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Abstract

Glucagon-like peptide-1 (GLP-1) is an endogenously produced incretin hormone that influences glucose regulation and satiety by acting upon GLP-1 receptors (GLP-1r) throughout the body. While semaglutide, a weekly injectable GLP-1r agonist medication, was originally developed for the treatment of type 2 diabetes, it was also found to cause robust weight loss. Clinical trials have demonstrated body weight loss of ~15% in adults with obesity, alongside losses of both fat and lean mass. Skeletal muscle constitutes ~50% of lean mass, contributes to ~25% resting energy expenditure, and is the primary sink for insulin mediated glucose disposal. Given the importance of skeletal muscle to overall health, the loss of this tissue could have unintended negative consequences. Increasingly younger individuals are being prescribed semaglutide and given that adolescence is a critical period of musculoskeletal development, it is important to determine the impact of GLP1r agonists on muscle and bone health in this age group. The aim of my thesis was to investigate the effects of semaglutide on visceral, muscular, and skeletal tissues in adolescent mice. I hypothesized that semaglutide would attenuate weight gain and cause reductions in mass and function for skeletal muscle and bone in adolescent mice with obesity. Adolescent male and female C57BL6/J mice (n=~20 per group) were weaned at 4 weeks old and placed on a high fat diet for ~4 weeks (HFD, 60% fat, 20% carbohydrate, 20% protein), then assigned to sex and weight-matched groups: 1) HFD, 2) HFD + Semaglutide. Mice were subcutaneously injected daily, for 3 weeks, at the start of dark phase with 10nmol/kg vehicle or semaglutide, with food intake and body weight measured daily. During the final week of treatment, an oral glucose tolerance test, metabolic caging, in vivo body composition analysis, grip strength testing, and tissue collection occurred. Visceral and subcutaneous fat were reduced with semaglutide treatment. There were no significant reductions in lean mass or most skeletal muscles, however grip strength was reduced as was femur weight and strength. Our results suggest that semaglutide, while preventing weight gain, has deleterious effects on skeletal muscle function and bone mass and function in adolescent mice fed a HFD.