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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.
Highlights
Noncommunicable diseases (NCDs) account for over 70% of deaths world-wide
We demonstrate that MOF-mediated H4K16ac is required for the transcriptional regulation of PPARγ and the downstream transcriptional network mediating glucose uptake and neutral lipid storage in white adipose tissue
The datasets clustered according to their tissue of origin in sparse partial least squares discriminant analysis, indicating tissuespecific differences (Fig. 1b)
Summary
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. 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. In particular noncommunicable diseases (NCDs), are major health challenges for modern societies and account for over 70% of deaths worldwide Metabolic disorders such as obesity and hyperglycemia are considered major risk factors for both development and maintenance of NCDs1,2. Alterations in levels of epigenetic regulators can translate into metabolite imbalances Both histone methyltransferase and histone deacetylase enzymes have been implicated in the regulation of obesity, including as factors mediating resistance to dietinduced obesity[12,13,14,15]. These mice show disrupted glucose assimilation and impaired insulin response, suggestive of a predisposition to developing a metabolic syndrome. We demonstrate that MOF-mediated H4K16ac is required for the transcriptional regulation of PPARγ and the downstream transcriptional network mediating glucose uptake and neutral lipid storage in white adipose tissue
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