Females are protected from semaglutide-induced muscle loss in <i>ob/ob</i> mice.

Obesity is a major contributor to cardiometabolic disease, and pharmacological therapies such as semaglutide are increasingly used to induce weight loss. However, the commonly used diet-induced obesity model in C57BL/6J mice is limited by relative resistance to weight gain in females, complicating the study of sex-specific effects. Here, we used leptin-deficient mice, which develop severe early-onset obesity in both sexes, to investigate sex-specific responses to semaglutide on skeletal muscle mass, function, and mitochondrial metabolism. The mice were treated daily with semaglutide or vehicle for three weeks, followed by assessments of body composition, muscle and organ mass, muscle contractile function, and mitochondrial efficiency. Semaglutide induced comparable reductions in body weight and food intake in both sexes but elicited distinct sex-specific changes in body composition. Male mice exhibited losses in both skeletal muscle and organ mass, whereas female mice preferentially lost fat and organ mass while preserving skeletal muscle. Despite these divergent structural adaptations, muscle force generation remained intact in both sexes. Collectively, these findings reveal pronounced sexual dimorphism in skeletal muscle and metabolic remodeling during pharmacologically induced weight loss, highlighting the importance of considering biological sex when evaluating the metabolic and therapeutic effects of anti-obesity interventions.