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

TY - JOUR

T1 - PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing

AU - Kissig, Megan

AU - Ishibashi, Jeff

AU - Harms, Matthew J

AU - Lim, Hee-Woong

AU - Stine, Rachel R

AU - Won, Kyoung-Jae

AU - Seale, Patrick

N1 - © 2017 The Authors.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

KW - Adipocytes/physiology

KW - Animals

KW - DNA-Binding Proteins/metabolism

KW - Gene Expression Regulation

KW - Interferon Regulatory Factor-1/antagonists & inhibitors

KW - Interferon Type I/metabolism

KW - Mice

KW - Mitochondria/metabolism

KW - STAT1 Transcription Factor/antagonists & inhibitors

KW - Thermogenesis

KW - Transcription Factors/metabolism

KW - Uncoupling Protein 1/metabolism

U2 - 10.15252/embj.201695588

DO - 10.15252/embj.201695588

M3 - Journal article

C2 - 28408438

SN - 0261-4189

VL - 36

SP - 1528

EP - 1542

JO - E M B O Journal

JF - E M B O Journal

IS - 11

ER -