Gut hormone FGF15 changes how mice respond to weight loss

Nearly 40% of the population in the United States develop obesity, which is linked to the development of several diseases, including type 2 diabetes and metabolic liver disease.

The rise in obesity is, in part, caused by high-calorie diets and sedentary habits.

Previous studies have shown that diet, bariatric surgery and therapeutic drugs such as GLP-1 receptor agonists, or GLP-1 RA can help reduce body weight in humans and mouse models of obesity.

The rapid weight loss, however, is also accompanied by a loss of lean mass, which includes skeletal muscle.

Preserving lean mass may help lower the risk of regaining weight by reducing how the body adjusts to energy expenditure and helping maintain physical function during and after obesity treatment.

In a new study published in Diabetes, University of Michigan researchers found that a gut hormone known as fibroblast growth factor 15, or FGF15, is essential for preserving lean mass during diet-induced weight loss.

SEE ALSO: Expert Q&A: Michigan Medicaid’s new limits on GLP-1 weight management medications

Their results suggest that effective weight-loss strategies need to be tailored to each patient.

FGF15 in mice and FGF19 in humans is produced in the small intestine and acts on the liver to control the amount of bile acids produced. These acids affect how the body absorbs lipids.

Previously, the same group had shown that FGF15 protects against lean mass loss after sleeve gastrectomy in mice, a bariatric surgery procedure.

They also found that baseline levels of FGF19 in humans can help predict how much lean mass they will lose after a very-low-energy diet.

“We were interested in understanding whether the levels of FGF15/19 could broadly predict weight loss outcomes,” said Nadejda Bozadjieva-Kramer, Assistant Professor of Surgery and member of Caswell Diabetes Institute.

FGF15 influences how diet and GLP-1RA affect lean mass

In the current study, the researchers studied the role of FGF15 after mice underwent rapid weight loss.

In the first group of mice, the control and mice deficient in FGF15 were fed a high-fat diet for 22 weeks and were switched a regular chow diet.

Mice lacking FGF15 had a greater loss of lean mass than the control.

In the second group, both the controls and the mice lacking FGF15 were given semaglutide, a GLP-1RA, while they remained on a high-fat diet for about four weeks.

Semaglutide treatment reduced lean mass, body weight and fat, regardless of whether the mice had FGF15.

While controlling the diet was more effective in liver fat and overall weight, semaglutide improved glucose tolerance, which is a measure of how well the body maintains healthy blood sugar levels.

“Weight loss is not a one-size-fits-all approach, and the specific treatment approach matters,” Bozadjieva-Kramer said.

“It involves complex communication between the gut and liver, and understanding weight loss can help us tailor specific weight loss interventions for our patients.”

The researchers acknowledge that clinical weight loss is most effective when GLP-1Ras are combined with diet and exercise, which was not investigated in the study.

They are working to combine dietary and pharmacological strategies to maximize metabolic benefits, such as improved glucose tolerance, while minimizing side effects like loss of lean mass.

Additional authors: Garrett McMahon, Ziru Li, Jordan Wean, Jae Hoon Shin, Andriy Myronovych, Robert W. O’Rourke, Ormond A. MacDougald and Randy J. Seeley.

Funding/disclosures: This research was supported by the Department of Veterans Affairs grants IK2BX005715 and I01CX001811. This study was supported by National Institutes of Health–funded Michigan Nutrition Obesity Research Center grant P30DK089503; Michigan Institute for Clinical and Health Research grant UL1TR002240 and NIH awards R01DK133140, R01DK137798 and R01DK125513, R25DK141426 and P20GM121301.

Tech transfer(s)/Conflict(s) of interest: Seeley has received research support from Fractyl, AstraZeneca, Congruence Therapeutics, Eli Lilly, Diasome, and Amgen; has been a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Crinetics, Amgen, Helicore, Gallant, General Medicines, AbbVie, Protagonist Therapeutics, Aardvark, Zealand, and Nuanced Health and has equity in Nuanced Health, Coronation Bio, Eccogene, Fractyl, and Rewind. MacDougald has received grant support from Regeneron, Dicerna, CombiGene AB, and Rejuvenate Bio. Shin is a paid employee of Amgen.

Paper cited: “Gut-Derived FGF15 Modulates Lean Mass, Bone, and Bile Acid Responses to Weight Loss,” Diabetes. DOI: 10.2337/db25-0466

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