Introduction and Objective: Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, the physiologic role of incretin hormones in controlling appetite and how incretin-mimetic drugs suppress caloric intake remain unclear.Methods: Hunger-promoting AgRP-expressing hypothalamic neurons are important in regulating food intake. Therefore, we asked how incretins affected their activity in vivo using fiber photometry.Results: Using a pharmacologic approach to block GIP or GLP-1 receptors, we found that GIP but not GLP-1 attenuated AgRP neural responses to nutrients. By contrast, pharmacologic activation of either the GIP receptor (GIPR) or the GLP-1 receptor (GLP-1R) inhibits AgRP neurons. The effects of the two hormones are additive, suggesting distinct mechanisms underlying AgRP neural inhibition by GIPR versus GLP-1R agonists. Finally, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, indicating that the full appetite-suppressing effects of incretin-based therapeutics depend on AgRP neuron inhibition.Conclusion: Together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies, which is crucial for developing next-generation obesity therapies with an improved therapeutic profile.
J. Xia: None.
American Diabetes Association (12-22-ACE-31); National Institutes of Health (P30-DK0205950, K08-DK118,188, R01-DK128477)
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