Hepatic Leptin Action and Leptin Resistance

描述(由申请人提供)：脂肪细胞衍生的激素瘦素对脂类代谢的作用被认为在防止组织脂毒性和脂类相关的胰岛素抵抗的发展中具有重要作用。这一点在瘦素缺乏状态下得到了最好的说明，在这种状态下，外源性瘦素的应用可以纠正全身性血脂异常、肝脏等周围组织中脂肪的过度储存以及与这种情况相关的胰岛素抵抗。此外，瘦素抵抗状态，如人类肥胖和饮食诱导肥胖(DIO)，其代谢表型与瘦素缺乏状态相似，提示瘦素作用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代谢和胰岛素作用的机制以及瘦素抵抗的机制仍知之甚少。我们最近的工作主要集中在瘦素对肝脏脂代谢的影响及其机制，肝脏是调节全身脂平衡的中心器官。简而言之，这些研究确立了瘦素在急性调节肝脏脂质水平中的新作用，这种作用在肥胖中受到损害，并确定了这种缺陷的生化机制。具体地说，我们已经证明：(I)瘦素迅速(在大约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)瘦素对肝脏甘油三酯水平的影响需要激活肝脏PI3-激酶；以及(Iv)肝脏PI3-激酶的缺陷激活是肥胖中瘦素抵抗的新机制。本方案的中心目标是扩展这些研究，以确定(I)瘦素强烈调控的肝脏脂代谢途径；(Ii)瘦素对肝脂代谢作用的生化/分子机制；(Iii)胰岛素和瘦素对肝脏代谢的相互作用；以及(Iv)肥胖时肝脏瘦素抵抗的生化机制。通过开展这些研究，我们将加深对瘦素作用机制的了解，以及瘦素抵抗在肥胖代谢异常中的作用。

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.