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

Area of Science:

• Endocrinology and Metabolism
• Gastroenterology
• Nutritional Science

Background:

• Rapid weight loss via diet, surgery, or medication can lead to lean mass reduction.
• Intestinal fibroblast growth factor 15 (FGF15) is implicated in lean mass preservation.
• Circulating FGF19 (human ortholog of FGF15) predicts lean mass retention in humans on very-low-energy diets.

Purpose of the Study:

• To investigate the role of intestine-derived FGF15 in regulating lean and bone mass, glucose tolerance, and bile acid/lipid profiles during weight loss.
• To compare the effects of dietary intervention versus semaglutide treatment on these parameters in mice with and without FGF15.
• To understand how intervention strategy and dietary context influence gut-liver and muscle communication.

Main Methods:

• Induction of rapid weight loss in intestine-specific FGF15-knockout and control mice using either dietary change (high-fat to standard chow) or daily semaglutide administration.
• Assessment of body weight, fat mass, lean mass, bone mass, glucose tolerance, hepatic triglycerides, and bile acid profiles.
• Comparative analysis between dietary and pharmacological weight loss interventions in the presence or absence of FGF15.

Main Results:

• Semaglutide reduced body weight, fat mass, and lean mass, with lean mass returning to baseline post-treatment; FGF15 did not affect semaglutide's impact on lean mass.
• Mice lacking FGF15 did not preserve lean mass during dietary intervention, unlike controls.
• Dietary intervention was more effective at reducing hepatic triglycerides, while semaglutide improved glucose tolerance and altered bile acid profiles, with more pronounced effects in FGF15-deficient mice.

Conclusions:

• Intestine-derived FGF15 is essential for lean mass preservation during dietary weight loss but not semaglutide-induced weight loss.
• Weight loss intervention strategy and dietary context significantly modulate gut-liver and muscle communication.
• FGF15 plays a role in regulating bile acid metabolism, which is further influenced by semaglutide treatment.