Semaglutide-Induced Weight Loss and Skeletal Muscle Mitochondrial Energy Efficiency

A recent emergence of glucagon like peptide-1 receptor (GLP-1R) agonists and other drugs made successful weight loss a reality and transformed the obesity-related healthcare. It has been postulated that weight loss from an overweight state is associated with an increase in skeletal muscle work efficiency, promoting reduced resting and exercise-induced energy expenditure and potentially contributing to weight regain. In the last five years, we have been studying the influence of weight loss on skeletal muscle mitochondrial efficiency.

During the COVID-19 pandemic when we were asked to reduce our mouse colonies and have animal facility staff do the majority of cage maintenance, one of our PhD students proposed to do a simple dietary-induced weight loss study that were still feasible for us to perform. In this study (Ferrara et al., Life Metab, 2023), we found that weight loss induced by a dietary intervention improves the energy efficiency of skeletal muscle ATP synthesis in mice, suggesting that muscle was capable of producing ~50% more ATP with same oxygen consumption. We now have preliminary data that this also happens with semaglutide-induced weight loss in mice (Choi et al., Obesity, 2025, Karasawa et al., Cell Metabolism, 2025). With an anticipated significant impact on these studies, we have rapidly pivoted to expand this line of work where we implicate a novel futile cycle through actions of both electron and proton leak. We also have an ongoing observational clinical study where we are studying skeletal muscle mitochondrial energy efficiency and submaximal exercise work efficiency, measured on patients pre- and 6 months-post weight loss drug prescription.