The effect of sex and endurance exercise training on the incretin signaling pathway in 17 rat tissues

Incretin-based pharmacotherapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists, have transformed the treatment of type 2 diabetes, with demonstrated benefits across multiple organ systems. Their success has driven investigation of related gut-derived hormones, most prominently dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, but extend to other targets with similar metabolic functions. For this class of drugs, the extent to which organ health improvements are secondary to improved systemic glycemic control versus direct tissue signaling remains unclear, partly because receptor availability across tissues is poorly annotated. We leveraged data from the Molecular Transducers of Physical Activity Consortium to annotate incretin receptor expression across 17 tissues in Fischer 344 rats and the Genotype-Tissue Expression (GTEx) Portal for human-level receptor expression. Further, given the role of exercise in the preservation of muscle mass during weight loss, we analyzed the effects of 1, 2, 4, or 8 weeks of treadmill exercise training on incretin-related signaling at the epigenetic, transcript and protein levels. Endurance training elicited sex- and tissue-specific changes in incretin receptor expression, including downregulation of Gcgr across brown adipose, adrenal glands, and white adipose tissues. Training-induced Gipr regulation occurred in the adrenal glands, brain cortex, and hippocampus. Collectively, these findings contribute to the map of incretin receptor biology and identify exercise-responsive regulatory axes that may underlie synergistic effects of exercise and incretin-based therapies on weight management and metabolic health.