Leptin and peripheral glucose metabolism

描述（由申请人提供）：超重和肥胖的发生率在美国人口的所有年龄组中持续上升。由于过度肥胖与慢性疾病和死亡率的风险增加有关，因此我们有必要了解调节肥胖的生理机制，以及环境因素如何使这些机制失效。本研究的重点是脂肪细胞来源的细胞因子瘦素如何改变全身能量代谢和脂肪细胞代谢。在接受生理剂量的瘦素治疗的实验动物中，瘦素反应似乎至少有三个不同的阶段：a)瘦素敏感性，促进瘦素对身体脂肪的减少；b)部分瘦素抵抗，导致瘦素对肥胖的增加；c)完全瘦素抵抗，阻止对外周给药的瘦素的任何代谢反应。本建议侧重于第二个条件。第一个特定目标将检查部分瘦素抵抗大鼠脂肪增加的机制基础。拟议的研究将验证这样的假设，即当外周给药的瘦素不能增加位于前脑的瘦素受体的活性，但可以刺激后脑和/或外周的受体时，那么能量平衡和代谢状态就会发生变化，有利于脂肪沉积。成功完成这一目标将确定在部分瘦素抵抗条件下加速体脂增加所需的条件和机制。这些研究将提供重要的新信息，说明环境因素如何降低负责调节体脂含量的机制的功效，甚至可能促进体重增加。第二个特定目标包括在部分瘦素抵抗动物中确定负责脂肪堆积的瘦素受体位置的研究。成功完成这一目标将为调节导致白色脂肪积累的内源性因子的活动提供机会，从而预防或逆转肥胖。公共卫生相关性：由于过度肥胖与许多慢性疾病的风险显著增加有关，因此肥胖的流行是一种主要的经济和社会负担。本提案中描述的研究将研究瘦素（一种从脂肪组织释放的细胞因子）如何在部分瘦素抵抗的情况下促进脂肪增加。这将提供重要的新信息，说明环境因素如何改变负责调节体脂储存大小的机制，甚至可能促进体重增加。

DESCRIPTION (provided by applicant): The incidence of overweight and obesity continue to escalate in all age groups of the US population. Because excess adiposity is associated with increased risk for chronic disease and mortality it is essential that we develop an understanding of the physiological mechanisms that are in place to regulate adiposity and how environmental factors can make these mechanisms ineffectual. This proposal focuses on how the adipocyte derived cytokine leptin modifies whole body energy metabolism and adipocyte metabolism. It appears that there are at least three different stages of leptin responsiveness in experimental animals treated with physiological doses of the hormone: a) leptin sensitivity that facilitates a loss of body fat in response to leptin b) partial leptin resistance that leads to an increase in adiposity in response to leptin and c) full leptin resistance that prevents any metabolic response to peripherally administered leptin. This proposal focuses on the second condition. The first Specific Aim will examine the mechanistic basis of fat gain in rats that are partially leptin resistant. The proposed studies will test the hypothesis that when peripherally administered leptin is unable to increase activity of leptin receptors located in the forebrain, but can stimulate receptors in the hindbrain and/or periphery, then there is a shift in energy balance and metabolic status that favors fat deposition. Successful completion of this Aim will determine the conditions required and mechanisms responsible for acceleration of body fat gain in conditions of partial leptin-resistance. These studies will provide important new information on how environmental factors decrease the efficacy of mechanisms responsible for the regulation of body fat content and may even promote weight gain. The second Specific Aim includes studies that will identify the location of leptin receptors responsible for the accretion of fat in partially leptin resistant animals. Successful completion of this Aim will provide opportunities to modulate activity of endogenous factors that lead to the accumulation of white fat, and thus prevent, or reverse, obesity. PUBLIC HEALTH RELEVANCE: Because excessive adiposity is associated with a significant increase in risk for a large number of chronic diseases the epidemic of obesity represents a major economic and societal burden. Studies described in this proposal will examine how leptin, a cytokine that is released from adipose tissue, promotes fat gain in conditions of partial leptin resistance. This will provide important new information on how environmental factors modify mechanisms responsible for regulating the size of body fat stores and may even promote weight gain.