Cellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Disease

dc.contributor.advisorSheets, Patrick
dc.contributor.authorReilly, Austin Michael
dc.contributor.otherRen, Hongxia
dc.contributor.otherBaucum, Anthony II
dc.contributor.otherEvans-Molina, Carmella
dc.contributor.otherLandreth, Gary
dc.date.accessioned2021-10-12T12:51:50Z
dc.date.available2021-10-12T12:51:50Z
dc.date.issued2021-09
dc.degree.date2021en_US
dc.degree.discipline
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractMetabolic survival mechanisms that defend body weight and conserve energy are currently at odds with modernized society which has a food supply that is ubiquitous, calorie dense, and highly palatable. Chronic overnutrition leads to a metabolic syndrome of obesity, insulin resistance, inflammation, and cardiovascular diseases that is increasingly prevalent and threatens health on a global scale. The brain is both a victim and culprit of metabolic diseases, and prolonged metabolic dysfunction can exacerbate the pathological mechanisms underlying both metabolic and neurodegenerative diseases. Since neuroendocrine pathways comprise an essential feedback mechanism that detects circulating hormones and nutrients in order to regulate satiety, energy expenditure, and glucose homeostasis, our research goals were to characterize molecular mechanisms within neuroendocrine pathways that could be leveraged for treating obesity, diabetes, and Alzheimer’s disease. First, we identified the expression of a G protein-coupled receptor, Gpr17, in POMC neurons and discovered that it protects aged mice from high-fat diet (HFD)-induced metabolic derangements. We examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, Pomc-Cre-driven Gpr17 knockout (PGKO) mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. Second, we generated a highly insulin resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in muscle, adipose, and GLUT4-expressing neuronal subpopulations. This genetic approach recapitulates the primary defect preceding type 2 diabetes (T2D) and revealed additional factors/mechanisms that drive the ultimate progression of overt diabetes. Third, we used 5xFAD mice as a model of Alzheimer’s disease and showed that they were more susceptible to HFD-induced metabolic dysregulation and expression of AD pathological markers in the hippocampus. Our results helped elucidate the molecular and cellular mechanisms responsible for increased AD pathology in high-fat diet-fed 5xFAD mice and suggest that metabolic dysfunctions are a therapeutic target to ameliorate AD pathology. In conclusion, metabolic diseases are pervasive and require nuanced approaches that target the neuroendocrine system in order to restore metabolic homeostasis and protect the brain from neurodegenerative processes that are associated with obesity and diabetes.en_US
dc.identifier.urihttps://hdl.handle.net/1805/26717
dc.identifier.urihttp://dx.doi.org/10.7912/C2/2087
dc.language.isoen_USen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectG protein-coupled receptoren_US
dc.subjectmetabolismen_US
dc.subjectobesityen_US
dc.subjectPOMC neuronsen_US
dc.subjecttype 2 diabetesen_US
dc.titleCellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Diseaseen_US
dc.typeThesis
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