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Browsing by Subject "G protein-coupled receptor"
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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 Characterization of an adulticidal and larvicidal interfering RNA pesticide that targets a conserved sequence in mosquito G protein-coupled dopamine 1 receptor genes(Elsevier, 2020) Hapairai, Limb K.; Mysore, Keshava; Sun, Longhua; Li, Ping; Wang, Chien-Wei; Scheel, Nicholas D.; Lesnik, Alexandra; Scheel, Max P.; Igiede, Jessica; Wei, Na; Severson, David W.; Duman-Scheel, Molly; Medical and Molecular Genetics, School of MedicineG protein-coupled receptors (GPCRs), key regulators of a variety of critical biological processes, are attractive targets for insecticide development. Given the importance of these receptors in many organisms, including humans, it is critical that novel pesticides directed against GPCRs are designed to be species-specific. Here, we present characterization of an interfering RNA pesticide (IRP) targeting the mosquito GPCR-encoding dopamine 1 receptor (dop1) genes. A small interfering RNA corresponding to dop1 was identified in a screen for IRPs that kill Aedes aegypti during both the adult and larval stages. The 25 bp sequence targeted by this IRP is conserved in the dop1 genes of multiple mosquito species, but not in non-target organisms, indicating that it could function as a biorational mosquito insecticide. Aedes aegypti adults treated through microinjection or attractive toxic sugar bait delivery of small interfering RNA corresponding to the target site exhibited severe neural and behavioral defects and high levels of adult mortality. Likewise, A. aegypti larval consumption of dried inactivated yeast tablets prepared from a Saccharomyces cerevisiae strain engineered to express short hairpin RNA corresponding to the dop1 target site resulted in severe neural defects and larval mortality. Aedes albopictus and Anopheles gambiae adult and larval mortality was also observed following treatment with dop1 IRPs, which were not toxic to non-target arthropods. The results of this investigation indicate that dop1 IRPs can be used for species-specific targeting of dop1 GPCRs and may represent a new biorational strategy for control of both adult and larval mosquitoes.Item Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion(Elsevier, 2022-01) Yan, Shijun; Conley, Jason M.; Reilly, Austin M.; Stull, Natalie D.; Abhyankar, Surabhi D.; Ericsson, Aaron C.; Kono, Tatsuyoshi; Molosh, Andrei I.; Kubal, Chandrashekhar A.; Evans-Molina, Carmella; Ren, Hongxia; Medicine, School of MedicineG protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.