Abstract
Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted much attention as a promising approach for the management of body weight. Thermogenic adipocytes are capable of burning fat to dissipate chemical energy into heat, thereby enhancing energy expenditure. After the recent re-discovery of thermogenic adipocytes in adult humans, much effort has focused on understanding the molecular mechanisms, especially the epigenetic mechanisms, which regulate thermogenic adipocyte development and function. A number of chromatin signatures, such as histone modifications, DNA methylation, chromatin accessibilities, and interactions, have been profiled at the genome level and analyzed in various murine and human thermogenic fat cell systems. Moreover, writers and erasers, as well as readers of the epigenome are also investigated using genomic tools in thermogenic adipocytes. In this review, we summarize and discuss the recent advance in these studies and highlight the insights gained into the epigenomic regulation of thermogenic program as well as the pathogenesis of human metabolic diseases.
Highlights
Adipose tissue plays a key role in the control of metabolic homeostasis in mammals
The authors showed that the chromatin structure at the enhancer/promoter regions of thermogenic genes became more accessible in mature beige adipocytes and these chromatin architecture changes were largely blocked by IL-10, resulting in the reduction of thermogenic gene expression and further energy expenditure [43]
In the context of thermogenic gene expression and adipogenesis, DNA methylation has been studied in a gene-specific manner at the Ucp1 promoter/enhancer, and the results showed that DNA methylation anti-correlates with Ucp1 expression [44,45,46]
Summary
Adipose tissue plays a key role in the control of metabolic homeostasis in mammals. As the main component and functional unit of adipose tissue, adipocytes store lipids, respond to insulin stimulation, and secrete various metabolic regulatory hormones known as adipokines. In 2009, several independent groups reported the identification of brown-like fat depots in healthy adults using PET-CT (Positron emission tomography-computed tomography) scans or human biopsies [6,7,8,9] These discoveries attracted significant interest in harnessing the thermogenic activity of BAT in obesity management and spurred intensive studies of brown fat biology and energy metabolism. To gain a fundamental understanding of the gene regulation networks that control the development of thermogenic adipocytes, it is necessary to systematically profile the epigenome and define the cis-regulatory elements, such as enhancers, that modulate adipogenic and thermogenic gene expression In recent years, these profiling works have been greatly facilitated by the discovery of signature histone modifications for these cis-elements [20,21,22,23] and the development of the ChIP-seq (chromatin Immunoprecipitation-sequencing) technique. Those studies have been reviewed extensively elsewhere [28,29]
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