Histone demethylases regulate adipocyte thermogenesis

Abstract

Adipocytes play a pivotal role in the regulation of energy metabolism. While white adipocyte stores energy, brown adipocyte dissipates energy by producing heat. In addition, another type of heat-producing adipocyte, beige adipocyte, emerges in white adipose tissue in response to chronic coldness. This phenotypic adaptation to the cold environment is considered to be attributed to the epigenetic modifications. Histone methylation is a chemically stable epigenetic modification and thus a proper mechanism for long-lasting cellular memory. Several histone methyl-modifying enzymes such as EHMT1, JMJD1A, JMJD3, and LSD1 are reported to be involved in the beige adipose cell fate determination. Among these, a histone demethylase JMJD1A senses cold environment by being phosphorylated at S265 in response to β-adrenergic receptor stimulation. Phosphorylated JMJD1A regulates both acute and cold thermogenesis. Under acute coldness, phosphorylated JMJD1A forms a complex with chromatin remodeler SWI/SNF and DNA-bound PPARγ, which recruits JMJD1A to the target genomic regions in brown adipocyte. This complex formation, in turn, induces the expression of target genes by bringing the enhancer and the promoter into close proximity. During chronic coldness, phosphorylated JMJD1A regulates beige adipogenesis through a two-step mechanism. In the first step, phosphorylated JMJD1A is recruited to the regulatory regions of target genes by forming a complex with PRDM16, PGC1α, and DNA-bound PPARγ. In the second step, JMJD1A demethylates histone H3K9me2 and induces stable expression of beige-selective genes. The phenotypic analyses of Jmjd1a-null mice and non-phosphorylated mutant S265A Jmjd1a knock-in mice indicate that JMJD1A is a potential therapeutic target for the treatment of obesity-related diseases including metabolic syndrome and type 2 diabetes.

Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics

“…Histone methylation is chemically stable and thus may act as a longterm cell memory mechanism. Several enzymes that regulate methylation of histone lysine residues, notably members of the lysine (K)-specific demethylase (KDM) family, are involved in the control of beige adipocyte metabolism 129 . The most studied family member is KDM1A, which activates a beiging programme while repressing WATspecific genes by interacting with the thermogenic transcription factors ZFP516 and PRDM16 [130][131][132] .…”

Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review

“…Further, with the acknowledged role of adipose tissue in the maintenance of metabolic homeostasis and altered adipogenesis associated with the MetS, studies have been undertaken to understand better the role of epigenetic processes in regulating the adipocyte function in the setting of such metabolic disorders [ 23 , 27 , 28 ]. A recent study by Daniel et al [ 23 ] identified global DNA methylation of LINE-1 to be associated with metabolic deterioration and glucose metabolism in visceral adipose tissue of individuals with and without MetS.…”

“…Alterations in histone modifications are identified as essential components of epigenetic networks, controlling energy homeostasis and altering adipocyte thermogenesis, thereby contributing to the pathogenesis of MetS ( Table 2 ) [ 28 , 41 ]. For example, a study involving mice deficient in histone demethylase, HDM2a, an enzyme responsible for H3K9 demethylation, reported the development of adult-onset obesity, hypertriglyceridemia and hypercholesterolemia, as well as insulin resistance (IR), in the deficient mice as compared to the wild type [ 41 ].…”

Epigenetic regulation of beige adipocyte fate by histone methylation

“…Brown adipocyte originates from sub-population of dermomyotome precursors expressing Myf5, Pax7, and engrailed 1 (En1). This dermomyotome precursor cell differentiates into either brown preadipocyte which expresses early B cell factor (EBF2) or MyoD-expressing myoblast [1,5,14]. The nature of precursor cells of beige adipocyte is more complicated as is reported that the concept of beige adipocyte does not include only one identical type of thermogenic cells, but encompasses diverse types of thermogenic cells which emerge in white adipose tissue and possibly in other organs in response to the external stimuli [1,15].…”

“…coldness). Indeed, recent studies have revealed that the cell fate of beige adipocyte is regulated by diverse histone methyl-modifying enzymes such as JMJD3 (also known as KDM6B) [22], euchromatic histone-lysine Nmethyltransferase 1 (EHMT1) (also known as GLP) [23], Jumonji domain containing 1A (JMJD1A) (also known as JHDM2A or KDM3A) [24], and LSD1 (also known as KDM1A or AOF2) [25,26] (reviewed in [5,14]) ( Table 1).…”