ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress

• DOI: 10.1126/scisignal.adk7971
• Publication Date: 2024-12-03T18:58:17Z
• Authors: Xu Xu; Arturo Mendoza; Christopher S. Krumm; Shi Su; Mariana Acuña; Curtis J. Bare; Corey D. Holman; Marissa Cortopassi; Hayley T. Nicholls; Vincent Dartigue; Anthony N. Hollen...; Ann-Hwee Lee; Susan J. Hagen; David E. Cohen
• Keywords: Lipogenesis; Carbohydrate-responsive element-binding protein; Carbohydrate Metabolism

Activation of thermogenic brown adipose tissue (BAT) and inducible beige (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate Them1 expression was induced BAT BeAT the carbohydrate response element binding protein (ChREBP) to chronic exposure activation integrated stress (ISR) excess. Under either condition, suppressed energy expenditure. Consequently, mice lacking exhibited resistance obesity glucose intolerance feeding with high-fat diet. During ISR activation, accumulated nucleus, where it interacted ChREBP reduced its target genes, those encoding enzymes mediate glycolysis de novo lipogenesis. These findings cold- nutrient-induced stress, induction limits thermogenesis while coordinately reducing utilization lipid biosynthesis through distinct cytoplasmic nuclear activities. Targeted inhibition could be potential therapeutic approach increase activity enhance expenditure management obesity-associated disorders.