Incretin Receptors in the Peripheral Nervous System: Implications for Obesity Treatment and Peripheral Neuropathy

There is currently a revolution in the pharmacologic treatment of obesity and diabetes with newly available agonists of incretin receptors. The health benefits of these novel treatments include not only metabolic effects but also improvements in brain neurodegenerative conditions. Receptors for incretins have been described in the hypothalamic appetite regulatory center; however, their expression in the peripheral nervous system (PNS) has been largely overlooked, despite likely contributing important effects. For example, the PNS is essential for the control of numerous metabolically relevant pathways in tissues such as liver, adipose, intestine, and muscle, and incretin receptors are found on nerves innervating some, if not all, of these metabolically important tissues. In this article, we summarize the knowledge to date regarding incretin receptors and incretin drug actions in the PNS, as well as PNS control over incretin release, and the related implications for metabolic disease states that are accompanied by peripheral neuropathy. Article Highlights The peripheral nervous system controls gut glucagon-like peptide 1 (GLP-1) release through enteric and sympathetic neurons. Sensory, motor, and enteric neurons express GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, and vagal neurons express the GLP-1 receptor only. GLP-1 and GIP receptors are expressed in both murine and human adipose tissue nerves and Schwann cells. Available data indicate incretin drugs are a promising novel treatment for peripheral nerve diseases. The differential pharmacodynamic properties of incretin drugs should be explored further in the prevention and treatment of metabolic disease–associated peripheral nerve degeneration.