选择性PPARγ激动剂INT131调控适应性产热和AD-MSCs分化成棕色样脂肪细胞的机制研究

Brown adipose tissue is the main target for adaptive thermogenesis, which dissipates excess energy to maintain body temperature, and reduce obesity and improve metabolic abnormalities though converting fat into heat. PPAR γ is an important transcriptional regulator critical for brown adipose tissue recruitment and white adipose tissue browning. The selective PPAR γ agonist INT131 retains the pharmacodynamic activity of the full agonist without the side effects. However, the mechanism of INT131 regulating adaptive heat production and differentiation of adipose-derived mesenchymal stem cells into brown-like adipocytes are still unclear.This project intends to use the high-fat diet-induced obese mouse model to evaluate the regulation of adaptive heat production by INT131, which is highly distributed in adipose tissues, and elucidate the differences of different PPAR γ ligands. Simultaneously, the effects of INT131 on the differentiation of adipose-derived mesenchymal stem cells from different adipose tissues of mice into brown-like adipocytes will be further elucidated. Additionally, we reveal the molecular mechanism and related signaling pathways of adaptive thermogenesis and brown adipocyte differentiation regulated by INT131 from the gene-protein-metabolites level, which provides theoretical support for its clinical application.

棕色脂肪组织是适应性产热的主要靶器官，通过燃烧脂肪将其转变为热量消耗体内过剩的能量以维持体温，同时可减轻肥胖和改善代谢异常。PPARγ是调节脂肪组织功能的重要转录因子，对棕色脂肪组织募集和白色脂肪组织褐变至关重要。选择性PPARγ激动剂INT131保留了全激动剂的药效学活性，但不会诱导泛激动活性相关副作用，然而其对适应性产热以及脂肪源间充质干细胞诱导分化成棕色样脂肪细胞的调控作用及其分子机制尚不明确。本项目拟利用高脂饮食诱导的肥胖小鼠模型评价具有较高脂肪组织靶向分布的INT131对适应性产热的调节作用，确定不同PPARγ配体作用的差异，同时阐明INT131对小鼠不同脂肪组织脂肪源间充质干细胞诱导分化成棕色样脂肪细胞的影响，并从基因-蛋白-代谢物层面揭示INT131对适应性产热和棕色脂肪细胞诱导分化调控的具体分子机制及相关信号通路，从而为其临床应用提供理论支持。

棕色脂肪组织（brown adipose tissue, BAT）是适应性产热的主要靶器官，激活BAT、促进白色脂肪组织（white adipose tissue, WAT）向米色脂肪细胞转化，通过调节机体适应性产热过程增加机体能量的消耗，是肥胖、胰岛素抵抗等代谢紊乱相关疾病治疗的热点。过氧化物酶体增殖物激活受体-γ (peroxisome proliferators-activated receptors γ, PPARγ)是调节脂肪组织功能的重要转录因子，对棕色脂肪组织募集和白色脂肪组织褐变至关重要。该研究中我们从动物水平、细胞水平和分子水平对INT131是否能够更安全、更高效的促进适应性产热，并诱导不同部位脂肪组织AD-MSCs分化成棕色样脂肪细胞进行了系统性研究；明确了PPARγ激动剂具有增加小鼠适应性产热能力，能够促进小鼠棕色脂肪激活并诱导皮下脂肪的棕色化，并且证实了选择性PPARγ激动剂INT131对适应性产热的调节作用较PPARγ全激动剂罗格列酮更强；同时INT131促进适应性产热的物质基础是通过优先利用脂质氧化代谢进行供能，INT131能够显著增加脂质的分解代谢，尤其是促进小鼠腹内脂肪的分解及转运；并证实了INT131能够促进小鼠不同部位脂肪组织AD-MSCs的分化成熟，INT131并且能够显著上调棕色特异性基因的表达。总体而言，PPARγ选择性激动剂INT131能够激活BAT、促进WAT棕色化，通过调节机体适应性产热过程，以增加机体能量的消耗，有望成为治疗肥胖、胰岛素抵抗等代谢异常病症的新策略。

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