Nat. Commun. 12, 6212 (2021)
Writing in Nature Communications, Rodrigues et al. show that the chromatin-modifying enzyme MOF, which deposits an acetyl group onto histone 4 lysine position 16 (H4K16ac), has a key role in central carbon metabolism, and that its dysregulation may therefore contribute to the development of metabolic disorders such as type II diabetes (T2D). By lowering the levels of MOF in mice and following the metabolic signatures in various tissues, they find that there is a systemic imbalance of amino acids and carbohydrates in Mof-deficient mice, which resembles the imbalances that precede those manifesting in T2D. To test whether this possible T2D predisposition could be aggravated by nutritional stress, the researchers subjected Mof-deficient mice to a high-fat diet. Oral glucose tolerance testing, a test for T2D diagnosis, revealed impairment in glucose assimilation to tissues and deficiencies in its uptake into adipose stores, resulting in an increase in blood glucose levels. The authors also observe a marked deficiency in glucose-dependent insulin secretion in these mice. By using transcriptomic analysis to determine the underlying molecular basis, they find that MOF-mediated H4K16ac deposition is required for transcription of Pparg, a master regulatory gene that controls the expression of a network of downstream glucose metabolism-related genes. Among those genes is Glut4, which encodes a transporter required to facilitate glucose uptake and subsequent storage into adipose tissues. Finally, the authors were able to restore glucose uptake and lipid storage in vitro in MOF-depleted adipocytes by ectopic expression of Glut4 or by administering a PPARγ agonist. This study provides molecular insight into how chromatin regulation affects metabolic disorders and diet-induced obesity.
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