Project Grant F31HL186712

HARNESSING THE VAGAL CIRCUITS TO COMBAT OBESITY AND OBESITY INDUCED HYPERTENSION - PROJECT SUMMARY OBESITY IS CHARACTERIZED AS HAVING A BODY MASS INDEX OVER 30 KG/M2 AND IT AFFECTS OVER 40% OF THE ADULT POPULATION IN THE UNITED STATES. THE HEALTH RISKS ASSOCIATED WITH OBESITY ARE WELL DOCUMENTED AND INCLUDE DIABETES, RESPIRATORY DISEASE, DIGESTIVE DISORDERS, AND IMPORTANTLY TO THIS PROPOSAL, CARDIOVASCULAR DISEASE. WHILE THE RELATIONSHIP BETWEEN OBESITY AND HYPERTENSION IS WIDELY RECOGNIZED, THERE IS A SUBSTANTIAL NUMBER OF THE POPULATION WHO ARE RESISTANT TO ANTI-OBESITY AND ANTI-HYPERTENSIVE TREATMENTS. THE PROPOSED EXPERIMENTS AIM TO ELUCIDATE ANOTHER POTENTIAL THERAPEUTIC TARGET THAT WOULD TARGET TO ALLEVIATE BOTH OBESITY AND THE DEVELOPMENT OF HYPERTENSION. MY STUDIES CONDUCTED IN MICE HAVE UNCOVERED A POPULATION OF OXYTOCIN RECEPTOR (OXTR) EXPRESSING NEURONS WITHIN THE NODOSE GANGLIA (NGOXTR) THAT INNERVATE THE HEART, GUT AND NUCLEUS OF THE SOLITARY TRACT. THERE IS A SUBPOPULATION OF OXTR NEURONS THAT ACT AS BARORECEPTORS TO SENSE BLOOD PRESSURE AND ANOTHER SUBPOPULATION THAT DETECT STRETCH OF THE GASTROINTESTINAL (GI) TRACT TO REGULATE FOOD INTAKE. INTERESTINGLY, CHEMOGENETIC ACTIVATION OF THE NGOXTR SIGNIFICANTLY REDUCES BLOOD PRESSURE, HEART RATE, AND FOOD INTAKE. COLLECTIVELY THESE RESULTS SUGGEST THAT NGOXTR SEND INFORMATION TO THE NUCLEUS OF THE SOLITARY TRACT TO MEDIATE THE INTEROCEPTION OF BLOOD PRESSURE AND GASTROINTESTINAL METABOLIC STATUS AND THE EXCITATION OF THESE NEURONS CAN BE STUDIED AS A POTENTIAL THERAPEUTIC TO TREAT OBESITY AND COMORBID HYPERTENSION. THESE OBSERVATIONS HAVE LED TO THE OVERALL HYPOTHESIS THAT OBESITY LEADS TO A BLUNTED MECHANOSENSATION OF THE HEART AND GUT CONTRIBUTING TO THE DEVELOPMENT OF CARDIOMETABOLIC DISEASES ASSOCIATED WITH OBESITY AND ENGAGING THE NGOXTR NEURONS COULD ALLEVIATE CARDIOMETABOLIC DISEASE. I PROPOSE THE FOLLOWING AIMS TO TEST THIS HYPOTHESIS; AIM 1 UTILIZES THE CRE-LOXP SYSTEM AND AAV-MEDIATED TRACING IN COMBINATION WITH A HIGH FAT DIET TO ASSESS VAGAL INNERVATION OF NGOXTR IN OXTR-CRE MICE. AIM 2 EXPERIMENTS WILL ALSO UTILIZE THE CRE-LOXP SYSTEM, AAV-MEDIATED VIRAL TRACING AND HIGH FAT DIET IN COMBINATION WITH RECORDINGS OF CARDIOVASCULAR PARAMETERS AND CHEMOGENETIC APPROACHES TO INVESTIGATE WHETHER EXCITATION OF NGOXTR MAY ALLEVIATE OBESITY AND CO-MORBID BAROREFLEX INSENSITIVITY AND HYPERTENSION. COLLECTIVELY THESE EXPERIMENTS WILL REVEAL, AT A DETAILED AND MECHANISTIC LEVEL, WHETHER 1.) OBESITY IMPAIRS MARKERS OF MECHANOSENSATION OF THE HEART AND GUT BY NGOXTR, 2.) WHETHER WE CAN CIRCUMVENT THE IMPAIRED MECHANOSENSATION OF THE HEART AND GUT AND IMPROVE CARDIOMETABOLIC FUNCTION IN OBESITY BY ACTIVATING THESE SPECIFIC (NGOXTR) VAGAL SENSORY AFFERENTS.