DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics

Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2021073118. doi: 10.1073/pnas.2021073118.

Abstract

White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.

Keywords: DNA methylation; adiposity; chromosome structure; metabolic disease; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Adiposity
  • Animals
  • CCCTC-Binding Factor / metabolism
  • Chromosome Structures
  • DNA (Cytosine-5-)-Methyltransferase 1 / deficiency
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA Methylation
  • Dynamins / genetics
  • Dynamins / metabolism
  • Energy Metabolism
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Lipid Metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Dynamics*
  • Obesity / metabolism
  • Obesity / pathology
  • Promoter Regions, Genetic
  • Protein Binding

Substances

  • CCCTC-Binding Factor
  • Ctcf protein, mouse
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse
  • Dnm1l protein, mouse
  • Dynamins