IRF4 Is a Key Thermogenic Transcriptional Partner of PGC-1α

Abstract

Summary Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various co-activators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these co-factors 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.

Adipose tissue in control of metabolism

“…Consistent with this, PGC1α is upregulated by FGF21 and mediates the prompting effect of FGF21 on browning of WAT (Fisher et al 2012). Moreover, IRF4 as the key thermogenic transcriptional partner of PGC1α promotes thermogenic genes expression and energy expenditure, suggesting the key role of PGC1α in regulating thermogenesis and WAT browning (Kong et al 2014). Furthermore, several other intracellular pathways including p38MAPK, mTORC1, Grb10, mineralocorticoid receptor (MR), and K (+) channel TASK1 have been shown to modulate thermogenic gene expression, browning of WAT and/or lipolysis through β3-adrenoceptor-dependent or independent mechanisms (Cao et al 2004a, Bordicchia et al 2012, Armani et al 2014, Liu et al 2016, Pisani et al 2016 (Fig.…”

“…Several transcriptional factors including PRDM16, PGC1α, PPARγ, C/EBPβ and interferon regulator factor 4 (IRF4) have been discovered to promote UCP1 expression (Kelly et al 1998, Barbera et al 2001, Seale et al 2007, Kajimura et al 2009, Kong et al 2014 (Fig. 3).…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…Ninetyfive to ninety-seven percent confluent cells were differentiated with a medium containing 5 μg/ml insulin, 125 μM indomethacin, 2 μg/ml dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine, 0.5 μM rosiglitazone, and 1 nM 3,3′,5-triiodo-l-thyronine (T3). After 2 days, medium was replaced with maintenance medium containing 5 μg/ml insulin and targeted allele and the Cre transgene (Adipoq-Cre-Ip6k1 (87). Briefly, 2-month-old LoxPs and AdKOs were placed in a cold room (5°C).…”

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

“…4 D and E). Finally, to examine whether the calcium-induced sensitivity of UCP1-KO BAT mitochondria is a feature of these organelles specifically or a feature of UCP1 deficiency generally, we examined the calcium-buffering capacity and Δψ in mitochondria from BAT-specific IRF4 KO mice (BATI4KO) that exhibit reduced UCP1 levels in BAT (40). Similar to what we observed in UCP1-KO BAT mitochondria, organelles from BATI4KO mice demonstrated increased sensitivity to calcium overload-induced permeability transition when respiring on pyruvate/malate (Fig.…”