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Introduction and Objective: Obesity and its related metabolic complications are major public health problems. Promoting thermogenesis in adipose tissue has been a promising strategy for the treatment of obesity and related metabolic complications. Our objective is to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism. Methods: 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 activates uncoupling protein 1 (Ucp1) expression in adipocytes. Results: Through consecutive screenings, we identified one candidate compound as a potential UCP1 activator. Further characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with little cytotoxicity. In addition, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure in a diet-induced obesity model. Mechanistically, 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 revealed two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627). Conclusions: 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 a crucial role in UCP1-dependent thermogenesis in adipocytes. Disclosure K. Onodera: None. Y. Hasegawa: None. Y. Ishigaki: None.
Onodera et al. (Fri,) studied this question.