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A signal to warm up to

IL-33 and its receptor ST2 induce a postnatal switch from coupled to uncoupled respiration in beige and brown adipocytes. Brown adipose tissue burns energy and generates heat (a process called thermogenesis) to maintain body temperature through uncoupled mitochondrial respiration mediated by uncoupling protein 1 (UCP1). White adipose tissue normally stores energy, but various stimuli, such as cold exposure or adrenergic stimulation, trigger the formation of beige adipose tissue. In this process, which is called “browning,” white adipocytes take on some of the characteristics of brown adipocytes, primarily the induction of Ucp1 expression. This process can be induced in adult mice by interleukin-33 (IL-33), a cytokine that is released by various cell types in response to stress or damage and that activates type 2 innate lymphoid cells (ILC2s). Odegaard et al. (see also Mathis) found that IL-33 and its receptor ST2 were required to switch beige and brown adipocytes from coupled to uncoupled respiration perinatally. In response to cold exposure, UCP1 abundance and thermogenesis increased in the inguinal white adipose tissue of 8-week-old wild-type mice but not in this fat depot in Il33–/– mice. However, beige adipocyte formation was not reduced in Il33–/– mice. Compared with its effects in wild-type mice, norepinephrine stimulation increased oxygen consumption to a lower extent in Il33–/– mice, suggesting a defect in brown fat thermogenesis. Consistent with the reduced thermogenic capacity of both white and brown fat depots, fewer 8.5-week-old (or younger) Il33–/– mice survived cold exposure. Ex vivo analysis showed that similar to beige adipose tissue, UCP1 protein was absent in brown adipose tissue from Il33–/– mice, which also consumed less oxygen than that from wild-type mice. Ucp1 mRNAs were present in brown adipose tissue from Il33–/– mice but showed a different splicing pattern from that of wild-type mice. These mRNAs included two variants, B and C, which used cryptic splice junctions between exons 4 and 5 and of which C was present in wild-type mice. However, Il33–/–- mice did not have splice variant A, which used the normal splice junctions between these exons and constituted most of the Ucp1 mRNA in wild-type mice. The switch in coupled to uncoupled respiration required ST2 because the beige and brown fat of Il1rl1–/– mice (Ilrl1 encodes ST2) did not contain UCP1, and cold exposure was fatal to these mice at 4.5 weeks of age. The switch in coupled to uncoupled respiration did not require ILC2s or MyD88, an adaptor protein that is downstream of ST2 in immune cells, suggesting that IL-33 and ST2 mediate the switch through a pathway that is yet to be determined. Thus, IL-33 and its receptor ST2 enable beige and brown adipocytes to act as thermoregulatory tissues by inducing a postnatal switch from coupled to uncoupled respiration through changes in the splicing of Ucp1 mRNA. J. I. Odegaard, M.-W. Lee, Y. Sogawa, A. M. Bertholet, R. M. Locksley, D. E. Weinberg, Y. Kirichok, R. C. Deo, A. Chawla, Perinatal licensing of thermogenesis by IL-33 and ST2. Cell 166, 841–854 (2016). [PubMed] D. Mathis, IL-33, imprimatur of adipocyte thermogenesis. Cell 166, 794–795 (2016). [PubMed]