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Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. Following twelve weeks of high fat feeding the animals became obese, hyperglycaemic, insulin resistant, had elevated levels of blood cholesterol and VLDL and developed hepatic steatosis. The nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed following the high fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine play an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high fat feeding are multifactorial indicating that the inter-play between several metabolic pathways is responsible for the pathological consequences.