ChREBP-mediated control of Them1 expression coordinates thermogenesis with glycolysis and lipogenesis

Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR). Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct activities in the cytoplasm and nucleus. Targeted inhibition of Them1 may represent a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders. Overall design: To characterize transcriptomic changes in BAT and BeAT in response to acute or chronic cold exposure, we analyzed mRNAs of both BAT and iWAT of WT mice acclimated to 30 °C before or after exposure to 4 °C for 3 days or 3 weeks.

产热棕色脂肪组织（thermogenic brown adipose tissue, BAT）与可诱导米色脂肪组织（inducible beige adipose tissue, BeAT）的激活可由环境或代谢刺激触发，涵盖寒冷环境温度与营养应激。硫酯酶超家族成员1（Thioesterase superfamily member 1, Them1）是一类富集于BAT的长链脂酰辅酶A硫酯酶，可抑制急性冷诱导产热。本研究证实，在慢性寒冷暴露或整合应激反应（integrated stress response, ISR）激活的情况下，碳水化合物反应元件结合蛋白（carbohydrate response element binding protein, ChREBP）可在BAT与BeAT中诱导Them1的表达。在上述两种条件下，Them1均会抑制机体能量消耗。因此，在BAT与BeAT中缺失Them1的小鼠，可抵抗高脂饮食诱导的肥胖与葡萄糖耐受不良。在慢性寒冷暴露或ISR激活期间，Them1会在细胞核内积累，在此处与ChREBP结合并降低其靶基因的表达，其中包括编码介导糖酵解与从头脂肪生成相关酶的基因。上述研究结果表明，在应对慢性寒冷或营养诱导的应激时，ChREBP介导的Them1诱导可通过其在细胞质与细胞核中的不同活性，同时限制产热并降低葡萄糖利用与脂质生物合成。靶向抑制Them1或可成为一种潜在的治疗策略，以增强BAT与BeAT的活性、提升能量消耗，从而用于肥胖相关代谢紊乱的临床管理。总体实验设计：为表征BAT与BeAT在急性或慢性寒冷暴露下的转录组变化，我们对适应30℃环境后，分别暴露于4℃环境3天或3周的野生型小鼠的BAT及腹股沟白色脂肪组织（inguinal white adipose tissue, iWAT）的mRNA进行了分析。