Semaglutide mitigates the loss of fat-free mass and decreased energy expenditure observed after diet restriction. Insights from an obese minipig model

Feb 11, 2026American journal of physiology. Endocrinology and metabolism

Semaglutide reduces muscle loss and lowers energy drop after dieting in obese minipigs

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Abstract

Diet-restricted minipigs gained 6.8% more body fat compared to those treated with semaglutide.

Semaglutide treatment resulted in a greater preservation of fat-free mass compared to diet restriction.
Diet-restricted minipigs exhibited a significant decrease in energy expenditure of -273 kcal/day compared to the control group.
No differences in energy expenditure were found between treatment groups when accounting for changes in body composition.
Energy balance modeling indicated significant metabolic adaptation in diet-restricted minipigs compared to both control and semaglutide groups.
Diet restriction was linked to decreased proton leak and reduced resting myosin ATP consumption in muscle tissue.

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OBJECTIVE: To compare the effects of diet restriction and semaglutide treatment on body composition (BC), energy expenditure (EE), and metabolic adaptation (MA) in Göttingen Minipigs as a model for human obesity.

METHODS: Diet-induced obese Göttingen Minipigs were divided into three groups (n=8): a control group receiving vehicle and fed, a group treated with the GLP-1 receptor agonist (GLP-1RA) semaglutide and fed, and a diet-restricted group receiving vehicle and weight-matched the semaglutide group. BC, EE, and plasma parameters were measured at baseline and after 10 weeks; tissue mitochondrial respiration and myosin conformation were measured after 10 weeks. ad libitum ad libitum

RESULTS: Diet-restricted minipigs gained 6.8 % (p<0.01) more body fat compared to semaglutide, mediated by a greater loss of fat-free mass (4.3 kg, p<0.05) and a tendency for a higher fat mass gain (p=ns). Diet restriction led to significantly decreased EE compared to the control group (-273 kcal/day, p<0.05), but no differences between groups were observed when adjusting EE for changes in BC. Energy balance modeling revealed significant MA in the diet-restricted animals (p<0.01) compared to both control and semaglutide groups. Diet restriction was further associated with decreased proton leak and resting myosin ATP consumption in muscle.

CONCLUSIONS: Semaglutide treatment improved BC and EE outcomes compared to diet restriction despite similar weight trajectories. Furthermore, semaglutide treatment prevented specific energy-conserving changes in tissues, thus highlighting novel mechanisms regulating energy balance during GLP-1RA treatment.

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Semaglutide mitigates the loss of fat-free mass and decreased energy expenditure observed after diet restriction. Insights from an obese minipig model

Abstract

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