Adipocyte lipolysis, adipose tissue function, and lipodystrophy

 描述（由申请人提供）：脂解的激活可以通过改善线粒体功能来促进“脂毒性”或增强氧化脂质处置。确切地说，脂肪分解如何以及为什么会产生这些不同的效果仍然是一个谜。鉴于影响脂解的许多疾病（即肥胖症、糖尿病）和治疗（即胰岛素），这种知识差距代表了一个重要问题。这项研究计划的长期目标是确定脂肪分解如何对代谢有益而有害。本提案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。核心假设是脂肪细胞脂解产生维持甚至促进脂肪组织内代谢稳态所需的必需脂质信号。这些脂质信号释放的中断损害脂肪组织功能，而这些脂质信号的增强释放改善脂肪组织功能。我们进一步假设PPARγ是这些效应的关键介质。该假设基于1）缺乏关键脂解蛋白的人类表型，2）我们的数据表明脂肪细胞脂解的慢性损伤降低了PPARγ靶基因表达并促进脂肪组织功能障碍和脂肪代谢障碍，3）证据表明脂解产生了必需的脂质信号（即PPARs）。拟议研究的基本原理是，脂解（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。在强有力的初步数据的指导下，该假设将通过追求两个特定目标进行检验：1）确定脂肪细胞脂解的长期变化导致的脂肪组织表型的生理相关性和自然史以及PPAR活化在介导这些效应中的作用;和2）确定影响脂解诱导的FA信号传导的关键生物学变量对脂肪细胞表型、线粒体功能和PPAR活化的影响。在目标1中，我们将使用已建立的方法来表征脂肪细胞特异性增加或减少关键脂肪酶（脂肪甘油三酯脂肪酶和脂肪敏感性脂肪酶）的年轻与老年小鼠的脂肪组织表型。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（即刺激的幅度/持续时间/类型，酶释放FA，来源和类型FA）如何影响脂肪细胞中的线粒体功能和PPAR信号传导。在申请人看来，这种方法是创新的，因为它通过将焦点转移到脂解的有益效果（增加脂解是好的，减少脂解是坏的）上而脱离了现状（增加脂解是坏的，减少脂解是好的）。这项研究意义重大，因为它有望在预防和治疗各种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解的许多疾病和疗法的理解，并为预防和/或治疗干预提供新的靶点。

 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.