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

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  • Cecilia Pessoa Rodrigues

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Freiburg
    International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB))

  • Aindrila Chatterjee

    (Max Planck Institute of Immunobiology and Epigenetics
    European Molecular Biology Laboratory)

  • Meike Wiese

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Thomas Stehle

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Witold Szymanski

    (Proteomics Facility, Max Planck Institute of Immunobiology and Epigenetics)

  • Maria Shvedunova

    (Max Planck Institute of Immunobiology and Epigenetics)

  • Asifa Akhtar

    (Max Planck Institute of Immunobiology and Epigenetics
    University of Freiburg)

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.

Suggested Citation

  • Cecilia Pessoa Rodrigues & Aindrila Chatterjee & Meike Wiese & Thomas Stehle & Witold Szymanski & Maria Shvedunova & Asifa Akhtar, 2021. "Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26277-w
    DOI: 10.1038/s41467-021-26277-w
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