Defining the role of skeletal muscle peroxisomes in glucose homeostasis

定义骨骼肌过氧化物酶体在葡萄糖稳态中的作用

• 批准号: 9188811
• 负责人: Robert Charles Noland
• 金额: $ 33.3万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188811
• 关键词: Aerobic; Caloric Restriction; Catabolism; Ceramides; Chemicals; Consumption; Development; Environment; Exercise; Exposure to; Fatty acid glycerol esters; Fumonisin B1; Future; Gene Expression; Genes; Goals; Health; High Fat Diet; Impairment; Insulin; Insulin Resistance; Intervention; Intramuscular; Investigation; Knowledge; Laboratories; Lead; Link; Lipids; Liver; Measures; Mediating; Membrane Potentials; Metabolic; Metabolic Diseases; Methionine; Mind; Mitochondria; Modeling; Monitor; Mus; Muscle; Muscle Fibers; Oils; Organelles; Pathogenesis; Pathway interactions; Play; Predisposition; Proteins; RNA; Regulation; Research; Resveratrol; Role; Route; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Stimulus; Stress; Testing; Therapeutic; Therapeutic Effect; Very Long Chain Fatty Acid; adiponectin; blood glucose regulation; design; diet and exercise; enzyme activity; gene function; improved; insight; insulin sensitivity; insulin sensitizing drugs; insulin signaling; lipid metabolism; mouse model; overexpression; oxidation; peroxisome; public health relevance; response; theories; therapeutic target; thermozymocidin; uptake

DESCRIPTION (provided by applicant): Excess intramuscular lipids are thought to play a causal role in insulin resistance. As such, examination of pathways involved in lipid uptake, storage and catabolism has provided great insight into mechanisms of lipid- induced insulin resistance. It is clear that lipid storage outpaces lipid catabolism in models of insulin resistanc, thus strategies designed to reduce cellular lipid accumulation offer therapeutic potential. Much research has investigated aspects of these pathways; however, the importance of peroxisomes in insulin resistance remains largely unknown. This may be a critical oversight as peroxisomes are almost exclusively involved in lipid metabolism. With this in mind, the presence of α, ß, and ω-oxidative pathways provides them with the capacity to metabolize a broad spectrum of lipids. With this extensive network of catabolic pathways, the study of peroxisomal function in lipid-induced insulin resistance seems likely to yield important insight relevant to the pathogenesis of this metabolic disease. The focus of my laboratory is to bridge this gap in knowledge. We have found peroxisomes are elevated in insulin resistant skeletal muscle. Alternatively, we have also consistently seen heightened peroxisomes in muscle from models protected from developing insulin resistance (increased aerobic capacity, caloric restriction, methionine restriction, and muscle-specific CPT1b deficiency). In combination, these results lead us to predict that the increase in peroxisomes in response to lipid-induced insulin resistance is a protective mechanism designed to alleviate a lipotoxic environment; however, this remains speculative. We will test this hypothesis in Specific Aims 1 & 2 by abrogating peroxisomal function and determining if this 1) results in a predisposition toward insulin resistance, and 2) limits the therapeutic effects of insulin sensitizing interventions (caloric restriction, exercise and muscle-specific CPT1b deficiency). Our studies show peroxisomal responses in muscle often differ than those in liver. This poses an interesting conundrum as most information regarding peroxisomal regulation has been established in the liver. If we are to achieve our long-term goal of using results from these studies to develop an approach targeting peroxisomes that offers therapeutic potential, it is critical to gain a mechanistic understanding of pathways that dictate peroxisomal adaptations in skeletal muscle. In this regard, our evidence leads us to hypothesize that peroxisomes in muscle are responsive to energy status and PGC1α is a primary regulator of these responses. This will be tested in Specific Aim 3 where peroxisomal adaptations will be monitored in muscle-specific, PGC1α-deficient models (myotubes and mouse models) in response to stimuli that induce peroxisomes (AICAR, resveratrol, high fat diet, exercise and caloric restriction). Collectively, results from Aims 1 & 2 are expected to yield insight that will define the role of skeletal muscle peroxisomes in glucose homeostasis, while findings from Aim 3 are designed to provide mechanistic insight as to how future investigations can be designed to develop strategies that regulate peroxisomal function in skeletal muscle to treat insulin resistance.

描述（由申请方提供）：认为过量肌内脂质在胰岛素抵抗中起因果作用。因此，对脂质摄取、储存和代谢途径的研究为脂质诱导的胰岛素抵抗机制提供了很好的见解。很明显，在胰岛素抵抗模型中，脂质储存的速度超过了脂质催化剂的速度，因此旨在减少细胞脂质积累的策略提供了治疗潜力。许多研究已经调查了这些途径的各个方面;然而，过氧化物酶体在胰岛素抵抗中的重要性在很大程度上仍然未知。这可能是一个关键的疏忽，因为过氧化物酶体几乎完全参与脂质代谢。考虑到这一点， α、β和ω-氧化途径使其具有代谢广谱脂质的能力。有了这个广泛的分解代谢途径网络，脂质诱导的胰岛素抵抗中过氧化物酶体功能的研究似乎可能产生重要的见解，这种代谢疾病的发病机制。我的实验室的重点是弥合这一知识差距。我们已经发现过氧化物酶体在胰岛素抵抗的骨骼肌中升高。或者，我们也一直看到在保护免受胰岛素抵抗（增加有氧能力，热量限制，甲硫氨酸限制和肌肉特异性CPT 1b缺乏症）的模型中，肌肉中的过氧化物酶体升高。结合起来，这些结果使我们预测，过氧化物酶体的增加，以响应脂质诱导的胰岛素抵抗是一种保护机制，旨在减轻脂毒性的环境，但是，这仍然是推测。我们将在特定目标1和2中通过消除过氧化物酶体功能并确定这是否1）导致胰岛素抵抗的易感性，以及2）限制胰岛素增敏干预（热量限制，运动和肌肉特异性CPT 1b缺乏症）的治疗效果来测试这一假设。我们的研究表明，肌肉中的过氧化物酶体反应往往不同于肝脏。这提出了一个有趣的难题，因为大多数关于过氧化物酶体调节的信息已经在肝脏中建立。如果我们要实现我们的长期目标，利用这些研究的结果来开发一种靶向过氧化物酶体的方法，提供治疗潜力，这是至关重要的，以获得一个机制的理解途径，决定骨骼肌过氧化物酶体的适应。在这方面，我们的证据使我们假设肌肉中的过氧化物酶体对能量状态有反应，而PGC 1 α是这些反应的主要调节因子。这将在特定目标3中进行测试，其中将在肌肉特异性PGC 1 α缺陷模型（肌管和小鼠模型）中监测过氧化物酶体适应，以响应诱导过氧化物酶体的刺激（AICAR、白藜芦醇、高脂饮食、运动和热量限制）。总的来说，目标1和2的结果预计将产生将定义骨骼肌过氧化物酶体在葡萄糖稳态中的作用的见解，而目标3的发现旨在提供关于如何设计未来研究以开发调节骨骼肌中过氧化物酶体功能以治疗胰岛素抵抗的策略的机制见解。