title: 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.
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;
authors: Xing
authors: X
authors: Zeng
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;
authors: Mark P
authors: MP
authors: Jedrychowski
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;
authors: Yi
authors: Y
authors: Chen
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA;
authors: Sara
authors: S
authors: Serag
authors: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors: Gareth G
authors: GG
authors: Lavery
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;
authors: Steve P
authors: SP
authors: Gygi
authors: Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;
authors: Bruce M
authors: BM
authors: Spiegelman
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism; D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010084:Oxidation-Reduction; D022722:Thermogenesis / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006657:Histones; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D009638:Norepinephrine
keywords: HSD11B1; LSD1; PRDM16; brown adipose tissue; mitochondria; thermogenesis