Onodera Ken, Hasegawa Yutaka, Yokota Nozomi, Tamura Shukuko, Kinno Hirofumi, Takahashi Iwao, Chiba Hiraku, Kojima Hirotatsu, Katagiri Hideki, Nata Koji, Ishigaki Yasushi
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan.
Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, School of Pharmacy, Iwate Medical University, Yahaba, Japan.
Obesity (Silver Spring). 2024 Feb;32(2):324-338. doi: 10.1002/oby.23948. Epub 2023 Nov 17.
Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.
To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes.
We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).
The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.
促进脂肪组织产热一直是对抗肥胖及相关代谢并发症的一种有前景的策略。我们旨在鉴定能促进脂肪细胞产热的化合物，并阐明它们在代谢中的功能和作用。
为了从4800种结构多样的化合物中鉴定出直接促进产热的化合物，我们利用了一个基于细胞的高通量筛选平台，该平台可诱导脂肪细胞中解偶联蛋白1（Ucp1）的表达。
我们鉴定出一种能激活UCP1的候选化合物。对该化合物的进一步表征显示，它能诱导脂肪细胞产生细胞产热，且细胞毒性可忽略不计。在随后的饮食诱导肥胖模型中，用该化合物处理的小鼠体重增加速度较慢，胰岛素敏感性提高，能量消耗增加。机制研究表明，该化合物通过提高最大呼吸作用增加线粒体生物合成，这部分是由蛋白激酶A（PKA）-p38丝裂原活化蛋白激酶（MAPK）信号通路介导的。对用这些化合物处理的脂肪细胞进行的进一步全面基因分析，鉴定出两个新的UCP1依赖性产热基因，钾电压门控通道亚家族C成员2（Kcnc2）和预测基因5627（Gm5627）。
所鉴定的化合物可作为治疗肥胖及其相关代谢紊乱的潜在治疗药物。此外，我们新阐明的产热基因在脂肪细胞中UCP1依赖性产热中起重要作用。
