Histone demethylases regulate adipocyte thermogenesis.

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.