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Fig. 2 | Genes & Nutrition

Fig. 2

From: Nutritional systems biology of type 2 diabetes

Fig. 2

Potential mechanisms underlying high-fat-diet-induced diabetes based on recent nutritional systems biology studies. High-fat diet can affect metabolites (left branch), microbiota (middle), and NAD+/NADH ratio (right). Left branch: The perturbed metabolites may affect methyl donors such as cysteine, methionine, SAM, and SAH, leading to changes in DNA methylation. Altered DNA methylation regulates gene expression through multiple mechanisms, such as promoter and gene body methylation. Middle branch: Butyrate-producing bacteria have been found to be decreased in gut microbiota, leading to lower levels of short-chain fatty acids (SCFAs) such as butyrate, which could modulate histone deacetylase (HDAC) activities to induce histone modifications and chromatin structural changes. Epigenomic changes may directly alter transcriptional activities or indirectly by reshaping the circadian rhythm including impaired CLOCK/BMAL1 recruitment to chromatin and induction of PPAR-γ recruitment. Right branch: Decreased NAD+/NADH ratio by HFD can switch off AMPK and SIRT1 signaling, leading to downregulation of PGC-1 and subsequent mitochondria dysfunction. The upstream regulatory mechanisms depicted from all three branches will trigger in perturbations of various biological processes such as lipid metabolism, Krebs cycle, fatty acid synthesis, oxidative phosphorylation, cell cycle, and inflammatory responses that lead to insulin resistance and compromised β cell functions that are primary features of T2D

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