A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders

Abstract

ObjectivePromoting 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.MethodsTo 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.ResultsWe 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).ConclusionsThe 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.

Identifying of immune‐associated genes for assessing the obesity‐associated risk to the offspring in maternal obesity: A bioinformatics and machine learning

“…A recent study identified Kcnc2 as a thermogenic gene in adipocytes. The PKA‐p38 MAPK‐KCNC2‐UCP1 signaling pathway is a potential target for obesity treatment 53 …”

“…The PKA-p38 MAPK-KCNC2-UCP1 signaling pathway is a potential target for obesity treatment. 53 The expression and potential function of Kcnc2 in hypothalamus…”