Hepatic Leptin Action and Leptin Resistance

肝脏瘦素作用和瘦素抵抗

• 批准号: 7142795
• 负责人: ROBERT M O'DOHERTY
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142795
• 关键词: carbohydrate metabolism; cytokine; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hormone sensitivity /resistance; insulin; laboratory mouse; leptin; lipid metabolism; liver metabolism; obesity; phosphatidylinositol 3 kinase

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.

描述（由申请人提供）：脂肪细胞衍生激素瘦素对脂质代谢的作用被认为在预防组织脂毒性和脂质相关胰岛素抵抗的发展中是重要的。这在瘦素缺乏状态中得到最好的说明，其中外源性瘦素的施用纠正了全身性血脂异常、脂质在外周组织如肝脏中的过度储存以及与这种状况相关的胰岛素抵抗。此外，瘦素抵抗状态如人肥胖和饮食诱导的肥胖（DIO）的特征在于与瘦素缺乏病症相似的代谢表型，暗示瘦素作用丧失在肥胖代谢异常的发病机制中的作用。然而，尽管取得了一些进展，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的理解仍然很差。近年来，我们的研究主要集中在瘦素对肝脏脂质代谢的影响及其机制。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，这种作用在肥胖症中受损，并确定了这种缺陷的生化机制。具体来说，我们已经证明（i）瘦素迅速（ii）DIO诱导对瘦素的急性甘油三酯降低作用的抵抗;（iii）肝PI 3-激酶的活化是瘦素对肝甘油三酯水平的影响所必需的，和（iv）肝脏PI 3-激酶的缺陷性瘦素激活是肥胖症中瘦素抵抗的新机制。目前建议的中心目标是扩展这些研究，以确定（i）肝脏中的脂质代谢途径，瘦素急性调节;（ii）的生化/分子机制瘦素对肝脏脂质代谢的作用;（iii）胰岛素和瘦素对肝脏代谢的相互作用，和（iv）肥胖症的肝脏瘦素抵抗的生化机制。通过这些研究，我们将加深对瘦素作用机制以及瘦素抵抗对肥胖代谢异常的作用的理解。