Jessica Zhang
Research Mentor: Martin Myers Jr
Mentor Department: Not Available, Medicine
Author(s): Iris Wu, Jessica Zhang
Session: Session 7 (4:00 PM – 4:50 PM)
Presentation Type: Poster 23
Abstract
Obesity represents a public health crisis in America, driving complications such as type 2 diabetes. Fortunately, new weight loss medications, such as glucagon-like peptide 1 receptor agonists (GLP1RAs) can treat obesity for many people. In the brainstem dorsal vagal complex (DVC), the area postrema (AP) senses many neuronal and circulating signals related to gut status and plays a key role in regulating energy balance. GLP1RAs also act via AP Glp1r-expressing neurons (Glp1rAP) to suppress food intake and promote weight loss. However, activation of Glp1rAP neurons promotes gut malaise-associated aversive side effects including nausea and vomiting, which limits the tolerability of GLP1RA drugs. Glucose-dependent insulinotropic peptide and its receptor (GIP; GIPR) have emerged as another therapeutic target. GIPR agonists enhance GLP1RA-mediated weight loss and can acutely blunt GLP1RA-induced malaises. Paradoxically, GIPR antagonists also promote weight loss and enhance GLP1RA efficacy. Recent studies demonstrate that GiprAP neurons innervate and inhibit Glp1rAP neurons, suggesting roles for GiprAP neurons in modulating GLP1RA effects. While previous data from our lab showed that acutely activated GiprAP cells inhibit the appetite-suppressing and aversive responses of GLP1RA, we hypothesize that chronic activation of GiprAP neurons downregulates GIPR signaling to enhance the appetite-suppressing effects of GLP-1R agonists. Using FOS detection as an assay of neuronal activation, we found that while acute GIPR agonists activate GiprAP neurons, this effect is lost with long-term GIPR agonism. To further investigate GiprAP neurons, we generated a GiprCre knock-in rat line and delivered Cre-inducible activating designer receptors exclusively activated by designer drug (DREADD) into the AP to precisely activate GiprAP neurons. Our data showed that?? long-term GiprAP activation did not produce further food suppression, and chronically blunts GLP1RA-induced weight loss in obese animals. Future studies will determine the roles of GiprAP neurons in controlling energy expenditure and how endogenous GiprAP neuron activity regulates food intake and aversion.
