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(或褐褐色)脂肪组织通过将化学能转化为热来燃烧脂肪，并且一直 被认为是对抗肥胖的新治疗靶点。生热功能的调节 在过去的几年里，脂肪组织在转录水平上得到了广泛的研究。然而， 控制生热基因和效应器转录机制的上游信号通路 棕色或米色脂肪细胞的机制在很大程度上仍不清楚。我们最近的研究表明 MTOR复合体1(MTORC1)信号的过度激活与生热功能受损有关 Vivo(Liu等人，2014，细胞代谢)。与此一致的是，我们的初步数据显示， 通过脂肪特异性消融mTORC1的关键成分Raptor，上调了mTORC1的表达 棕色脂肪组织(BAT)和腹股沟白色脂肪组织(IWAT或米色脂肪)中的生热基因。在……里面 此外，我们还发现，mTORC1下游的自噬途径被冷应激激活，并 一种体内和细胞内的β3-肾上腺素能受体激动剂，抑制自噬可减少β3-肾上腺素能受体激动剂- 诱导原代脂肪细胞表达UCP1。为了支持这一点，通过脂肪特异性抑制自噬 自噬蛋白7(ATG7)的缺失抑制了基础和冷诱导的能量消耗、脂解和 UCP1在IWAT体内的表达。基于这些发现，我们假设自噬起着关键作用。 调节白色脂肪组织的褐变并介导mTORC1抑制的有益作用 人棕色脂肪细胞的产热作用。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。我们会 然后研究自噬是否是mTORC1下游调控的重要效应者。 利用脂肪特异性自噬相关蛋白7(ATG7)/猛禽双KO小鼠在WAT中产热。 最后，我们将描述mTORC1和自噬在调节原始人产热中的作用。 棕色脂肪细胞。这项研究将导致将mTORC1/自噬途径确定为关键 米色脂肪细胞分化和募集的调节因子对各种环境因素的反应。在……里面 此外，阐明与白色脂肪褐变有关的潜在信号机制可能揭示 有希望的抗肥胖药物靶点和导致肥胖相关的新治疗方法 代谢性疾病。