Semaglutide and Exercise Synergy in Obesity: Preserving Muscle Mass and Uncovering Organ Crosstalk.

BACKGROUND

Semaglutide, a glucagon-like peptide-1 receptor agonist, effectively promotes weight loss and improves metabolic parameters in individuals with obesity. However, its use is often accompanied by reductions in lean mass, raising concerns about long-term muscle health. This study explored whether combining semaglutide with exercise could preserve muscle mass and enhance metabolic outcomes.

METHODS

Ldlr-/-.Leiden mice with diet-induced obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis and atherosclerosis were either left untreated (control) or treated with semaglutide, exercise or the combination for 14 weeks. Histological and transcriptomic analyses were conducted on 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 with exercise improved insulin sensitivity and plasma lipids. The combination improved adipose tissue inflammation, liver steatosis, liver inflammation and atherosclerotic lesion area. Only combination treatment significantly improved grip strength and diameter of gastrocnemius myofibers. Multi-organ histological and transcriptomic analyses revealed organ-specific and synergistic effects of combination therapy, including activation of pathways involved in mitochondrial function, glucose metabolism, and inflammation resolution.

CONCLUSION

Semaglutide improves metabolic, liver, vascular and adipose parameters but reduces lean mass and muscle strength. Combining semaglutide intervention with exercise enhances these benefits with partial preservation of muscle mass and function and activation of distinct molecular pathways not engaged by either monotreatment, thereby underscoring the potential of integrating lifestyle interventions with pharmacological treatment.