Adipocyte lipolysis, adipose tissue function, and lipodystrophy

脂肪细胞脂肪分解、脂肪组织功能和脂肪营养不良

• 批准号: 9211580
• 负责人: ERIN E. KERSHAW
• 金额: $ 11.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211580
• 关键词: Adipocytes; Adipose tissue; Animal Model; Biogenesis; Biological; Cardiovascular Diseases; Cells; Chronic; Complex; Data; Diabetes Mellitus; Disease; Dyslipidemias; Enzymes; Fatty Liver; Functional disorder; Funding; Gene Expression; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Impairment; Insulin; Insulin Resistance; Knowledge; Lead; Lipase; Lipids; Lipodystrophy; Lipolysis; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Mission; Mitochondria; Morbidity - disease rate; Mus; Muscle Cells; Natural History; Obesity; Outcome; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Positioning Attribute; Prevention; Preventive; Process; Proteins; Public Health; Research; Role; Signal Transduction; Source; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Transgenic Organisms; Translations; Triglycerides; United States National Institutes of Health; Work; adipocyte biology; base; diabetes mellitus therapy; disorder prevention; improved; innovation; metabolic phenotype; mortality; novel strategies; oxidation; prevent; programs; sterol esterase

 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.

 描述（由适用提供）：脂解的激活可以促进“脂肪毒性”或通过改善线粒体功能来增强氧化脂质处置。确切地说，脂解会产生这些不同的影响仍然是一个谜。考虑到影响脂解的众多疾病（即肥胖，糖尿病）（即胰岛素），这一知识差距代表了一个重要的问题。该研究计划的长期目标是确定脂解如何替代代谢益处与损害。该建议的总体目的是表征脂肪细胞脂解对脂肪组织功能本身的影响。中心假设是脂肪细胞脂解会产生在脂肪组织内维持甚至促进代谢稳态所需的必需脂质体征。这些脂质信号释放的破坏会损害脂肪组织功能，而这些脂质信号的释放增强可改善脂肪组织功能。我们进一步假设PPARγ是这些影响的关键介体。 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).拟议研究的理由是，脂解（和特定脂肪酶）替代或防止脂肪组织功能障碍的生物变量和潜在机制的表征将导致预防或治疗代谢疾病的新方法。在强有力的初步数据的指导下，将通过追求两个具体目的来检验该假设：1）确定脂肪组织表型的生理相关性和自然历史，这是由于脂肪细胞脂肪解析的长期变化以及PPAR激活在介导这些作用中的作用而引起的； 2）确定关键生物学变量的影响影响脂肪分解诱导的FA信号对脂肪细胞表型，线粒体功能和PPAR激活的影响。在AIM 1中，我们将使用已建立的方法来表征年轻小鼠的脂肪组织表型与脂肪细胞特异性脂肪酶（脂肪甘油三酸酯脂肪酶和马敏感脂肪酶）的脂肪特异性增加或减少。在AIM 2中，我们将同时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FAS，源和FAS型FAS）在脂肪细胞中影响线粒体功能和PPAR信号传导。在申请人的看来，这种方法具有创新性，因为它偏离了现状（增加脂肪分解是不良的，减少脂解的良好）是通过将注意力转移到脂解的有益作用上（增加脂肪溶解是好的，减少脂肪分解是不好的）。拟议的研究很重要，因为预计它将在预防和治疗多种代谢疾病方面具有广泛的翻译重要性。最终，这种知识有望提高我们对影响脂肪分解的众多疾病和疗法的理解，并为预防和/或治疗干预提供新的靶标。