Regulation of Beige Fat Development by mTORC1 and Autophagy

mTORC1 和自噬对米色脂肪发育的调节

• 批准号: 9207190
• 负责人: Meilian Liu
• 金额: $ 30.71万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9207190
• 关键词: 3-methyladenine; Ablation; Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Agonist; Alpha Cell; Anti-Obesity Agents; Autophagocytosis; Biopsy; Brown Fat; Cells; Cellular Metabolic Process; Chemicals; Clinical; Complex; Data; Development; Diet; Disease; Down-Regulation; Drug Targeting; Energy Metabolism; Environmental Risk Factor; FRAP1 gene; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Glucose Intolerance; Goals; Health; High Fat Diet; Human; Impairment; Inflammation; Insulin Resistance; Isoproterenol; Knock-out; Knockout Mice; Lead; Lipids; Lipolysis; Mediating; Metabolic Diseases; Metabolism; Mus; Obesity; Pathway interactions; Play; Proteins; Raptors; Recruitment Activity; Regulation; Resistance; Rodent; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; Study models; Testing; Thermogenesis; Thinness; Transcriptional Regulation; United States; Up-Regulation; adipocyte differentiation; base; diabetic; in vivo; inhibition of autophagy; lipid biosynthesis; mTOR inhibition; new therapeutic target; non-diabetic; novel; novel therapeutic intervention; obesity treatment; prevent; response; subcutaneous; therapeutic target; uncoupling protein 1

Brown and Beige (or brite) adipose tissues burn lipid by converting chemical energy into heat, and have been considered as a new therapeutic target to counteract obesity. The regulation of thermogenic function in adipose tissue at the transcriptional level has been extensively studied in the past several years. However, the upstream signaling pathways that control the transcriptional machinery of thermogenic genes and effector mechanisms in brown or beige adipocytes remain largely unknown. Our recent study demonstrated that overactivation of mTOR Complex 1 (mTORC1) signaling is associated with impaired thermogenic function in vivo (Liu et al., 2014, Cell Metabolism). Consistent with this, our preliminary data showed that inactivation of mTORC1 by adipose-specific ablation of raptor, a key component of mTORC1, up-regulated the expression of thermogenic genes in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT or beige fat). In addition, we also found that the autophagy, a pathway downstream of mTORC1 is activated by cold stress and a β3-adrenoceptor agonist in vivo and in cells, and inhibition of autophagy diminishes β3-adrenoceptor agonist- induced UCP1 expression in primary adipocytes. In support of this, inhibition of autophagy by adipose-specific deletion of autophagy protein 7 (ATG7) suppresses basal and cold-induced energy expenditure, lipolysis and UCP1 expression in iWAT in vivo. Based on these findings, we hypothesize that autophagy plays a critical role in regulating the browning of white adipose tissue and mediates the beneficial effect of mTORC1 inhibition on thermogenesis in human brown adipocytes. We will first determine whether and how inhibiting mTORC1 and autophagy alters beige adipocyte differentiation and thermogenesis via cell-autonomous mechanisms. We will then investigate whether autophagy is an essential effector downstream of mTORC1 in regulating thermogenesis in WAT using adipose-specific autophagy-related protein 7 (ATG7)/raptor double KO mice. Lastly, we will delineate the role of mTORC1 and autophagy in regulating thermogenesis in primary human brown adipocytes. This study will lead to the identification of the mTORC1/autophagy pathway as a critical regulator of beige adipocyte differentiation and recruitment in response to various environmental factors. In addition, elucidation of the underlying signaling mechanisms involved in the browning of white fat may reveal promising new anti-obesity drug targets and lead to novel therapeutic approaches for obesity-associated metabolic diseases.

棕色和米色（或棕色）脂肪组织通过将化学能转化为热量来燃烧脂质，并且已被 被认为是对抗肥胖的新治疗靶点。 在过去的几年里，人们主要在转录水平上研究脂肪组织，然而， 控制产热基因和效应子转录机制的上游信号通路 我们最近的研究表明，棕色或米色脂肪细胞的机制仍然很大程度上未知。 mTOR 复合物 1 (mTORC1) 信号传导的过度激活与产热功能受损有关 与此一致，我们的初步数据表明，体内的失活 通过对 raptor（mTORC1 的关键组成部分）进行脂肪特异性消融，mTORC1 上调了 棕色脂肪组织（BAT）和腹股沟白色脂肪组织（iWAT 或米色脂肪）中的产热基因。 此外，我们还发现冷应激会激活mTORC1下游的自噬通路， 体内和细胞中的 β3-肾上腺素受体激动剂，并且抑制自噬会减少 β3-肾上腺素受体激动剂- 诱导原代脂肪细胞中的 UCP1 表达支持这一点，脂肪特异性抑制自噬。 自噬蛋白 7 (ATG7) 的缺失会抑制基础和寒冷诱导的能量消耗、脂肪分解和 基于这些发现，我们认为自噬在体内 iWAT 中发挥着关键作用。 调节白色脂肪组织的褐变并介导 mTORC1 抑制的有益作用 我们将首先确定是否以及如何抑制 mTORC1 和 自噬通过细胞自主机制改变米色脂肪细胞的分化和产热作用。 然后研究自噬是否是 mTORC1 下游调节的重要效应子 使用脂肪特异性自噬相关蛋白 7 (ATG7)/raptor 双 KO 小鼠在 WAT 中产热。 最后，我们将描述 mTORC1 和自噬在调节原代人类生热作用中的作用 这项研究将确定 mTORC1/自噬途径是一个关键的途径。 调节米色脂肪细胞分化和招募以响应各种环境因素。 此外，阐明白色脂肪褐变所涉及的潜在信号机制可能会揭示 有前景的新抗肥胖药物靶点，并为肥胖相关疾病带来新的治疗方法 代谢性疾病。