title: IRF4 is a key thermogenic transcriptional partner of PGC-1α.
abstract: 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.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Kong
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Banks
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Liu
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kazak
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Rao
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cohen
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60614, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Yu
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Lo
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ruidan
authors.initials: R
authors.lastname: Xue
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleiner
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sona
authors.initials: S
authors.lastname: Kang
authors.affiliation: Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: erosen@bidmc.harvard.edu.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D003080:Cold Temperature; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D022722:Thermogenesis; D013851:Thinness / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D000071256:Uncoupling Protein 1; D000099218:Interferon Regulatory Factor-4
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000242:Cyclic AMP; D050835:Interferon Regulatory Factors; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D000099218:Interferon Regulatory Factor-4; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse