipolysis. These changes were associated with amelioration of inflammation and oxidative stress with a marked attenuation in M1-like macrophages in the liver. Therefore, dulaglutide has therapeutic effects on the liver that may further synergize with GLP-1 RA–mediated weight loss to reduce hepatic steatosis and inflammation, a major complication of obesity. ARTICLE HIGHLIGHTS Glucagon-like peptide-1 receptor agonists are promising therapies in treating various obesity-associated diseases; however, the mechanisms are convoluted with the benefits of weight loss. Dulaglutide has weight-independent therapeutic effects on the liver, reducing hepatic steatosis and improving liver function. Dulaglutide reduces de novo lipogenesis, lipid droplet stability, inflammation, and oxidative stress in the liver and lipolysis in adipose tissue. Weight loss may play an important role in glucagon-like peptide-1 receptor agonists’ effect on decreasing coronary vascular disease risk.