Semaglutide and exercise synergy in obesity: preserving muscle mass and uncovering organ crosstalk

Background and aims: The glucagon-like peptide-1 receptor agonist semaglutide is an antidiabetic medication that has recently been approved for treatment of obesity as well. While its efficacy on weight management is well established, associated concomitant loss of muscle mass can be a potential drawback. In this study, we investigated whether combining semaglutide with exercise could enhance its metabolic effects while mitigating muscle loss. Method: Ldlr−/−.Leiden mice were fed a high fat diet (HFD) for 20 weeks to induce obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. Mice were subsequently left untreated (control) or treated for 14 weeks with semaglutide, exercise (running wheel) or the combination thereof. Histological examination and comprehensive transcriptome analyses were conducted on white adipose tissue, muscle, liver and heart to explore underlying mechanisms. Results: Semaglutide significantly reduced fat mass (-31%) but also lean mass (-11%). Combining semaglutide with exercise further reduced fat mass (-45%) and lean mass as well but to a lesser extent (-8%). Semaglutide alone or combined with exercise significantly improved insulin sensitivity, plasma cholesterol and triglycerides. The combination of semaglutide with exercise improved , adipose tissue inflammation, liver steatosis, liver inflammation and atherosclerotic lesion area. With regard to muscle parameters, combination treatment significantly improved grip strength and diameter of gastrocnemius myocytes, while these parameters were not affected by either treatment alone. Pathway analysis revealed complementary effects of semaglutide and exercise on metabolic, inflammatory and a variety of other pathways, thereby substantiating the added value of combining semaglutide with exercise. Conclusion: Semaglutide has broad beneficial effects on circulating risk factors of metabolic syndrome, liver, vascular and adipose parameters but decreases lean mass and muscle strength. By combining semaglutide intervention with exercise, these parameters are further improved with a partial preservation of lean mass and muscle function.