Dietary induction of obesity and insulin resistance is associated with changes in Fgf21 DNA methylation in liver of mice

• DOI: 10.1016/j.jnutbio.2021.108907
• Publication Date: 2021-11-18T16:37:50Z
• Authors: Cathleen Geißler; Christin Krause; Anne-Marie Neumann; Jan H. Britsemmer; Natalie Taege; Martina Grohs; Meike Kaehler; Ingolf Cascorbi; Alfor G. Lewis; Randy J. Seeley; Henrik Oster; Henriette Kirchner
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Fatty Acids; DNA Methylation; Diet, High-Fat; Fibroblast Growth Factors; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Glucose; Liver; Weight Loss; Animals; Obesity; Insulin Resistance; Transcriptome

DNA methylation is dynamically regulated in metabolic diseases, but it remains unclear whether the changes are causal or consequential. Therefore, we used a longitudinal approach to refine the onset of metabolic and DNA methylation changes at high temporal resolution. Male C57BL/6N mice were fed with 60 % high-fat diet (HFD) for up to 12 weeks and metabolically characterized weekly. Liver was collected after 1, 2, 4, 5, 6, 7, 8, and 12 weeks and hepatic DNA methylation and gene expression were analyzed. A subset of obese mice underwent vertical sleeve gastrectomy (VSG) or metformin treatment and livers were studied. Distinct hepatic gene expression patterns developed upon feeding HFD, with genes from the fatty acid metabolism pathway being predominantly altered. When comparing metabolic data with gene expression and DNA methylation, in particular Fgf21 DNA methylation decreased before the onset of increased Fgf21 expression and metabolic changes. Neither weight loss induced by VSG nor improved glucose tolerance by metformin treatment could revert hepatic Fgf21 DNA methylation or expression. Our data emphasize the dynamic induction of DNA methylation upon metabolic stimuli. Reduced Fgf21 DNA methylation established before massive overexpression of Fgf21, which is likely an adaptive effort of the liver to maintain glucose homeostasis despite the developing insulin resistance and steatosis. Fgf21 DNA methylation resisted reversion by intervention strategies, illustrating the long-term effects of unhealthy lifestyle. Our data provide a temporal roadmap to the development of hepatic insulin resistance, comprehensively linking DNA methylation with gene expression and metabolic data.