Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation

Abstract

Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.

LSD1—a pivotal epigenetic regulator of brown and beige fat differentiation and homeostasis

“…Studies by Sambeat et al (2016) demonstrated that LSD1 interacts with Zfp516 to activate UCP1 and other BAT genes. Similar to the work of Zeng et al (2016), Sambeat et al (2016) showed that LSD1 ablation in brown fat resulted in impaired BAT development, increased fat mass, and decreased energy expenditure. A previous report demonstrated that Zfp516 interacts with PRDM16, suggesting that LSD1 forms a transcriptional complex to demethylate H3K9 (Dempersmier et al 2015).…”

“…In this issue of Genes & Development, Zeng andcolleagues (pp. 1822-1836) identify lysine-specific demethylase 1 (LSD1) as a pivotal regulator of whole-body energy expenditure by controlling the oxidative and thermogenic activity of brown adipose tissue (BAT).…”

“…In particular, PRDM16, a key transcriptional coregulator, has been shown to control this process through the induction of BAT-specific genes and repression of select WAT genes most abundantly expressed in visceral WAT (Seale et al 2007;Kajimura et al 2008). In this issue of Genes & Development, Zeng et al (2016) demonstrate that lysine-specific demethylase 1 (LSD1) demethylates H3K4 at genomic loci near WATspecific genes in brown adipocytes by interacting and colocalizing with PRDM16 (Zeng et al 2016). They further show that LSD1 acts independently of PRDM16 to repress hydroxysteroid 11-β-dehydrogenase isozyme 1 (HSD11B1) and prevent the production of anti-thermogenic glucocorticoids (GC).…”

“…Chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) analysis of histone modifications has shown that distinct chromatin marks exist in brown and white fat. Zeng et al (2016) showed that PRDM16 association with LSD1, a monohistone and dihistone demethylase, promotes nonshivering thermogenesis by demethylating H3K4 and repressing WATselective genes. They further demonstrated the importance of repressing select genes in establishing the energy-expending character of brown and beige adipocytes and the role played by LSD1 in this mechanism.…”

“…LSD1 deletion in adipose tissue had a more pronounced metabolic phenotype compared with PRDM16-deficient mice. In fact, Zeng et al (2016) showed that LSD1 represses glucocorticoid-activating enzyme HSD11B1 independently of PRDM16. The deletion of HSD11B1 in adipose-specific LSD1 knockout mice restores energy-expending functions in brown adipocytes, suggesting that increased HSD11B1 expression and elevated GC levels are major contributors to BAT dysfunction in LSD1 knockout mice.…”