Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge

Abstract

Brown adipose tissue (BAT) is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine BAT thermogenic capacity prior to environmental cold are unknown. Here we show that Histone Deacetylase 3 (HDAC3) is required to activate BAT enhancers to ensure thermogenic aptitude. Mice with BAT-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. UCP1 is nearly absent in BAT lacking HDAC3 and there is also marked down-regulation of mitochondrial oxidative phosphorylation (OXPHOS) genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of Estrogen-Related Receptor α (ERRα) in BAT. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Pgc-1α and OXPHOS genes. Importantly, HDAC3 promotes the basal transcription of these genes independent of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged upon exposure to dangerously cold temperature.

β-adrenergic Receptor Stimulation Revealed a Novel Regulatory Pathway via Suppressing Histone Deacetylase 3 to Induce Uncoupling Protein 1 Expression in Mice Beige Adipocyte

“…Accordingly, our study clarifies the outcome of WAT browning in HDAC3 deficient mice might be because it has the same effect of HDAC3 suppression originated from β-AR stimulation to regulate Ucp1 expression. Interestingly, the other study showed that the ablation of HDAC3 in mice during cold exposure (4 °C, 24 h) failed to activate the thermogenesis program in BAT [37]. In contrast, this study suggests a positive regulation of HDAC3 to browning.…”

ERRγ Preserves Brown Fat Innate Thermogenic Activity

“…A complementary story was recently published identifying a role for HDAC3 in establishing a transcriptional landscape in BAT required for the rapid response to acute cold challenge (Emmett et al, 2017). Dating mining of RNA-seq from HDAC3 KO BAT (Emmett et al, 2017) and comparison with RNA-seq from ERRγKO BAT (both performed at TN) revealed commonly downregulated genes in HDAC3KO and ERRγKO BAT, including the key genes UCP1 and Cox7a1, raising the logical possibility of cooperation between HDAC3 and ERRγ in BAT (Figure S2F).…”

“…Dating mining of RNA-seq from HDAC3 KO BAT (Emmett et al, 2017) and comparison with RNA-seq from ERRγKO BAT (both performed at TN) revealed commonly downregulated genes in HDAC3KO and ERRγKO BAT, including the key genes UCP1 and Cox7a1, raising the logical possibility of cooperation between HDAC3 and ERRγ in BAT (Figure S2F). However, the majority of the downregulated genes were unique to the specific model, consistent with predominantly parallel and possibility complementary regulatory pathways.…”

“…These results, combined with the finding that ERRγ maintains a highly oxidative state in muscle in the absence of exercise (Narkar et al, 2011), implicate ERRγ in controlling metabolism under innate rather than adaptive conditions. A complementary story was recently published identifying a role for HDAC3 in establishing a transcriptional landscape in BAT required for the rapid response to acute cold challenge (Emmett et al, 2017). Future studies elucidating the unique and overlapping functions of ERRγ and HDAC3 in BAT will an important avenue of future research.…”

Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits

“…Mechanistically, this trade-off between thermogenic capacity and overall organismal fitness is due to the specific reduction of mtDNA-encoded gene expression in the BAT (Figure 7). In contrast, reducing Pgc1α-mediated mitochondrial biogenesis in brown-adipocyte-specific Irf4 and Hdac3 knockout mice affected the expression of both mtDNA- and nuclear-encoded genes in BAT, leading to thermogenic defects but without metabolic benefits (Emmett et al, 2017; Kong et al, 2014). Tfam BKO mice are resistant to long-term HFD-induced insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease, which might be secondary to reduced adiposity.…”