Bjorkman Sarah H, Marti Alex, Jena Jayashree, Garcia Pena Luis M, Weatherford Eric T, Kato Kevin, Koneru Jivan, Chen Jason, Sood Ayushi, Potthoff Matthew J, Adams Christopher M, Abel E Dale, Pereira Renata O
bioRxiv. 2023 Sep 13:2023.03.09.531964. doi: 10.1101/2023.03.09.531964.
In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially via upregulation of FGF21. In the present study, we tested the hypothesis that and induction in BAT are both required for BAT thermogenesis by generating mice selectively lacking either ATF4 BKO or (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in -fed ATF4 BKO mice, which correlated with downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue (WAT). Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under -fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis by activating amino acid metabolism in BAT in a FGF21-independent manner.
在棕色脂肪组织（BAT）中，短期冷暴露会诱导激活转录因子4（ATF4）及其下游靶点成纤维细胞生长因子21（FGF21）。BAT中ATF4的诱导以响应线粒体应激是体温调节所必需的，部分是通过FGF21的上调实现的。在本研究中，我们通过生成在表达解偶联蛋白1（UCP1）的脂肪细胞中选择性缺失ATF4（ATF4基因敲除小鼠，ATF4 BKO）或FGF21（FGF21基因敲除小鼠，FGF21 BKO）的小鼠，来测试BAT中ATF4和FGF21的诱导对于BAT产热均是必需的这一假设。冷暴露3天后，喂食的ATF4 BKO小鼠的核心体温显著降低，这与棕色和米色脂肪细胞中FGF21的下调以及白色脂肪组织（WAT）的褐变受损相关。相反，尽管FGF21 BKO小鼠的褐变减少，但冷暴露后其核心体温保持正常。从机制上讲，ATF4而非FGF21在冷刺激下调节氨基酸的摄取和代谢，这可能有助于喂食条件下BAT的产热能力。重要的是，在禁食条件下，冷暴露小鼠的产热需要ATF4和FGF21两者。因此，ATF4通过以不依赖FGF21的方式激活BAT中的氨基酸代谢来调节BAT产热。
