Project Grant R01DK140308

PATHOPHYSIOLOGICAL MECHANISMS IN THE BRAIN'S ENDOGENOUS GLUCAGON-LIKE PEPTIDE 1 SYSTEM MEDIATED BY OBESOGENIC DIETS - TITLE: PATHOPHYSIOLOGICAL MECHANISMS IN THE BRAIN'S ENDOGENOUS GLUCAGON-LIKE PEPTIDE 1 SYSTEM MEDIATED BY OBESOGENIC DIETS PHARMACOTHERAPIES THAT TARGET THE GLUCAGON-LIKE PEPTIDE 1 RECEPTOR (GLP-1R) SYSTEM ARE COMMONLY PRESCRIBED FOR THE TREATMENT OF TYPE II DIABETES AND, MORE RECENTLY, FOR WEIGHT LOSS. ALTHOUGH SUCCESSFUL AT REDUCING APPETITE AND BODYWEIGHT, THERE ARE SEVERAL LIMITATIONS OF GLP-1R AGONISTS THAT LIMIT THEIR WIDESPREAD USE. MOREOVER, THE ROLE OF THE ENDOGENOUS GLP-1 AND GLP-1R SYSTEM, PARTICULARLY IN THE BRAIN, AND ITS ROLE IN OBESITY PATHOGENESIS IS UNCLEAR. IN THIS APPLICATION, OUR MULTIDISCIPLINARY TEAM WILL ADDRESS THIS PRIMARY GAP IN KNOWLEDGE BY DISSECTING THE FUNCTION AND ACTIVITY STATES OF GLP-1-PRODUCING NEURONS IN THE NUCLEUS OF THE SOLITARY TRACT (NTS) AND THEIR OUTPUTS TO GLP-1R-EXPRESSING NEURONS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVH) IN A MODEL OF DIET-INDUCED OBESITY. IN AIM 1, WE WILL USE CONVERGENT ELECTROPHYSIOLOGICAL, ANATOMICAL, AND OPTICAL METHODS TO MEASURE THE WIRING AND ACTIVITY STATES OF GCGNTS NEURONS, THE PRIMARY SOURCE OF GLP-1 IN THE BRAIN, AFTER EXPOSURE TO OBESOGENIC HIGH FAT DIET. FURTHER, WE WILL USE CUSTOM TOOLS AND NOVEL TRANSGENIC MICE TO DISSECT NEUROTRANSMISSION BETWEEN GCGNTS NEURONS AND ONE OF THEIR PRIMARY OUTPUTS IN THE PVH, GLP1RPVH NEURONS, EX VIVO AND IN VIVO. IN AIM 2, WE WILL DETERMINE THE CAUSAL ROLE OF GCGNTS NEURONS AND OUTPUTS TO THE PVH IN PROGRESSIVE AND INTERVENTIONAL MODELS OF DIET-INDUCED OBESITY USING INTERSECTIONAL VIRAL TOOLS. THESE EXCITING EXPERIMENTS WILL YIELD IMPORTANT INSIGHT INTO THE PATHOPHYSIOLOGICAL ROLE OF THE BRAIN'S ENDOGENOUS GLP-1/GLP- 1R SYSTEM AND ESTABLISH IF TARGETING GCGNTS NEURONS IS A THERAPEUTICALLY TRACTABLE STRATEGY FOR NEW OBESITY TREATMENTS.