Defining the role of skeletal muscle peroxisomes in glucose homeostasis

描述(由申请人提供)：肌肉内过多的脂肪被认为在胰岛素抵抗中起到了因果作用。因此，对参与脂肪摄取、储存和分解代谢的途径的研究为了解脂肪诱导的胰岛素抵抗的机制提供了很好的见解。显然，在胰岛素抵抗模型中，脂肪储存的速度超过了脂肪分解代谢的速度，因此，旨在减少细胞内脂肪堆积的策略提供了治疗潜力。许多研究已经研究了这些途径的各个方面；然而，过氧化体在胰岛素抵抗中的重要性在很大程度上仍然不清楚。这可能是一个关键的疏忽，因为过氧化体几乎完全参与脂类代谢。考虑到这一点， α、ç和ω-氧化途径为它们提供了代谢广泛脂类的能力。有了这个广泛的分解代谢途径网络，研究过氧体在脂质诱导的胰岛素抵抗中的作用似乎可能产生与这种代谢性疾病的发病机制相关的重要见解。我的实验室的重点是弥合这一知识差距。我们发现，在胰岛素抵抗的骨骼肌中，过氧化物体水平升高。或者，我们也一直在防止胰岛素抵抗(有氧能力增加、热量限制、蛋氨酸限制和肌肉特异性CPT1b缺乏症)的模型中看到肌肉中过氧化物酶的升高。综上所述，这些结果使我们预测，脂质诱导的胰岛素抵抗导致的过氧化体增加是一种旨在缓解脂毒环境的保护性机制；然而，这仍然是推测。我们将通过消除过氧化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(卡路里限制、运动和肌肉特异性CPT1b缺乏)的治疗效果，在特定的目标1和2中测试这一假设。我们的研究表明，肌肉中的过氧化物体反应通常与肝脏中的不同。这提出了一个有趣的难题，因为关于过氧化物体调节的大多数信息都已在肝脏中建立。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针对过氧化物体的方法，提供治疗潜力，关键是从机制上理解决定骨骼肌中过氧化物体适应的途径。在这方面，我们的证据引导我们假设肌肉中的过氧化物体对能量状态做出反应，而Pgc1α是这些反应的主要调节因子。这将在特定的目标3中进行测试，在该目标中，将监测肌肉特异性的Pgc1α缺陷模型(肌管和小鼠模型)对诱导过氧酶体的刺激(AICAR、白藜芦醇、高脂饮食、运动和热量限制)的反应。总而言之，AIMS 1和AIMS 2的结果预计将产生定义骨骼肌过氧化体在葡萄糖稳态中的作用的洞察力，而AIMS 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过氧体功能以治疗胰岛素抵抗的策略的机械性见解。

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.