PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing

• Published in: The EMBO journal 2017-06, Vol.36 (11), p.1528-1542
• Main Authors: Kissig, Megan, Ishibashi, Jeff, Harms, Matthew J, Lim, Hee‐Woong, Stine, Rachel R, Won, Kyoung‐Jae, Seale, Patrick
• Format: Article
• Language: English
• Subjects: Activation; Adipocytes; Adipocytes - physiology; Animals; Binding; Body fat; brown adipose; DNA-Binding Proteins - metabolism; EMBO19; EMBO21; Gene expression; Gene Expression Regulation; Genes; In vitro methods and tests; Interferon; interferon regulatory factor; Interferon regulatory factor 1; Interferon Regulatory Factor-1 - antagonists & inhibitors; Interferon Type I - metabolism; Mice; Mitochondria; Mitochondria - metabolism; Prdm16; Preadipocytes; Stat1 protein; STAT1 Transcription Factor - antagonists & inhibitors; Thermogenesis; Transcription Factors - metabolism; Ucp1; Uncoupling protein 1; Uncoupling Protein 1 - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201695588

Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat‐specific genes while repressing white fat and muscle‐specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)‐stimulated genes (ISGs), including Stat1 , in adipocytes in vitro and in vivo . Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression. Prdm16 ‐deficient adipose displays an exaggerated response to type I IFN, including higher STAT1 levels and reduced mitochondrial gene expression. Mechanistically, PRDM16 represses ISGs through binding to promoter regions of these genes and blocking the activating function of IFN regulatory factor 1 (IRF1). Together, these data indicate that PRDM16 diminishes responsiveness to type I IFN in adipose cells to promote thermogenic and mitochondrial function. Synopsis In addition to activating expression of brown fat‐specific genes, PRDM16 prevents the induction of type I interferon‐stimulated genes, thereby ensuring maintenance of mitochondrial function and brown and beige adipocyte character. PRDM16 suppresses type I interferon (IFN)‐stimulated genes (ISGs) in preadipocytes and adipocytes. Activation of type I (IFN) signaling in adipocytes leads to a loss of brown adipocyte character and reduced mitochondrial function in adipocytes. PRDM16 blocks the activation of ISGs by IFN regulatory factor 1 (IRF1) by competing for binding at promoter regions. Graphical Abstract In addition to activating expression of brown fat‐specific genes, PRDM16 prevents the induction of type I interferon‐stimulated genes, thereby ensuring maintenance of mitochondrial function and brown and beige adipocyte character.