Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Cell. 2014 Jul 3;158(1):69-83. doi: 10.1016/j.cell.2014.04.049.
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.
棕色脂肪可以通过热量的消耗来减少肥胖。通过诱导各种共激活因子，特别是 PGC-1α，来控制生热基因的表达。相比之下，这些共因子的转录因子伴侣（s）描述得很差。在这里，我们将干扰素调节因子 4（IRF4）鉴定为生热作用的主要转录效应因子。IRF4 可被寒冷和 cAMP 在脂肪细胞中诱导，足以促进增加的生热基因表达、能量消耗和耐寒性。相反，在 UCP1(+)细胞中敲除 IRF4 会导致生热基因表达和能量消耗减少、肥胖和耐寒性降低。IRF4 还诱导 PGC-1α 和 PRDM16 的表达，并与 PGC-1α 相互作用，驱动 Ucp1 的表达。最后，在没有 IRF4 的情况下，寒冷、β-激动剂或强制表达 PGC-1α 都不能引起生热基因的表达。这些研究确立了 IRF4 作为生热基因表达和能量消耗程序的转录驱动因子。
