Group X sPLA2: Regulator of Lipolysis and Glucose Homeostasis

X 组 sPLA2：脂肪分解和葡萄糖稳态的调节剂

• 批准号: 8531906
• 负责人: Nancy R Webb
• 金额: $ 30.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531906
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Animal Model; Biology; Blood Circulation; Bone Marrow Cells; Bone Marrow Transplantation; Cardiovascular Diseases; Catabolism; Cell physiology; Data; Defect; Deposition; Developed Countries; Development; Diabetes Mellitus; Diet; Dyslipidemias; Endocrine; Endocrine Glands; Equilibrium; Exhibits; Exposure to; Fatty acid glycerol esters; Functional disorder; Glucose; Goals; Health; Hepatic; Hormones; Human; Hydrolysis; Hypertrophy; Impairment; Individual; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Link; Lipids; Lipolysis; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Peripheral; Phospholipase A2; Play; Production; Proteins; Regulation; Risk Factors; Role; Study models; Testing; Tissues; Transplantation; Triglycerides; Wild Type Mouse; adipokines; adrenergic; base; blood glucose regulation; energy balance; glucose metabolism; glucose uptake; group X secretory phospholipase A(2); improved; insight; insulin secretion; insulin sensitivity; insulin signaling; macrophage; mouse model; novel; prevent; reconstitution; research study; response; sterol esterase

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.

描述（由申请人提供）：肥胖现在是工业化国家最常见的代谢紊乱，是2型糖尿病发展的最普遍危险因素之一。虽然肥胖和糖尿病之间的密切关系早已被认识到，但了解脂肪量的增加如何导致胰岛素抵抗和2型糖尿病的进展已经被证明是困难的。肥胖和胰岛素抵抗的一个可能机制是脂肪细胞储存的游离脂肪酸（FFA）的过度动员，这导致胰岛素信号转导的紊乱，通过FFA的直接作用或通过非脂肪组织中的异位脂质沉积。我们最近开发了一种新的小鼠模型，缺乏GX分泌型磷脂酶A2的表达（GX KO小鼠）。出乎意料的是，与野生型同窝出生的小鼠相比，这些小鼠的肥胖症显著增加。肥胖的增加与脂肪细胞肥大有关，这似乎至少部分是由于2-肾上腺素能刺激的脂解缺陷。然而，尽管肥胖显著增加，但与野生型小鼠相比，GX KO小鼠显示出对葡萄糖激发的改善的响应，表明胰岛素敏感性在这些小鼠中可能受到保护。基于我们的初步研究结果，我们推测脂肪组织巨噬细胞表达的GX sPLA 2调节脂肪细胞脂质储存和脂质代谢之间的平衡。因此，GX sPLA 2调节脂肪细胞肥大、脂肪组织炎症、FFA通量和全身胰岛素敏感性。为了验证这些假设，我们提出了以下3个具体目标：目标1。为了检验GX sPLA 2缺陷小鼠脂肪组织中FFA通量减少与胰岛素敏感性增加和脂肪组织炎症减少相关的假设。这将通过以下方式实现：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 sPLA 2缺乏是否防止高脂肪饮食诱导的胰岛素抵抗;和c）确定GX sPLA 2缺乏对小鼠脂肪组织炎症的影响。目标二。探讨巨噬细胞表达的GX sPLA 2在脂肪组织中的作用。这将通过进行骨髓移植实验来实现，其中野生型和GX KO小鼠将用源自野生型或GX KO小鼠的骨髓细胞重建。将在每组移植小鼠中评估脂肪细胞肥大、脂肪组织炎症和胰岛素敏感性。目标3。验证GX sPLA 2正调控TAG动员的假设。这将通过a）确定GX sPLA 2是否改变脂肪细胞中TAG合成或水解的速率;和B）确定GX sPLA 2是否通过激活激素敏感性脂肪酶促进TAG动员来实现。这些研究的结果有可能为调节脂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通量以降低胰岛素抵抗的新靶点。公共卫生相关性：在美国，肥胖现在是发展为2型糖尿病的最常见的危险因素。对人类和动物模型的研究表明，在长期暴露于营养过剩的情况下，脂肪储存效率低下可能会引发病理性炎症反应，破坏胰岛素发挥作用的能力。这项研究的目的是验证一个假设，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的影响。这一建议可以为预防或治疗糖尿病提供新的策略。

项目成果

Group X secretory phospholipase A(2) augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice.

• DOI: 10.1016/j.atherosclerosis.2010.08.054
• 发表时间: 2011-01
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Zack, Melissa;Boyanovsky, Boris B.;Shridas, Preetha;Bailey, William;Forrest, Kathy;Howatt, Deborah A.;Gelb, Michael H.;de Beer, Frederick C.;Daugherty, Alan;Webb, Nancy R.
• 通讯作者: Webb, Nancy R.