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

Research output: Contribution to journalArticlepeer-review

Authors

  • Xing Zeng
  • Mark P Jedrychowski
  • Yi Chen
  • Sara Serag
  • Steve P Gygi
  • Bruce M Spiegelman

Colleges, School and Institutes

External organisations

  • Department of Cell Biology, Harward Medical School, Boston, Massachusetts, 02115, USA
  • Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA;

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.

Details

Original languageEnglish
Pages (from-to)1822-1836
Number of pages15
JournalGenes & Development
Volume30
Issue number16
Publication statusPublished - 15 Aug 2016

Keywords

  • LSD1, PRDM16, HSD11B1, brown adipose tissue, thermogenesis, mitochondria