GCN2 is required to maintain core body temperature in mice during acute cold
GCN2 is required to maintain core body temperature in mice during acute cold
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DOI：
10.1152/ajpendo.00181.2023
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发表时间：
2023-11-04
影响因子：
5.1
通讯作者：
Anthony, Tracy G.
中科院分区：
文献类型：
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作者：
Levy, Jordan L.;Mirek, Emily T.;Anthony, Tracy G.
啮齿类动物的非寒战产热需要大量营养物质在低温条件下产生热量。在这项研究中，我们研究了营养敏感激酶，一般控制非抑制2 （GCN2）在小鼠急性冷暴露期间指导适应性产热的作用。我们假设GCN2是通过激活综合应激反应（ISR）来适应急性冷应激所必需的，从而导致肝脏产生FGF21和增加氨基酸运输以支持非寒战产热。与我们的假设一致，缺乏GCN2的雌性和雄性小鼠未能充分增加能量消耗并转向麻木。给予GCN2小分子抑制剂的小鼠也对急性冷应激极度不耐受。Gcn2缺失也会阻碍肝脏来源的FGF21，但仅在男性中。在棕色脂肪组织（BAT）中，急性寒冷暴露增加了雄性和雌性的ISR激活及其转录执行。BAT的RNA测序鉴定出编码肌动球蛋白机制和跨膜运输的转录本在低温暴露时需要GCN2。这些转录物包括II类肌球蛋白重链和氨基酸转运蛋白，它们在冷胁迫下对最大产热至关重要。重要的是，Gcn2缺失与冷胁迫下BAT中较高的循环氨基酸和较低的细胞内氨基酸相对应。总之，我们确定了GCN2激活的性别无关的作用，通过摄取氨基酸进入棕色脂肪来支持适应性产热。
Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress. Gcn2 deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose tissue (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly, Gcn2 deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose.