Gut-Derived FGF15 Modulates Lean Mass, Bone, and Bile Acid Responses to Weight Loss

We evaluated the role of intestinal fibroblast growth factor 15 (FGF15) in regulating lean mass, glucose tolerance, bile acid, and lipid profiles after diet- compared with semaglutide-induced weight loss in mice. Mice lacking FGF15 lost more lean mass during dietary intervention, whereas semaglutide decreased lean mass irrespective of FGF15; dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance and elevated cecal bile acid levels were observed with semaglutide; and loss of FGF15 altered bile acid levels, whereas semaglutide treatment further regulated these levels in both genotypes, with particularly pronounced changes observed in the absence of FGF15. Weight-loss intervention strategy and dietary context modulate gut-liver and muscle communication and preservation of lean mass.