ATF4 Expression in Thermogenic Adipocytes is Required for Cold-Induced Thermogenesis in Mice via FGF21-Independent Mechanisms

In brown adipose tissue (BAT), short-term cold exposure induces the integrated stress response (ISR) main effector, activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). We recently demonstrated that induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, at least in part, via induction of FGF21. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis 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 (WAT). Conversely, although Fgf21 deletion in thermogenic adipocytes also reduced cold-induced browning of WAT, ad libitum-fed FGF21 BKO mice had preserved core body temperature after cold exposure. When cold-exposed under fasting conditions, both ATF4 BKO and FGF21 BKO mice had reduced cold tolerance. Mechanistically, ATF4 downregulation in thermogenic adipocytes decreased amino acid import and metabolism in BAT, likely contributing to impaired brown adipocyte thermogenic capacity under ad libitum-fed conditions. Thus, Atf4 regulates Fgf21 expression in thermogenic adipocytes during cold stress, which is required to mediate cold-induced browning of iWAT but is dispensable for thermoregulation in the fed state. In contrast, in the fasted state, both Atf4 and Fgf21 expression in thermogenic adipocytes are required for thermoregulation in mice. ### Competing Interest Statement The authors have declared no competing interest.