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

Abstract

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 , in adipocytes and Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression.-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.

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

“…IRF3 represses thermogenic gene expression (22). Interestingly, the thermogenic transcription factor Prdm16 suppresses ISG expression (23). Our data extend these findings by demonstrating that the capacity for thermogenic respiration itself may regulate ISG abundance.…”

Dissection of Influenza Infection In Vivo by Single-Cell RNA Sequencing

“…Studies of several cell types have demonstrated that the type I IFN response is accompanied by an antagonistic suppression of mitochondrially encoded genes (Jovanovic et al, 2015;Kissig et al, 2017). However, those studies relied on data from a single cell type, ignoring the possible generality of the findings.…”

“…Recent studies demonstrated substantial suppression of mitochondrial-encoded genes in response to IFN and lipopolysaccharide treatments, which was attributed to either a metabolic shift in oxidative phosphorylation or removal of the entire mitochondrial fraction through mitophagy (Jovanovic et al, 2015;Kissig et al, 2017). However, the generality of these findings in different cell types and their relevance for influenza stimulation remained unknown.…”

“…Complexity may also be related to a wide range of viral transcriptional states within the infected cells (Russell et al, 2018;Xin et al, 2018;Zanini et al, 2018), as well as to the heterogeneity of host-response states (Avraham et al, 2015). Another complication may be attributable to the dual role of the metabolic machinery in supporting the host while also limiting the energetic demands of the viral life cycle (Jovanovic et al, 2015;Kissig et al, 2017). Yet another source of heterogeneity may derive from the possibility that only a subset of the cells are actually infected by influenza, while most of the cells in the population are bystanders (exposed but uninfected) and typically respond to defensive host signals such as type I interferons (IFNs) (McFadden et al, 2009).…”

Latest advances in STAT signaling and function in adipocytes

“…PRDM16 is a well-characterized transcriptional co-regulator that plays a pivotal role in both brown and beige adipocyte development and function [50,51]. PRDM16 can repress WAT-specific genes and activate BAT-specific genes [50]. Recent studies have shown that PRDM16 can antagonize IFN signaling in brown adipocytes by binding to the promoters of type I IFN-stimulated genes (ISGs), including STAT1.…”