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

该项目旨在了解从头脂肪生成（DNL）调节适应性产热以及冷诱导的组织重塑的功能意义。这两个过程在哺乳动物的冷应激下被触发，并有助于维持体温。适应性产热通过棕色脂肪细胞（在棕色脂肪组织中）和米色脂肪细胞（在白色脂肪组织中）（统称为“产热脂肪细胞”）中的ATP-解偶联燃料氧化来介导。作为慢性冷暴露的结果，形成更多的产热脂肪细胞和血管内皮细胞，增加产热能力。最近的研究表明，产热脂肪细胞存在于成年人中，并且其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是从非脂质前体如葡萄糖合成脂肪酸，在活化的产热脂肪细胞中被强烈诱导。然而，其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酶起着关键作用，并且这对于适当的冷适应是必要的。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，提出了有和没有ChREBP缺陷的体内和体外代谢研究。研究分析血管生成和血管化，细胞器的适应性，全身脂质和燃料代谢以及适应性产热计划了解DNL在产热脂肪细胞的功能作用。

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.