Regulators of adipocyte oxidative metabolism

项目总结 脂肪氧化代谢对人类健康至关重要。脂肪细胞线粒体缺陷与 脂肪细胞功能障碍和胰岛素抵抗，而生活方式干预和药物治疗 促进脂肪细胞氧化能力，促进代谢健康和胰岛素敏感性。研究结束 几年来已经确定了脂肪细胞氧化代谢的重要调节因子，如成员 PGC-1共激活因子家族和PPAR(过氧化体增殖物激活的)核受体 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 通过对数百个基因的直接和间接调节来影响基因表达和细胞功能 协调推进线粒体生物发生和氧化代谢。挖掘受以下因素调控的基因 PGC-1和ERRS，结合生物信息学方法确定PGC-1/ERR的关联 具有PPAR途径和新陈代谢的靶点，使我们发现了一种新的、特征不佳的 蛋白质，Mcrip2，与脂肪细胞氧化代谢高度相关。这项建议的前提是 Mcrip2是一种细胞和分子功能未知的蛋白质，目前还没有与 代谢或生理，是由PGC-1，PPAR和ERR因子诱导的，作用于增强基础和 肾上腺素刺激氧化代谢基因的表达，因此是 控制脂肪细胞氧化代谢的调控网络。Mcrip2与蛋白质的相互作用 参与mRNA的加工和转换提示Mcrip2通过调控基因发挥作用 转录后水平的表达。值得注意的是，我们对控制后遗症的机制知之甚少。 脂肪细胞氧化代谢途径中的转录步骤。拟议的工作将定义角色 Mcrip2在脂肪细胞基础氧化代谢和肾上腺素能反应中的表达 在原代棕色和腹股沟脂肪细胞中的功能途径，并描绘了Mcrip2的水平 影响基因表达。它还将确定mcrip2对线粒体的生理学意义。 功能和适应性产热，使用小鼠模型。最后，这些研究将阐明 通过定义Mcrip2蛋白结构域来影响脂肪细胞生物学的机制 基础脂肪细胞和肾上腺刺激脂肪细胞的功能和关键的Mcrip2相互作用伙伴。在……里面 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， 并可能为疾病的治疗干预提出新的目标和途径，这些疾病可以从 氧化能力增强，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.