Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea.
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
Metabolism. 2020 Apr;105:154173. doi: 10.1016/j.metabol.2020.154173. Epub 2020 Feb 5.
Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood.
We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development.
We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice.
These results suggested that the IDH1-α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.
解偶联蛋白 1 介导的非颤抖性产热作用使棕色脂肪细胞在能量稳态调节中发挥重要作用。最近的研究表明，棕色脂肪细胞作为治疗肥胖症和相关疾病（如 2 型糖尿病）的新靶点。然而，棕色脂肪细胞分化和功能的分子机制尚不完全清楚。
我们采用了以前通过蛋白质组学研究获得的发现，这些研究用于评估在棕色脂肪细胞分化过程中表达水平发生改变的蛋白质。在这里，我们进行了测定，以确定它们在棕色脂肪生成和发育过程中表达水平改变的功能意义。
我们发现异柠檬酸脱氢酶 1（IDH1）在棕色脂肪细胞分化过程中上调，随后的研究表明 IDH1 的异位表达抑制棕色脂肪生成，而 IDH1 水平的抑制促进棕色脂肪细胞的分化。此外，Idh1 的过表达导致细胞内α-酮戊二酸（α-KG）水平升高，并抑制与棕色脂肪生成相关的基因的表达。外源性α-KG 处理在分化的早期阶段减少棕色脂肪生成，ChIP 分析显示 IDH1 介导的α-KG 降低了与棕色脂肪生成相关基因启动子中组蛋白 H3 赖氨酸 4 的三甲基化。此外，α-KG 通过调节小鼠棕色脂肪组织中的组蛋白甲基化来降低脂肪生成基因的表达。
这些结果表明，IDH1-α-KG 轴在调节棕色脂肪细胞分化中起重要作用，可能成为治疗代谢疾病的治疗靶点。
