Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis

感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态

• 批准号: 10621522
• 负责人: Bingzhong Xue
• 金额: $ 12.62万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621522
• 关键词: Ablation; Adipose tissue; Afferent Neurons; Animal Model; Appetite Stimulants; Body Temperature; Brain; Brown Fat; Capsaicin; Cardiovascular Diseases; Dependovirus; Diameter; Dyslipidemias; Eating; Endocrine; Energy Metabolism; Epidemic; Fiber; Food deprivation (experimental); GHS-R1a; Gastrointestinal tract structure; Goals; Grant; High Fat Diet; Homeostasis; Hormones; Human; Injections; Insulin Resistance; Internal Ribosome Entry Site; Knowledge; Large Intestine; Malignant Neoplasms; Maps; Measures; Mediating; Mediator; Melanocortin 4 Receptor; Metabolic; Metabolic Control; Metabolic Diseases; Mus; Nerve; Neurons; Neurosecretory Systems; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nutrient; Obesity; Organ; Pathway interactions; Peripheral; Regulation; Reporter; Risk Factors; Role; Sensory; Sensory Ganglia; Signal Pathway; Signal Transduction; Small Intestines; Spinal; Spinal Ganglia; Stimulus; Stomach; Stretching; Testing; Thermogenesis; Tracer; Vagotomy; Vertebral column; Viral; Visualization; Work; afferent nerve; cell motility; designer receptors exclusively activated by designer drugs; diet-induced obesity; gastrointestinal; genetic approach; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; lipid metabolism; nerve supply; neuronal circuitry; new therapeutic target; novel; obesity treatment; prevent; receptor; response

Obesity has become a world-wide epidemic problem, and is an independent risk factor for a panel of metabolic diseases, including insulin resistance/type 2 diabetes, dyslipidemia, cardiovascular diseases, and cancer. The stomach-derived orexigenic hormone ghrelin acting through its receptor growth hormone secretagogue receptor 1a (GHSR) is a key mediator of energy homeostasis. GHSR is widely expressed in the brain and on gastrointestinal vagal sensory neurons. In the current proposal, we discovered that in addition to the well characterized vagal GHSRs, gastrointestinal sensory neurons emanating from spinal dorsal root ganglia (DRG) robustly express GHSRs. In addition, DRG GHSR-containing neurons innervates the gastrointestinal tract, and DRG GHSR is markedly induced by energetic challenges, including food deprivation and cold exposure, suggesting DRG ghrelin/GHSR signaling is important in regulating energy homeostasis. Interestingly, sensory GHSR deletion protects against diet-induced obesity primarily due to increased energy expenditure via increased adipose tissue sympathetic outflow and thermogenesis. Thus, we have identified a novel pathway in which gut non-vagal sensory GHSR neurons negatively regulate energy homeostasis via suppression of adipose tissue sympathetic outflow, thermogenesis and whole body energy expenditure. The overall goal of this project is to test the importance of ghrelin/GHSR signaling on peripheral sensory neurons in regulating whole body metabolic homeostasis, and to investigate the neuronal mechanisms by which sensory GHSR regulates adipose tissue sympathetic outflow. In Specific Aim 1, the importance of sensory GHSR in regulating energy homeostasis will be tested using DRG sensory neuron-specific deletion or re-activation of GHSR. In Specific Aim 2, the neuronal circuitry connecting gut sensory GHSR signaling to adipose tissue sympathetic outflow will be investigated via viral tract tracer mapping. In addition, the possible involvement of central melanocortin signaling pathways as a downstream target connecting sensory GHSR signaling to adipose tissue sympathetic outflow will be tested. Completing this project will greatly expand our current knowledge of the neuroendocrine regulation of energy homeostasis, and will provide novel therapeutic targets in the preventing and treatment of obesity.

肥胖已经成为一个全球性的流行病问题，并且是一组代谢的独立危险因素