Leptin and Peripheral Glucose Metabolism

 描述(申请人提供)：超重或肥胖的美国人比理想体重范围内的人多。减肥手术是治疗肥胖症的唯一有效的长期治疗方法，但它并不能降低医疗保健成本，这种侵入性手术的终生后果尚未完全阐明。因此，开发有效的非手术策略来预防和逆转体重增加是至关重要的。瘦素在1994年被确认为调节能量平衡的负反馈信号，但瘦素在预防或逆转人类肥胖方面进展甚微。这可能部分归因于许多旨在研究内源性生理机制的研究的药理学性质。在这项建议中，我们使用了接近生理剂量的瘦素，只有当前脑和后脑中的瘦素受体(ObRb)都被激活时，才会启动反应。当瘦素单独注入第三脑室或第四脑室时，剂量太低，不会影响能量平衡，同时给予瘦素，12天内体内脂肪减少75%。食物摄入最初被抑制40%-60%，但在6天后与对照组没有什么不同。更多的数据表明，后脑中ObRb的激活促进了前脑中信号转导和转录3(PSTAT3)的磷酸化。PSTAT3是瘦素引起的能量平衡改变所必需的，是公认的ObRb激活的标志。这些数据有力地支持了这样的假设，即瘦素需要前脑和后脑中ObRb的同时激活才能诱导能量负平衡状态。我们认为，后脑ObRb的激活降低了前脑ObRb的激活阈值，当循环中的瘦素与身体ft的增加平行时，启动核团对中枢瘦素的微妙升高做出反应。这导致了一个非常灵敏的反馈系统来控制能量平衡。目的其中一项建议将证实和推广实验数据，即后脑注射瘦素可降低第三脑室对瘦素的反应阈值，并验证下丘脑的敏化是由神经机制介导还是由瘦素从第四脑室扩散到第三脑室所致。目的二将测试下丘脑pSTAT3的增加是否仅限于表达ObRb的细胞，测试第四脑室注射瘦素是否激活前脑中不表达STAT3的区域，并确定下丘脑对瘦素诱导的体重减轻至关重要的核团。总而言之，这些目标将为控制能量平衡的敏感和精确系统提供新的和有影响力的信息。他们还将提供有关后脑和下丘脑神经活动整合的新信息。

 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.