Leptin and Peripheral Glucose Metabolism

瘦素和周围葡萄糖代谢

• 批准号: 9221304
• 负责人: Ruth B Harris
• 金额: $ 34.2万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221304
• 关键词: American; Animals; Area; Bariatrics; Blood - brain barrier anatomy; Body Weight; Body Weight decreased; Body fat; Bolus Infusion; Brain; Brain region; Cell Nucleus; Cells; Chronic; Chronic Disease; Complex; Data; Development; Diffuse; Dorsal; Dose; Eating; Energy Metabolism; Evaluation; Fatty acid glycerol esters; Feedback; Genetic Transcription; Health; Health Care Costs; Hormones; Human; Hypothalamic structure; Infusion procedures; Injection of therapeutic agent; Leptin; Life; Mediating; Mediation; Mediator of activation protein; Metabolic; Nature; Neurons; Obesity; Operative Surgical Procedures; Overweight; Peripheral; Pharmacology; Phosphorylation; Physiological; Prevention strategy; Prosencephalon; Protocols documentation; Regulation; Research; Research Design; Risk; STAT3 gene; Signal Transduction; Site; Societies; System; Testing; Thermogenesis; Transducers; Translating; Weight; Weight Gain; Work; bariatric surgery; base; body system; energy balance; glucose metabolism; hindbrain; injection/infusion; insight; leptin receptor; neural circuit; neuromechanism; novel; novel therapeutic intervention; obesity treatment; permissiveness; prevent; public health relevance; relating to nervous system; response

 DESCRIPTION (provided by applicant): More Americans are overweight or obese than are within the ideal weight range. Bariatric surgery is the only effective long-term treatment for obesity, but it does not reduce health care costs and the life-long consequences of this invasive surgery have yet to be fully elucidated. Therefore, development of effective, non surgical strategies for prevention and reversal of weight gain is essential. Leptin was identified as a negative feedback signal in the regulation of energy balance in 1994, but little progress has been made using leptin to prevent or reverse human obesity. This may be due in part to the pharmacologic nature of many studies designed to investigate an endogenous physiologic mechanism. In this proposal we use near-physiologic doses of leptin that initiate a response only when leptin receptors (ObRb) in both the forebrain and hindbrain are activated. Doses of leptin too low to influence energy balance when infused into either the 3rd or the 4th ventricle separately, reduce body fat by 75% in 12 days when given simultaneously. Food intake is initially inhibited by 40-60%, but is not different from controls after 6 days. Additional data sho that activation of ObRb in the hindbrain facilitates phosphorylation of signal transducer and transcription 3 (pSTAT3) in the forebrain. pSTAT3 is required for leptin induced changes in energy balance and is an accepted marker of ObRb activation. These data strongly support the hypothesis that simultaneous activation of ObRb in the forebrain and hindbrain is required for leptin to induce a state of negative energy balance. We propose that activation of hindbrain ObRb lowers the threshold for activation of forebrain ObRb, priming the nuclei to respond to subtle elevations in central leptin when circulating leptin rises in parallel with increased body ft. This results in a very sensitive feedback system for the control of energy balance. Aim One of this proposal will confirm and extend pilot data that hindbrain leptin infusion lowers the threshol of response to 3rd ventricle leptin and test whether sensitization of the hypothalamus is mediated by a neural mechanism or is caused by leptin diffusing from the 4th into the 3rd ventricle. Aim Two will test whether increased hypothalamic pSTAT3 is limited to cells that express ObRb, test whether 4th ventricle leptin infusion activates areas of the forebrain that do not express STAT3 and identify hypothalamic nuclei that are essential for leptin-induced weight loss. Taken together these Aims will provide new and impactful information on a sensitive and precise system for the control of energy balance. They also will provide novel information on the integration of hindbrain and hypothalamic neural activity.

 描述（由申请人提供）：更多的美国人超重或肥胖，而不是在理想的体重范围内。减肥手术是肥胖症唯一有效的长期治疗方法，但它并不能降低医疗费用，而且这种侵入性手术的终身后果尚未完全阐明。因此，开发有效的非手术策略来预防和逆转体重增加至关重要。1994年，瘦素被认为是调节能量平衡的负反馈信号，但利用瘦素预防或逆转人类肥胖的研究进展甚微。这可能部分是由于许多旨在研究内源性生理机制的研究的药理学性质。在这个建议中，我们使用接近生理剂量的瘦素，只有当前脑和后脑中的瘦素受体（ObRb）被激活时才启动反应。剂量太低，影响能量平衡的瘦素分别注入第三或第四脑室时，减少75%的体脂在12天内同时给予。食物摄入最初被抑制40- 60%，但6天后与对照组没有差异。另外的数据表明，在后脑中激活ObRb促进前脑中信号转导和转录3（pSTAT 3）的磷酸化。pSTAT 3是瘦素诱导的能量平衡变化所必需的，并且是ObRb活化的公认标志物。这些数据有力地支持了这一假设，即前脑和后脑中的ObRb的同时激活是瘦素诱导负能量平衡状态所必需的。我们建议，激活后脑ObRb降低阈值激活前脑ObRb，启动核反应微妙的升高，中央瘦素时，循环瘦素上升，平行增加身体英尺。这导致用于控制能量平衡的非常灵敏的反馈系统。目的进一步证实和扩展前脑瘦素灌注降低第三脑室瘦素反应阈值的实验数据，并验证下丘脑的增敏作用是由神经机制介导的，还是瘦素从第四脑室扩散到第三脑室所致。目的二将测试是否增加下丘脑pSTAT 3仅限于表达ObRb的细胞，测试第四脑室瘦素输注是否激活前脑不表达STAT 3的区域，并确定瘦素诱导的体重减轻所必需的下丘脑核。这些目标将为控制能量平衡的灵敏和精确系统提供新的和有影响力的信息。他们也将提供新的信息整合后脑和下丘脑神经活动。