Regulators of adipocyte oxidative metabolism

项目摘要 脂肪氧化代谢对人体健康至关重要。脂肪细胞线粒体的缺陷与 脂肪细胞功能障碍和胰岛素抵抗，而生活方式干预和药物 促进脂肪细胞氧化能力，促进代谢健康和胰岛素敏感性。来的研究 几年来，已经鉴定了脂肪细胞氧化代谢的重要调节剂，例如 PGC-1辅激活因子家族的核受体和过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活的 受体）和ERR（雌激素相关受体）亚家族。这些转录因子发挥它们的作用 通过直接和间接调节数百个基因来影响基因表达和细胞功能， 协同促进线粒体生物合成和氧化代谢。挖掘受 PGC-1和ERR，结合生物信息学方法确定PGC-1/ERR的关联 靶点与过氧化物酶体增殖物激活受体途径和代谢，使我们确定了一个新的和不明确的特点， Mcrip 2蛋白与脂肪细胞氧化代谢高度相关。这项提议的前提是 是Mcrip 2，一种未知细胞和分子功能的蛋白质， 由PGC-1、PPAR和ERR因子诱导的代谢或生理学，用于增强基础和 肾上腺素能刺激的氧化代谢基因的表达，因此是一个关键因素， 控制脂肪细胞氧化代谢的调节网络。Mcrip 2与蛋白质的相互作用 参与mRNA的加工和周转，表明Mcrip 2通过调节基因表达来发挥其功能。 在转录后水平表达。值得注意的是，我们对控制后- 脂肪细胞氧化代谢途径中的转录步骤。拟议的工作将确定 Mcrip 2在脂肪细胞基础氧化代谢和肾上腺素能反应中的作用， 在原代棕色和腹股沟脂肪细胞中的功能方法，并描绘了Mcrip 2 影响基因表达。这也将确定Mcrip 2对线粒体的生理意义。 功能和适应性产热，使用小鼠模型。最后，这些研究将阐明 Mcrip 2影响脂肪细胞生物学的机制，通过定义 在基础和肾上腺素能刺激的脂肪细胞中的功能和关键的Mcrip 2相互作用伙伴。在 总之，这项工作将首次深入了解脂肪细胞氧化功能的转录后调控， 并可能提出新的目标和途径，用于治疗干预疾病， 氧化能力增加，如肥胖和肥胖相关疾病。

PROJECT SUMMARY Adipose oxidative metabolism is central to human health. Defects in adipocyte mitochondria are linked to adipocyte dysfunction and insulin resistance, whereas lifestyle interventions and pharmacological agents that promote adipocyte oxidative capacity promote metabolic health and insulin sensitivity. Studies over several years have identified important regulators of adipocyte oxidative metabolism, such as members of the PGC-1 coactivator family, and nuclear receptors of the PPAR (peroxisome proliferator-activated receptor) and ERR (Estrogen-related receptor) subfamilies. These transcription factors exert their effects on gene expression and cellular function by both direct and indirect regulation of hundreds of genes that coordinately promote mitochondrial biogenesis and oxidative metabolism. Mining of genes regulated by PGC-1s and ERRs, coupled to bioinformatic approaches to determine associations of PGC-1/ERR targets with PPAR pathways and metabolism, has led us to identify a new and poorly characterized protein, Mcrip2, as highly associated with adipocyte oxidative metabolism. The premise of this proposal is that Mcrip2, a protein of unknown cellular and molecular function, that has not been linked yet to metabolism or physiology, is induced by PGC-1, PPAR and ERR factors, acts to enhance basal and adrenergically stimulated expression of oxidative metabolism genes, and is thus a critical element of the regulatory networks that control adipocyte oxidative metabolism. Interactions of Mcrip2 with proteins involved in mRNA processing and turnover suggest that Mcrip2 exerts its function by regulating gene expression at the post-transcriptional level. Notably, we know little about mechanisms controlling post- transcriptional steps in adipocyte oxidative metabolism pathways. The proposed work will define the role of Mcrip2 in adipocyte basal oxidative metabolism and adrenergic responses, using gain- and loss-of function approaches in primary brown and inguinal adipocytes, and delineate the level at which Mcrip2 impacts gene expression. It will also determine the physiologic significance of Mcrip2 for mitochondrial function and adaptive thermogenesis, using a mouse model. Finally, the studies will elucidate the mechanism by which Mcrip2 impacts adipocyte biology, by defining Mcrip2 protein domains required for function and critical Mcrip2 interacting partners in basal and adrenergically stimulated adipocytes. In sum, the work will give first insights into post-transcriptional regulation of adipocyte oxidative function, and may suggest new targets and avenues for therapeutic intervention in diseases that can benefit from increases in oxidative capacity, such as obesity and obesity-related diseases.