Article ; Online: ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.
2024 Volume 14, Issue 1, Page(s) 1563
Abstract: 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 ... ...
| Abstract | 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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| MeSH term(s) | Animals ; Mice ; Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism ; Adipocytes/metabolism ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Amino Acids/metabolism ; Cold Temperature ; Fibroblast Growth Factors ; Mice, Inbred C57BL ; Thermogenesis/genetics ; Uncoupling Protein 1/genetics ; Uncoupling Protein 1/metabolism |
| Chemical Substances | Activating Transcription Factor 4 (145891-90-3) ; Amino Acids ; fibroblast growth factor 21 ; Fibroblast Growth Factors (62031-54-3) ; Uncoupling Protein 1 ; Atf4 protein, mouse |
| Language | English |
| Publishing date | 2024-01-18 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2615211-3 |
| ISSN | 2045-2322 ; 2045-2322 |
| ISSN (online) | 2045-2322 |
| ISSN | 2045-2322 |
| DOI | 10.1038/s41598-024-52004-8 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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