Group X sPLA2: Regulator of Lipolysis and Glucose Homeostasis

描述(申请人提供)：肥胖现在是工业化国家最常见的代谢紊乱，也是导致2型糖尿病发展的最普遍的危险因素之一。虽然肥胖症和糖尿病之间的密切关系早已被认识到，但事实证明，理解脂肪质量增加如何导致胰岛素抵抗和2型糖尿病的进行性发展是困难的。肥胖和胰岛素抵抗之间的一个可能机制是脂肪细胞储存的游离脂肪酸(FFA)过度动员，这导致胰岛素信号的紊乱，要么通过FFAs的直接作用，要么通过非脂肪组织中的异位脂肪沉积。我们最近建立了一种新的GX分泌型磷脂酶A2表达缺失的小鼠模型(GX KO小鼠)。出乎意料的是，与野生型小鼠相比，这些小鼠的肥胖率显著增加。肥胖症的增加与脂肪细胞肥大有关，这似乎至少部分是由于2-肾上腺素能刺激脂解作用的缺陷。然而，尽管肥胖显著增加，与野生型小鼠相比，GX KO小鼠对葡萄糖挑战的反应有所改善，这表明这些小鼠的胰岛素敏感性可能受到保护。根据我们的初步发现，我们假设脂肪组织巨噬细胞表达的GX sPLA2调节脂肪细胞脂肪储存和脂质分解代谢之间的平衡。因此，Gx sPLA2调节脂肪细胞肥大、脂肪组织炎症、FFA流量和全身胰岛素敏感性。为了验证这些假说，我们提出了以下三个具体目标：目的1.验证Gx sPLA2缺陷小鼠脂肪组织中FFA流量减少与胰岛素敏感性增加和脂肪组织炎症减轻相关的假说。这将通过a)确定GX KO小鼠脂肪组织中FFA动员减少是否与非脂肪组织中葡萄糖摄取和胰岛素敏感性增加相关；b)确定Gx sPLA2缺乏是否可以预防高脂饮食诱导的胰岛素抵抗；以及c)确定Gx sPLA2缺乏对小鼠脂肪组织炎症的影响。目的2.明确巨噬细胞表达的Gx sPLA2在脂肪组织中的作用。这将通过进行骨髓移植实验来实现，在该实验中，野生型和GX KO小鼠将与来自野生型或GX KO小鼠的骨髓细胞重组。将对每组移植小鼠的脂肪细胞肥大、脂肪组织炎症和胰岛素敏感性进行评估。目的3.验证GX sPLA2正向调节TAG动员的假说。这将通过a)确定Gx sPLA2是否改变脂肪细胞中Tag的合成或水解率；以及b)确定Gx sPLA2是否通过激活激素敏感脂肪酶来促进Tag动员。这些研究的结果有可能为调节脂肪分解的新机制提供重要的见解，并可能确定调节脂肪细胞肥大和FFA流量以减少胰岛素抵抗的新靶点。与公共健康相关：在美国，肥胖现在是患2型糖尿病最常见的风险因素。在人类和动物模型中的研究表明，长期暴露在营养过剩的环境中，如果脂肪储存效率低下，可能会引发病理性炎症反应，从而破坏胰岛素的功能。这项提议的目的是验证这样一种假设，即增强脂肪组织储存脂肪的能力将对炎症和胰岛素敏感性产生有益影响。这项提议可能会为预防或治疗糖尿病提供新的策略。

DESCRIPTION (provided by applicant): Obesity is now the most common metabolic disorder in industrialized countries and represents one of the most prevalent risk factors for the development of type 2 diabetes. While the close relationship between obesity and diabetes has long been recognized, understanding how an expanded fat mass results in the progressive development of insulin resistance and type 2 diabetes has proven difficult. One possible mechanism linking obesity and insulin resistance is the excess mobilization of free fatty acids (FFAs) from adipocyte stores, which leads to derangements in insulin signaling either through direct actions of FFAs or through ectopic lipid deposition in non-adipose tissues. We recently developed a novel mouse model that lacks the expression of GX secretory phospholipase A2 (GX KO mice). Unexpectedly, these mice have significantly increased adiposity compared to wild-type littermates. The increase in adiposity is associated with adipocyte hypertrophy, which appears to be due at least in part to a defect in 2-adrenergic stimulated lipolysis. However, despite a marked increase in adiposity, GX KO mice show improved response to glucose challenge compared to wild- type mice, suggesting that insulin sensitivity may be protected in these mice. Based on our preliminary findings, we hypothesize that GX sPLA2 expressed by adipose tissue macrophages modulates the equilibrium between adipocyte lipid storage and lipid catabolism. As a consequence, GX sPLA2 regulates adipocyte hypertrophy, adipose tissue inflammation, FFA flux, and whole body insulin sensitivity. To test these hypotheses, we propose the following 3 specific aims: Aim 1. To test the hypothesis that reduced FFA flux in adipose tissue of GX sPLA2-deficient mice is associated with increased insulin sensitivity and reduced adipose tissue inflammation. This will be achieved by a) determining whether decreased FFA mobilization in adipose tissue of GX KO mice is associated with increased glucose uptake and insulin sensitivity in non-adipose tissue; b) determining whether GX sPLA2 deficiency protects against high fat diet-induced insulin resistance; and c) defining the effect of GX sPLA2 deficiency on adipose tissue inflammation in mice. Aim 2. To define the role of macrophage-expressed GX sPLA2 in adipose tissue. This will be achieved by performing a bone marrow transplant experiment in which wild-type and GX KO mice will be reconstituted with bone marrow cells derived from either wild-type or GX KO mice. Adipocyte hypertrophy, adipose tissue inflammation and insulin sensitivity will be assessed in each of the groups of transplanted mice. Aim 3. To test the hypothesis that GX sPLA2 positively regulates TAG mobilization. This will be achieved by a) determining whether GX sPLA2 alters the rate of TAG synthesis or hydrolysis in adipocytes; and b) determining whether GX sPLA2 promotes TAG mobilization by activating hormone sensitive lipase. Results from these studies have the potential to provide important insights into a novel mechanism regulating lipolysis, and may identify new targets for modulating adipocyte hypertrophy and FFA flux to reduce insulin resistance. PUBLIC HEALTH RELEVANCE: In the U.S., obesity is now the most common risk factor for the development of type-2 diabetes. Studies in humans and animal models suggest that inefficient storage of fat during long-term exposure to nutrient excess may trigger pathological inflammatory responses that disrupt the ability of insulin to function. The goal of this proposal is to test the hypothesis that enhancing the capacity of adipose tissue to store fat will have a beneficial effect on inflammation and insulin sensitivity. This proposal could provide new strategies to prevent or treat diabetes.