An emerging role for epigenetic regulation of Pgc-1α expression in environmentally stimulated brown adipose thermogenesis

Abstract

Metabolic disease is a leading cause of death worldwide, and obesity, a central risk factor, is reaching epidemic proportions. Energy expenditure and brown adipose tissue (BAT) thermogenesis are implicated in metabolic disease, and it is becoming evident that impaired BAT activity is regulated by gene/environment interactions. Peroxisome proliferator-activated receptor γ coactivator 1α (Pgc-1α) is a critical regulator of BAT thermogenesis, which is highly inducible by environmental stimuli such as cold and diet. This review focuses on the environmentally mediated epigenetic and transcriptional regulation of Pgc-1α gene expression during BAT thermogenesis. We illustrate interactions between histone modifications and transcription factors at the Pgc-1α promoter that cause BAT Pgc-1α transcription in response to cold. Histone modifications also modulate BAT Pgc-1α transcription in response to nutrients though diet has been less characterized than cold with respect to regulation of Pgc-1α transcription. Pgc-1α DNA methylation and RNA expression were also correlated to indicators of adiposity and glucose homeostasis across numerous human tissues. Although post-translational modification of Pgc-1α protein has been well-characterized across diverse tissues and environments, comparatively little is known of the epigenetic mechanisms regulating Pgc-1α transcription, particularly in BAT thermogenesis.

Keywords: brown adipose tissue; coactivator 1α; epigenetics; gene regulation; peroxisome proliferator-activated receptor γ; thermogenesis.

Figure 1:

signaling factors influencing the Pgc-1α promoter activity and Pgc-1α gene structural comparison, representing 93% amino acid sequence identity between human and mouse. Promoters, green; exons, orange. The expanded inset is a graphical representation of the human Pgc-1α proximal promoter upstream of the transcription start site (TSS). Environmentally induced signaling pathways modulate transcription factors (purple diamonds) with binding sites (yellow) on the human Pgc-1α promoter. All transcription factor binding consensus sequences here are conserved between human and mouse. Signaling pathways include diet-induced protein kinase B (Akt) activity, which modulates cytoplasmic levels of FoxO1; diet may also regulate Pgc-1α activity through the transcription factor PBX1; and cold stimulates the β₃-adrenergic receptors, leading to PKA regulation of CREB, PPARγ, and p38MAPK; cold activates SIRT3, stimulating CREB phosphorylation; cold induced SNS stimulation also transcriptionally activates Pgc-1α through PRDM16 by interacting with the transcription factor ZFP516. ATF2, activating transcription factor 2; IRS, insulin response sequence; CRE, cAMP response element; MEF2, myocyte enhancer factor 2; SREBF1, sterol regulatory element binding transcription factor 1.