Regulators of adipocyte oxidative metabolism

脂肪细胞氧化代谢的调节因子

• 批准号: 10391144
• 负责人: Anastasia Kralli
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391144
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Biogenesis; Bioinformatics; Biology; Body Temperature; Brown Fat; Cardiovascular Diseases; Cell Respiration; Cell physiology; Cells; Code; Coupled; Defect; Development; Disease; ERR1 protein; Environment; Estrogen Nuclear Receptor; Family; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Grant; Health; Heart; Homeostasis; Human; Insulin Resistance; Intervention; Kidney; Lead; Link; Lipids; Liver; Messenger RNA; Metabolic; Metabolism; Mining; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Myopathy; Nature; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nuclear; Nuclear Orphan Receptor; Nuclear Receptors; Nutrient; Obesity; Obesity associated disease; Organelles; Oxidative Phosphorylation; Oxides; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmacology; Physiological; Physiology; Post-Transcriptional Regulation; Proteins; Publishing; Receptor Signaling; Regulation; Regulator Genes; Regulatory Element; Role; Signal Transduction; Skeletal Muscle; Sum; Tertiary Protein Structure; Testing; Therapeutic Intervention; Thermogenesis; Tissues; Work; adipocyte biology; base; cell type; estrogen-related receptor; gene induction; insight; insulin sensitivity; lifestyle intervention; loss of function; member; mouse model; novel; overexpression; oxidation; physiologic stressor; recruit; response; trait; transcription factor

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.

项目概要 脂肪氧化代谢对于人类健康至关重要。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制剂 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 多年来已经确定了脂肪细胞氧化代谢的重要调节因子，例如成员 PGC-1 共激活因子家族的成员和 PPAR（过氧化物酶体增殖物激活因子）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 协调促进线粒体生物发生和氧化代谢。挖掘受调控的基因 PGC-1 和 ERR，与生物信息学方法相结合以确定 PGC-1/ERR 的关联 PPAR 途径和代谢的靶标，使我们发现了一种新的且特征不明的 Mcrip2 蛋白与脂肪细胞氧化代谢高度相关。本提案提出的前提 是 Mcrip2，一种细胞和分子功能未知的蛋白质，尚未与 代谢或生理学，由 PGC-1、PPAR 和 ERR 因子诱导，起到增强基础和 肾上腺素能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节网络。 Mcrip2 与蛋白质的相互作用 参与 mRNA 加工和周转表明 Mcrip2 通过调节基因发挥其功能 转录后水平的表达。值得注意的是，我们对控制后期的机制知之甚少。 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 使用增益和丢失来研究 Mcrip2 在脂肪细胞基础氧化代谢和肾上腺素能反应中的作用 原代棕色和腹股沟脂肪细胞中的功能方法，并描绘了 Mcrip2 的水平 影响基因表达。它还将确定 Mcrip2 对线粒体的生理意义 功能和适应性生热作用，使用小鼠模型。最后，研究将阐明 Mcrip2 影响脂肪细胞生物学的机制，通过定义所需的 Mcrip2 蛋白域 基础脂肪细胞和肾上腺素刺激脂肪细胞中的功能和关键的 Mcrip2 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节， 并可能为疾病的治疗干预提出新的目标和途径，这些目标和途径可以受益于 氧化能力增加，例如肥胖和肥胖相关疾病。