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Browsing by Subject "POMC neurons"
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Item Cellular and Molecular Targets in the Neuroendocrine System That Defend Against Diabetes, Obesity, and Alzheimer's Disease(2021-09) Reilly, Austin Michael; Sheets, Patrick; Ren, Hongxia; Baucum, Anthony II; Evans-Molina, Carmella; Landreth, GaryMetabolic 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.Item Understanding Cilia Function on POMC Neurons in Appetite and Satiety(Office of the Vice Chancellor for Research, 2016-04-08) Boyle, Julianne; Whitehouse, Logan; Engle, Staci; Bansal, Ruchi; Berbari, Nicolas F.Over one-third of adults in the United States are obese. Obese individuals are at an increased risk for cardiovascular diseases, type 2 diabetes, cancer, and other health conditions, resulting in premature death. Interestingly, cilia have been linked to controlling satiety in both mice and humans, and individuals with dysfunctional cilia are often obese. Cilia are cellular appendages composed of microtubules and can be motile or immotile. Primary (immotile) cilia function as sensors for important signaling pathways. The loss of cilia, specifically from hypothalamic proopiomelanocortin (POMC) expressing cells, disrupts satiety, leading to overeating and obesity. While it is known that cilia loss in POMC cells in the hypothalamus causes obesity, the age or developmental stage at which cilia loss is important for this phenotype remains unclear. The aim of this research is to determine the time point critical for proper cilia function on POMC neurons to maintain normal feeding behaviors. To do this, we utilize an inducible POMC-CreER mouse model. This model allows us to disrupt cilia formation and maintenance at specific stages of life. We take a multifaceted approach to analyze the impact of cilia loss by measuring longterm body weight and feeding behavior in adult mice, studying changes in embryonic development, as well as analyzing physiological changes in cultured primary neurons. These studies will contribute to a better understanding of the role of cilia in satiety signaling which will help lead to the development of effective treatments for weight related diseases.