Adipocyte lipolysis, adipose tissue function, and lipodystrophy

 描述(申请人提供)：激活脂肪分解可通过改善线粒体功能来促进“脂肪毒性”或增强氧化脂质处置。脂肪分解究竟如何以及为什么会产生这些不同的影响仍然是个谜。鉴于影响脂肪分解的多种疾病(如肥胖、糖尿病)和治疗方法(如胰岛素)，这一认识差距是一个重要问题。这项研究计划的长期目标是确定脂肪分解如何交替地对代谢有益而不是有害。这项建议的总体目标是描述脂肪细胞脂解对脂肪组织功能本身的影响。中心假说是脂肪细胞脂解产生维持，甚至促进脂肪组织内代谢动态平衡所需的必要的脂类信号。这些脂类信号释放的中断会损害脂肪组织的功能，而这些脂类信号的增强释放会改善脂肪组织的功能。我们进一步假设，PPARγ是这些效应的关键调节因子。这一假说基于1)缺乏关键脂解蛋白的人类的表型，2)我们的数据表明，脂肪细胞脂解的慢性损害降低了PPARγ靶基因的表达，并促进了脂肪组织功能障碍和脂肪营养不良，以及3)证据表明，脂解产生了基本的脂质信号(即PPAR)。这项拟议研究的基本原理是，对脂解作用(和特定脂肪酶)交替促进或预防脂肪组织功能障碍的生物学变量和潜在机制的表征将导致预防或治疗代谢性疾病的新方法。在强大的初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)确定脂肪细胞脂解长期变化导致的脂肪组织表型的生理学相关性和自然历史，以及PPAR激活在介导这些效应中的作用；2)确定影响脂解诱导的FA信号的关键生物学变量对脂肪细胞表型、线粒体功能和PPAR激活的影响。在目标1中，我们将使用已建立的方法来表征年轻和老年小鼠的脂肪组织表型，这些小鼠的关键脂肪酶(脂肪甘油三酯脂肪酶和激素敏感脂肪酶)具有脂肪细胞特异性的增加或减少。在目标2中，我们将使用细胞和动物模型来确定关键的生物学变量(即刺激的大小/持续时间/类型、酶释放FA S、FAs的来源和类型)如何影响脂肪细胞的线粒体功能和PPAR信号。在申请人看来，这种方法是创新的，因为它改变了现状(增加脂肪分解是不好的，减少脂肪分解是好的)，将重点转移到脂肪分解的好处上(增加脂肪分解是好的，减少脂肪分解是不好的)。这项拟议的研究具有重要意义，因为它有望在预防和治疗广泛的代谢性疾病方面具有广泛的翻译重要性。最终，这些知识有望提高我们对影响脂肪分解的多种疾病和治疗方法的了解，并为预防和/或治疗干预提供新的目标。

 DESCRIPTION (provided by applicant): Activation of lipolysis can alternatively promote "lipotoxicity" or enhance oxidative lipid disposal by improving mitochondrial function. Precisely how and why lipolysis can have these divergent effects remains a mystery. This knowledge gap represents an important problem given the numerous diseases (i.e. obesity, diabetes) and therapies (i.e. insulin) that influence lipolysis. The long-term goal of this research program is t determine how lipolysis alternatively contributes to metabolic benefit versus harm. The overall objective of this proposal is to characterize the impact of adipocyte lipolysis on adipose tissue function itself. The central hypothesis is that adipocyte lipolysis generates essential lipid signas required to maintain, and even promote, metabolic homeostasis within adipose tissue. Disruption in the release of these lipid signals impairs adipose tissue function, whereas enhanced release of these lipid signals improves adipose tissue function. We further hypothesize that PPARγ is a critical mediator of these effects. This hypothesis is based on 1) the phenotypes of humans lacking key lipolytic proteins, 2) our data demonstrating that chronic impairment of adipocyte lipolysis reduces PPARγ target gene expression and promotes adipose tissue dysfunction and lipodystrophy, and 3) evidence suggesting that lipolysis generates essential lipid signals (i.e. for PPARs). The rationale for the proposed research is that characterization of the biological variables and underlying mechanisms by which lipolysis (and specific lipases) alternatively promote or prevent adipose tissue dysfunction will lead to new approaches for preventing or treating metabolic disease. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) to determine the physiological relevance and natural history of adipose tissue phenotypes resulting from long-term changes in adipocyte lipolysis as well as the role of PPAR activation in mediating these effects; and 2) to determine the impact of key biological variables influencing lipolysis-induced FA signaling on adipocyte phenotype, mitochondrial function, and PPAR activation. In Aim 1, we will use established methods to characterize the adipose tissue phenotype of young versus old mice with adipocyte-specific increases or decreases in key lipases (adipose triglyceride lipase and hormone-sensitive lipase). In Aim 2, we will use both cell and animals models to determine how key biological variables (i.e. magnitude/duration/type of stimulus, enzyme releasing FA s, source and type FAs) influence mitochondrial function and PPAR signaling in adipocytes. This approach is innovative, in the applicant's opinion, because it departs from the status quo (increasing lipolysis is bad, decreasing lipolysis is good) by shifting focus onto the beneficial effect of lipolysis (increasing lipolysis is good, decreasing lipolysis is bad). The proposed research is significant because it is expected to have broad translation importance in the prevention and treatment of a wide range of metabolic diseases. Ultimately, such knowledge is expected to improve our understanding of numerous diseases and therapies that impact lipolysis as well as provide new targets for prevention and/or therapeutic intervention.