According to the World Obesity Federation, the prevalence of patients who are overweight or obese has tripled since the 1970s, currently affecting almost 3 billion people worldwide. After decades of unsuccessful attempts of designing safe and effective anti-obesity medications (AOM), the discovery of incretin-based therapies has revolutionized the battle against obesity. For example, the GLP-1 receptor agonist (GLP-1RA) semaglutide caused 15% weight loss compared to baseline after 68 weeks of treatment in patients without diabetes (1). However, in a subpopulation of this study investigated for changes in body composition, it was found that almost 40% of this weight loss was due to a decrease in lean body mass (LBM) (1). Traditionally, the loss of LBM during physiological interventions such as calorie restriction is estimated to be ~25% (2). With a rapidly increasing number of patients relying on these AOM, this spurred a concern for the effect of incretin-based therapies on muscle mass and function, ultimately impacting the prevalence of sarcopenia and sarcopenic obesity (3). To test whether incretin-based therapies affect skeletal muscle pre-clinically, we performed a 2-week trial in mice with diet-induced-obesity (DIO). Changes in body composition, muscle mass, muscle fiber size, and grip strength were compared between groups that received GLP1-RA, long-acting glucagon receptor agonist (LA-GCGRA), a triple agonist (GLP-1RA/GiPRA/GCGRA), no treatment (vehicle), or calorie reduction. Each of the pharmacological treatments was subdivided into a low and a high dose. We found that, both, pharmacological and physiological interventions caused significant reductions in body weight, fat, and LBM. However, muscle mass and grip strength were barely affected by the loss of LBM. In contrast, we saw robust decreases in liver mass and intra-hepatic fat. To further assess the effect of incretin-based therapies on muscle function, we performed a separate experiment, where we treated DIO mice for 4-weeks with a triple agonist and tested running performance. We found that the mice with the largest loss of body weight and LBM registered the best running performance. Our data in mice is in line with surveys from patients with obesity, who reported improved mobility and physical function despite a decrease in LBM with semaglutide (1). As such, we conclude that incretin-based therapies not just effectively cause weight loss but also appear to favorably affect body composition without disproportionately compromising muscle mass. A decrease in LBM and muscle is offset by an even larger decrease in fat mass, resulting in an improved ratio of muscle mass and function to body weight. Nevertheless, our pre-clinical data needs to be confirmed in patients with obesity. In addition, future research will need to address the effect of repeated weight loss and -regain with AOM and after AOM cessation as well as how this impacts the prevalence of sarcopenia and sarcopenic obesity.