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Review
. 2021 Oct 21;13(7):480-499.
doi: 10.1093/jmcb/mjab043.

Epigenetic regulation of energy metabolism in obesity

Wei Gao  1   2 , Jia-Li Liu  1   2 , Xiang Lu  1   2 , Qin Yang  3
Affiliations
Review

Epigenetic regulation of energy metabolism in obesity

Wei Gao et al. J Mol Cell Biol. .

Abstract

Obesity has reached epidemic proportions globally. Although modern adoption of a sedentary lifestyle coupled with energy-dense nutrition is considered to be the main cause of obesity epidemic, genetic preposition contributes significantly to the imbalanced energy metabolism in obesity. However, the variants of genetic loci identified from large-scale genetic studies do not appear to fully explain the rapid increase in obesity epidemic in the last four to five decades. Recent advancements of next-generation sequencing technologies and studies of tissue-specific effects of epigenetic factors in metabolic organs have significantly advanced our understanding of epigenetic regulation of energy metabolism in obesity. The epigenome, including DNA methylation, histone modifications, and RNA-mediated processes, is characterized as mitotically or meiotically heritable changes in gene function without alteration of DNA sequence. Importantly, epigenetic modifications are reversible. Therefore, comprehensively understanding the landscape of epigenetic regulation of energy metabolism could unravel novel molecular targets for obesity treatment. In this review, we summarize the current knowledge on the roles of DNA methylation, histone modifications such as methylation and acetylation, and RNA-mediated processes in regulating energy metabolism. We also discuss the effects of lifestyle modifications and therapeutic agents on epigenetic regulation of energy metabolism in obesity.

Keywords: energy metabolism; epigenetics; obesity; treatment.

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Figures

Figure 1
Figure 1
Relationship between environment, genome, and epigenetic modification in obesity. Genetic preposition and environmental factors such as sedentary lifestyle and energy-dense nutrition are established etiology for the development of obesity, which confers a higher risk for T2DM, cardiovascular diseases, cancer, and aging. Both genetic proposition and environmental factors may alter epigenetic modifications, including DNA methylation, histone modification, and ncRNA, to modulate energy metabolism in obesity. Obesity may in turn affect epigenetic modifications to regulate energy metabolism.
Figure 2
Figure 2
Modifiers for histone acetylation and methylation. Histone acetylation and deacetylation are catalyzed by HATs and HDACs, respectively. Extensive studies of HATs and HDACs have emphasized the crucial role of histone acetylation and deacetylation in bridging epigenetic, transcriptional, and signaling phenomena to metabolism in obesity. Histone methylations are dynamically regulated by HMTs and HDMs. Histone methylation occurs on basic residues lysine and arginine and confers active or inhibitory transcription, depending on their location and methylation status. Red color indicates the modifiers participated in energy metabolism.
Figure 3
Figure 3
Metabolites as cofactors of the epigenetic machinery. The activity of epigenetic factors is regulated at multiple levels including transcription, translation, and post-translational modifications. It is increasingly recognized that small-molecule metabolites such as acetyl-CoA, SAM, NAD+, FAD, and α-KG serve as essential cofactors to modulate epigenetic factor activity. These metabolites are therefore regarded as metabolic sensors for programing pathway network of energy metabolism. Metabolic cofactors are produced in respective metabolic pathways, which participate in epigenetic modification processes through enzymes. Epigenetic modifications can be assessed by detecting relevant metabolic cofactors, which can be interfered with by targeting the regulation of metabolic cofactor expression.
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