Physiological genomicsAug 24, 2026

How sex and endurance exercise affect hormone signaling that controls insulin in 17 rat tissues

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 25, 2026

Abstract

Endurance training led to sex- and tissue-specific changes in incretin receptor expression across multiple organs.

Incretin-based therapies, especially GLP-1 receptor agonists, have shown benefits in type 2 diabetes treatment and organ health.
The precise mechanisms of organ health improvements due to these therapies remain uncertain, particularly regarding receptor signaling versus glycemic control.
Data from Fischer 344 rats and the GTEx Portal were used to assess incretin receptor expression in 17 tissues.
Treadmill exercise training for 1 to 8 weeks resulted in the downregulation of Gcgr in brown adipose, adrenal glands, and white adipose tissues.
Regulation of Gipr was observed in the adrenal glands, brain cortex, and hippocampus following endurance training.
These findings enhance understanding of incretin receptor biology and highlight potential interactions between exercise and incretin therapies.

Simplified

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.

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How sex and endurance exercise affect hormone signaling that controls insulin in 17 rat tissues

Abstract

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