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

Dietary, surgical, and pharmacological methods can effectively reduce body weight; however, rapid weight loss can also be accompanied by a loss of lean mass. Previously, we found that intestinal fibroblast growth factor 15 (FGF15; mouse ortholog of human FGF19) protects against lean mass loss after sleeve gastrectomy in mice and that circulating FGF19 predicts lean mass retention after very-low-energy diets in humans. We investigated the regulatory functions of intestine-derived FGF15 in lean and bone mass, glucose tolerance, and changes in bile acid and lipid parameters after weight loss in mice. Rapid weight loss was induced either by transitioning high-fat diet-fed intestine-specific FGF15-knockout and control mice to standard chow for 25 days or by administering daily semaglutide. Semaglutide decreased body weight, fat mass, and lean mass, all of which returned to baseline levels after treatment cessation. Lean mass was not preserved during dietary intervention in mice lacking FGF15, whereas semaglutide decreased lean mass irrespective of FGF15. Dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance was observed with semaglutide. Semaglutide modulated shifts in bile acid composition, with particularly pronounced changes seen in the absence of FGF15. These data indicate that multiple factors, including intervention strategy and dietary context, modulate gut-liver and muscle communication and preservation of lean mass. ARTICLE HIGHLIGHTS: We evaluated the role of intestinal fibroblast growth factor 15 (FGF15) in regulating lean mass, glucose tolerance, bile acid, and lipid profiles after diet-induced 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.