Hepatic Leptin Action and Leptin Resistance

描述（由申请人提供）：脂肪细胞来源的激素瘦素对脂质代谢的作用被认为在预防组织脂肪毒性和脂质相关胰岛素抵抗的发展中很重要。这在瘦素缺乏的状态下得到了最好的说明，在这种状态下，外源性瘦素的使用纠正了全体性血脂异常、脂肪在周围组织（如肝脏）的过度储存以及与此相关的胰岛素抵抗。此外，瘦素抵抗状态，如人类肥胖和饮食诱导的肥胖（DIO），其特征是与瘦素缺乏条件具有相似的代谢表型，这意味着瘦素作用的丧失在肥胖代谢异常的发病机制中起作用。然而，尽管取得了一些进展，但我们对瘦素调节脂质代谢和胰岛素作用的机制以及瘦素抵抗的机制仍然知之甚少。我们最近的工作主要集中在瘦素对脂质代谢的作用和机制。肝脏是调节全身脂质平衡的中枢器官。简而言之，这些研究确立了瘦素在肝脏脂质水平的急性调节中的新作用，这种作用在肥胖中受损，并确定了这种缺陷的生化机制。具体来说，我们已经证明(1)瘦素迅速（约100分钟内）降低肝脏甘油三酯水平；（ii） DIO诱导对瘦素急性降低甘油三酯作用的抵抗；（iii）肝脏pi3激酶的激活是瘦素对肝脏甘油三酯水平的影响所必需的，（iv）肝脏pi3激酶激活缺陷是肥胖中瘦素抵抗的新机制。当前提案的中心目标是扩展这些研究以确定(i)瘦素急性调节的肝脏脂质代谢途径；（ii）瘦素作用于肝脏脂质代谢的生化/分子机制；（iii）胰岛素和瘦素对肝脏代谢的相互作用；（iv）肥胖患者肝脏瘦素抵抗的生化机制。在开展这些研究中，我们将增加对瘦素作用机制的理解以及瘦素抵抗对肥胖代谢异常的贡献。

DESCRIPTION (provided by applicant): The actions of the adipocyte-derived hormone leptin on lipid metabolism are proposed to be important in preventing the development of tissue lipotoxicity and lipid-related insulin resistance. This is best illustrated in leptin-deficient states, where the administration of exogenous leptin corrects systemic dyslipidemia, excessive storage of lipid in peripheral tissues such as the liver, and insulin resistance associated with this condition. Furthermore, states of leptin resistance such as human obesity and diet-induced obesity (DIO) are characterized by a similar metabolic phenotype to leptin deficient conditions, implicating a role for a loss of leptin action in the pathogenesis of the metabolic abnormalities of obesity. However, despite some progress, our understanding of the mechanisms of leptin regulation of lipid metabolism and insulin action, and the mechanisms of leptin resistance remains poor. Our recent work has focused on the effects and mechanisms of leptin action on lipid metabolism .in liver, a central organ in the regulation of whole-body lipid homeostasis. In brief these studies established a novel role for leptin in the acute regulation of hepatic lipid levels, an effect that is impaired in obesity, and identified a biochemical mechanism for this defect. Specifically, we have demonstrated (i) that leptin rapidly (within approximately 100 min) decreases liver triglyceride levels; (ii) that DIO induces resistance to the acute triglyceride-lowering effects of leptin; (iii) that activation of liver PI3-kinase is required for the effects of leptin on hepatic triglyceride levels, and (iv) that defective leptin activation of liver PI3-kinase is a novel mechanism of leptin resistance in obesity. The central objective of the current proposal is to extend these studies to determine (i) the lipid metabolic pathways in liver acutely regulated by leptin; (ii) the biochemical/molecular mechanisms of leptin action on hepatic lipid metabolism; (iii) the interactions of insulin and leptin on hepatic metabolism, and (iv) the biochemical mechanisms of hepatic leptin resistance in obesity. In undertaking these studies, we will increase our understanding of the mechanisms of leptin action and the contribution of leptin resistance to the metabolic abnormalities of obesity.