Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice

Nat Commun. 2021 Oct 27;12(1):6212. doi: 10.1038/s41467-021-26277-w.

Abstract

Noncommunicable diseases (NCDs) account for over 70% of deaths world-wide. Previous work has linked NCDs such as type 2 diabetes (T2D) to disruption of chromatin regulators. However, the exact molecular origins of these chronic conditions remain elusive. Here, we identify the H4 lysine 16 acetyltransferase MOF as a critical regulator of central carbon metabolism. High-throughput metabolomics unveil a systemic amino acid and carbohydrate imbalance in Mof deficient mice, manifesting in T2D predisposition. Oral glucose tolerance testing (OGTT) reveals defects in glucose assimilation and insulin secretion in these animals. Furthermore, Mof deficient mice are resistant to diet-induced fat gain due to defects in glucose uptake in adipose tissue. MOF-mediated H4K16ac deposition controls expression of the master regulator of glucose metabolism, Pparg and the entire downstream transcriptional network. Glucose uptake and lipid storage can be reconstituted in MOF-depleted adipocytes in vitro by ectopic Glut4 expression, PPARγ agonist thiazolidinedione (TZD) treatment or SIRT1 inhibition. Hence, chronic imbalance in H4K16ac promotes a destabilisation of metabolism triggering the development of a metabolic disorder, and its maintenance provides an unprecedented regulatory epigenetic mechanism controlling diet-induced obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adipocytes / metabolism
  • Adipose Tissue / metabolism
  • Amino Acids / metabolism
  • Animals
  • Carbon / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat / adverse effects*
  • Gene Expression Regulation
  • Genetic Predisposition to Disease / genetics
  • Glucose / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Haploinsufficiency
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Histones / metabolism*
  • Lipid Metabolism
  • Lysine / metabolism*
  • Mice
  • Obesity / etiology*
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism

Substances

  • Amino Acids
  • Glucose Transporter Type 4
  • Histones
  • PPAR gamma
  • Pparg protein, mouse
  • Slc2a4 protein, mouse
  • Carbon
  • Histone Acetyltransferases
  • Kat8 protein, mouse
  • Glucose
  • Lysine