Fig. 3

Proposed hypothesis of epigenetic mechanisms in liver contributing to IR in severe obesity, based on findings from Kirchner et al. [47]. Increased hepatic glycolysis and de novo lipogenesis are associated with DNA hypomethylation within ATF motifs of genes involved in glycolysis and IR. An excess of pyruvate from glycolysis is not used for ATP synthesis in the tricarboxylic acid (TCA) cycle and is converted to fatty free acids (FFA), which activate transcription of CƐ kinase that remains silenced by hypomethylation, increasing CE kinase (PRKCE) levels. The action and increased levels of PRKCE have been implicated in decreased insulin signaling. Therefore, the liver of severely obese patients is programmed to become insulin-resistant, possibly contributing to T2D and nonalcoholic fatty liver disease (NAFLD). Continuous arrows represent activation of studied glycolysis and lipogenesis pathways. Discontinuous arrows represent the proposed hypothesis