O037 - WEIGHT LOSS-INDEPENDENT EFFECTS OF GLP-1 MEDICINES ON LIVER, MUSCLE AND HEART

O037

WEIGHT LOSS-INDEPENDENT EFFECTS OF GLP-1 MEDICINES ON LIVER, MUSCLE AND HEART

H. Langer^1,*, A. Joshi¹, N. Haritonow², K. Norman¹, U. Müller-Werdan³, A. Roos⁴, A. Hentschel⁵, N. Gilmore⁶, C. Hayden⁶, K. Baar⁶

¹Geriatrics and Medical Gerontology, Charité, Berlin, Germany, ²Geriatrics and Medical Gerontology, Charité, Davis, United States, ³Geriatrics and Medical Gerontology, Charité, Davis, Germany, ⁴Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Universität Essen, Essen, United States, ⁵Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany, ⁶Neurobiology, Physiology and Behavior, University of California Davis, Davis, United States

Rationale: GLP-1 medicines are powerful weight loss drugs with proven benefits for cardiometabolic diseases. However, their tissue-specific effects are relatively poorly understood.

Methods: We investigated the effect of GLP-1 medicines across various models, with a focus on how they affect protein turnover and substrate metabolism in a tissue-specific matter in liver, skeletal muscle and the heart. We treated muscle cells with semaglutide to measure phosphorylation of key proteins and muscle protein synthesis. We corroborated these results through in vivo studies in mice with diet-induced obesity (DIO). In the same studies, we also collected the liver to examine substrate concentration levels and performed proteomics. Finally, we treated human iPSC-derived cardiomyocytes with semaglutide to look at heart-specific effects on protein turnover.

Results: Effects of GLP-1 medicines on skeletal muscle in vitro and in vivo were relatively modest. Compared to physiological weight loss, muscle mass did not seem further reduced. However, we did find an increase in mitochondrial proteins and protein remodeling. In the liver, we found similar reductions in mass between GLP-1 medicines and calorie-restriction but a distinct proteome. Additionally, we found diverse substrate preferences between and a relative preservation of triglycerides (TG) with regular calorie-restriction but a robust decrease in glycogen, while semaglutide decreased liver TG but maintained glycogen levels. In heart cells, we found that GLP-1 medicines decreased protein synthesis and anabolic signaling.

Conclusion: In conclusion, despite similar changes in body weight compared to regular calorie-restriction, GLP-1 medicines exert tissue-specific effects on the liver, skeletal muscle and the heart.

References: 1. Langer HT et al., Weight loss with GLP-1 medicines does not result in a disproportionate loss of muscle mass or function in obese mice and humans. Cell Reports Medicine 2026.

Disclosure of Interest: H. Langer Consultant for: Almac Discovery, Alchemab Therapeutics, Actimed Therapeutics, A. Joshi: None declared, N. Haritonow: None declared, K. Norman: None declared, U. Müller-Werdan: None declared, A. Roos: None declared, A. Hentschel: None declared, N. Gilmore: None declared, C. Hayden: None declared, K. Baar Consultant for: SinewUS, PepsiCo, Ynsect, Advanced Muscle Technologies, GelTor, Evergrain, and Digestiva