TY - JOUR
T1 - IRF4 is a key thermogenic transcriptional partner of PGC-1α
AU - Kong, Xingxing
AU - Banks, Alexander
AU - Liu, Tiemin
AU - Kazak, Lawrence
AU - Rao, Rajesh R.
AU - Cohen, Paul
AU - Wang, Xun
AU - Yu, Songtao
AU - Lo, James C.
AU - Tseng, Yu Hua
AU - Cypess, Aaron M.
AU - Xue, Ruidan
AU - Kleiner, Sandra
AU - Kang, Sona
AU - Spiegelman, Bruce M.
AU - Rosen, Evan D.
N1 - Funding Information:
The authors gratefully acknowledge Ulf Klein (Columbia University) for the Irf4 flox mice. PGC-1α constructs were the gift of Pere Puigserver; other plasmids were from Lisa Madisen and Hongkui Zeng. The Electron Microscopy core of the Beth Israel Deaconess Medical Center (BIDMC) performed the EM analysis. We thank members of the E.D.R. and B.M.S. laboratories, and Saverio Cinti, for helpful discussions and technical advice. This work was funded by an American Heart Association (AHA) postdoctoral fellowship to X.K., NIH R01 DK31405 to B.M.S., and NIH R01 DK085171 to E.D.R. B.M.S. is a founder of and shareholder in Ember Therapeutics, and S.K. is an employee of the Genomics Institute of the Novartis Research Foundation.
PY - 2014/7/3
Y1 - 2014/7/3
N2 - Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1+ cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, β-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.
AB - Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1+ cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, β-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.
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U2 - 10.1016/j.cell.2014.04.049
DO - 10.1016/j.cell.2014.04.049
M3 - Article
C2 - 24995979
AN - SCOPUS:84903989695
SN - 0092-8674
VL - 158
SP - 69
EP - 83
JO - Cell
JF - Cell
IS - 1
ER -