Semaglutide Exacerbates Stunting in Growth-Impaired Juvenile Male Mice via Reduced Energy Metabolism

Animals rely on linear growth to attain their full adult size. The regulators of this multifactorial process, including environmental and endocrine cues, are still incompletely understood. Notably, GLP-1, glucagon-like peptide 1 (GLP-1) has emerged as a potential player in this process. Here, we employ semaglutide, a pharmaceutical GLP-1R agonist as a tool to mechanistically dissect the interplay between GLP-1 receptor activation, energy metabolism, and linear growth during the juvenile period, independent of its clinical applications. Using a juvenile mouse model, we show that chronic semaglutide treatment lowers blood glucose without affecting food intake or weight gain in juveniles with a normal growth pattern. However, in growth-stunted juveniles, semaglutide treatment exacerbates linear growth impairment through at least 2 concomitant mechanisms: a moderate reduction in food intake, and a decreased catabolic activity incompatible with tissue growth. These data suggest a complex interplay between GLP-1 signaling, energy metabolism, and growth during juvenile development. Overall, these findings highlight the value of semaglutide as a mechanistic tool for understanding how GLP-1 receptor activation modulates growth and metabolism in juveniles, emphasizing the importance of developmental context for interpreting its effects. Overall design: To investigate the effect of semaglutide treatment on undernourished juveniles males, we analyzed the liver of those mice at 8 weeks (after a 5 weeks dietary challenge with low-protein diet, 5% in kcal). Bulk RNA sequencing was performed after RNA isolation from the tissue. We used vehicle-treated animals as the reference (5 mice), and semaglutide-treated animal as the experimental condition (5 mice).