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The role of ChREBP-dependent de novo lipogenesis in metabolic and thermogenic activities of brown and white adipose tissue

ChREBP 依赖性从头脂肪生成在棕色和白色脂肪组织代谢和产热活动中的作用

基本信息

批准号：
402129868
负责人：
Dr. Ludger Scheja
金额：
--
依托单位：
Institut für Biochemie und Molekulare Zellbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/402129868?language=en
关键词：
role ChREBP dependent de novo

项目摘要

The proposed project aims at understanding the functional significance of de novo lipogenesis (DNL) for regulating adaptive thermogenesis as well as cold-induced tissue remodeling. Both processes are triggered in mammals under cold stress and contribute to maintaining body temperature. Adaptive thermogenesis is mediated through ATP-uncoupled fuel oxidation in brown adipocytes (in brown adipose tissue) and beige adipocytes (in white adipose tissue), collectively called "thermogenic adipocytes". As a consequence of chronic cold exposure, more thermogenic adipocytes and vascular endothelial cells are formed, increasing thermogenic capacity. Recent studies show that thermogenic adipocytes are present in adult humans and that the number can be increased by repeated cold stimuli, providing new opportunities for the prevention and treatment of overweight-associated diseases. DNL, the synthesis of fatty acids from non-lipid precursors such as glucose, is strongly induced in activated thermogenic adipocytes. The induction mechanism and the physiological significance are, however, not known. Here, we postulate that the transcription factor carbohydrate response element-binding protein (ChREBP) plays a key role by inducing DNL enzymes in thermogenic adipocytes, and that this is necessary for proper cold adaptation. Our preliminary work using ChREBP-deficient mice shows that DNL in brown adipose tissue is especially dependent on ChREBP. For assessing the functional relevance of DNL, metabolic in vivo and in vitro studies with and without ChREBP deficiency are proposed. Studies analyzing angiogenesis and vascularization, cell organell adaptations, systemic lipid and fuel metabolism as well as adaptive thermogenesis are planned to understand the functional role of DNL in thermogenic adipocytes.

该项目旨在了解从头脂肪生成(DNL)对于调节适应性产热和冷诱导的组织重塑的功能意义。这两个过程在冷应激下的哺乳动物身上都会被触发，并有助于维持体温。适应性产热是通过棕色脂肪细胞(在棕色脂肪组织中)和米色脂肪细胞(在白色脂肪组织中)通过ATP解偶联燃料氧化来调节的，统称为“生热脂肪细胞”。由于慢性冷暴露，形成了更多的生热脂肪细胞和血管内皮细胞，从而增加了生热能力。最近的研究表明，在成人中存在生热脂肪细胞，而且这种细胞的数量可以通过反复的冷刺激而增加，这为预防和治疗超重相关疾病提供了新的机会。DNL是从葡萄糖等非脂类前体合成脂肪酸，在激活的生热脂肪细胞中被强烈诱导。然而，诱导机制和生理意义尚不清楚。在这里，我们假设转录因子碳水化合物反应元件结合蛋白(ChREBP)通过诱导产热脂肪细胞中的DNL酶发挥关键作用，这是适当的冷适应所必需的。我们使用ChREBP缺陷小鼠的初步工作表明，棕色脂肪组织中的DNL特别依赖于ChREBP。为了评估DNL的功能相关性，提出了在体内和体外进行ChREBP缺乏和不缺乏的代谢研究。为了了解DNL在生热脂肪细胞中的功能作用，正在计划进行分析血管生成和血管形成、细胞细胞器适应、全身脂肪和燃料代谢以及适应性产热的研究。