Semaglutide with exercise preserves muscle mass, enhances metabolic benefits in obese mice

While obesity treatments like semaglutide, a GLP-1R agonist, effectively reduce weight and improve metabolic markers, they often lead to undesirable lean mass loss. This reduction in muscle mass can compromise long-term health, mobility, and metabolic regulation. Understanding how to mitigate this side effect while maximizing therapeutic benefits is crucial for optimizing obesity management strategies. This study investigates whether concurrent exercise can counteract semaglutide-induced muscle loss and enhance overall metabolic outcomes.

Researchers utilized Ldlr-/-.Leiden mice with diet-induced obesity, insulin resistance, metabolic dysfunction-associated steatohepatitis, and atherosclerosis. Mice were divided into four groups: untreated control, semaglutide treatment, exercise, or a combination of semaglutide and exercise for 14 weeks. The study assessed changes in fat mass, lean mass, insulin sensitivity, plasma lipids, and grip strength. Multi-organ histological and transcriptomic analyses were performed on adipose tissue, muscle, liver, and heart to elucidate underlying mechanisms.

Semaglutide monotherapy significantly reduced fat mass by -31% but also decreased lean mass by -11%. The combination of semaglutide with exercise further reduced fat mass by -45% and attenuated lean mass loss to -8%. Both semaglutide alone and the combination improved insulin sensitivity and plasma lipids. The combined treatment demonstrated superior benefits, improving adipose tissue inflammation, liver steatosis, liver inflammation, and atherosclerotic lesion area. Importantly, only the combination treatment significantly improved grip strength and the diameter of gastrocnemius myofibers.

Multi-organ histological and transcriptomic analyses revealed synergistic effects of combination therapy, activating pathways involved in mitochondrial function, glucose metabolism, and inflammation resolution not engaged by either monotherapy.