Folic Acid Reduces Insulin Resistance in Mice With Diet‐Induced Obesity by Altering One‐Carbon Metabolism and DNA Methylation Patterns of Hypothalamic and Hepatic Insulin Receptor Gene

Diet-induced obesity and insulin resistance (IR) are associated with alterations in one-carbon (1C) metabolism, gene methylation, and expression. Folate, a methyl donor in 1C metabolism, is essential in gene methylation and expression and has been shown to reduce IR but the precise mechanism(s) remains unclear. Therefore, we investigated whether reduced IR can be explained by 1C metabolism modifications and differences in hypothalamic and hepatic IR-related genes expression and methylation patterns. Four-week-old male C57BL/6J mice (n = 12/group) received high-fat diets (HFDs) with 1- (control), 5- (5FA-HFD), or 10-fold (10FA-HFD) AIN-93G amounts folic acid (FA) for 15 weeks. Body weight, hepatic 1C metabolites, plasma insulin and glucose, and hepatic and hypothalamic expression and methylation of IR-related genes were measured. 5FA-HFD and 10FA-HFD mice had ∼50% lower HOMA-IR compared to control. 10FA-HFD mice also had lower body weight (9%) and adiposity (13%) and higher s-adenosylmethionine levels (19%). 5FA-HFD mice had higher hepatic s-adenosylhomocysteine levels (26%) and DNA methyltransferase 3b expression (45%). Methylation of the InsR gene was correlated with gene expression and the improved metabolic phenotype. FA supplementation reduced IR by modifying 1C metabolism in DIO male mice by differentially altering hypothalamic and hepatic methylation patterns of InsR gene.