ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.
ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.
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产热脂肪细胞中的ATF 4表达是小鼠冷诱导产热所必需的，其机制不依赖于FGF 21。
DOI：
10.1038/s41598-024-52004-8
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发表时间：
2024-01-18
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在棕色脂肪组织（BAT）中，短期冷暴露诱导激活转录因子4（ATF 4）及其下游靶向成纤维细胞生长因子21（FGF 21）。在BAT中响应线粒体应激诱导ATF 4是体温调节所需的，部分是通过增加FGF 21表达。在本研究中，我们通过在表达UCP1的脂肪细胞中选择性缺乏Atf4（ATF4 BKO）或Fgf21（FGF21 BKO）的小鼠来测试BAT中的Atf4和Fgf21诱导都是生理应激下BAT产热所需的假设。冷暴露3天后，自由采食的ATF 4 BKO小鼠的核心体温显著降低，这与棕色和米色脂肪细胞中的Fgf 21下调以及白色脂肪组织的布朗宁受损相关。相反，尽管布朗宁减少，但FGF21 BKO小鼠在冷暴露后保持了核心体温。从机制上讲，ATF 4而不是FGF 21调节氨基酸输入和代谢以响应寒冷，可能有助于自由采食条件下BAT的产热能力。重要的是，在禁食条件下，ATF 4和FGF 21都是冷暴露小鼠产热所必需的。因此，ATF4在进食条件下可能以FGF21非依赖性方式调节BAT产热，部分通过增加氨基酸摄取和代谢。
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 by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. 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 ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.
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DOI：
10.1152/ajpendo.00181.2023
发表时间：
2023-11-04
影响因子：
5.1
作者：
Levy, Jordan L.;Mirek, Emily T.;Anthony, Tracy G.
通讯作者：
Anthony, Tracy G.
循环的FGF21是肝脏的，并在进食和过度喂养过程中增强了葡萄糖的摄取。
影响因子：
7.7
作者：
Markan KR;Naber MC;Ameka MK;Anderegg MD;Mangelsdorf DJ;Kliewer SA;Mohammadi M;Potthoff MJ
通讯作者：
Potthoff MJ
影响因子：
4.8
作者：
Ebert, Scott M.;Dyle, Michael C.;Adams, Christopher M.
通讯作者：
Adams, Christopher M.
影响因子：
29
作者：
Cypess AM;Weiner LS;Roberts-Toler C;Franquet Elía E;Kessler SH;Kahn PA;English J;Chatman K;Trauger SA;Doria A;Kolodny GM
通讯作者：
Kolodny GM
影响因子：
4.6
作者：
Labbé SM;Mouchiroud M;Caron A;Secco B;Freinkman E;Lamoureux G;Gélinas Y;Lecomte R;Bossé Y;Chimin P;Festuccia WT;Richard D;Laplante M
通讯作者：
Laplante M