Metabolic Inflexibility in Response to Lipid Oversupply with Obesity: Epigenetic Modifications Play a Role

Abstract

The ability to adjust substrate oxidation according to nutrient availability has been termed `metabolic flexibility' and is a critical factor in overall metabolic health. In respect to fatty acid oxidation (FAO) metabolic flexibility appears to be compromised with severe obesity (BMI > 40kg/m2). When given a high-fat diet, healthy lean individuals increase their FAO, which is accompanied by increased expression of lipid-oxidizing genes. We observed an impairment in the ability to increase FAO in response to a high-fat diet in the skeletal muscle of obese individuals, which was accompanied by little or no change in the transcriptional upregulation of genes involved in FAO. These data indicate a differential response to lipid oversupply with obesity which could contribute to positive lipid balance and weight gain. The molecular mechanisms contributing to this metabolic inflexibility with severe obesity are not evident. Acute epigenetic modifications of the genome, such as DNA methylation and histone acetylation, may provide a connection between nutritional factors, gene expression, and metabolic health. The purpose of the present study was therefore to determine if the expression of genes linked with FAO differed in a manner indicative of a lack of metabolic flexibility with obesity and to what extent the differential responses to lipid oversupply were linked with the chromatin environment and/or the methylation signature of these genes. By utilizing human skeletal muscle cultures (HSkMC) we were able to study the molecular adaptations to a lipid stimulus in the skeletal muscle of lean and obese humans. The main findings were that: 1) the coordinated activation of genes linked with FAO among lean individuals in response to lipid oversupply is largely absent with obesity as evidenced by a blunted upregulation of several vital transcriptional regulators and 2) that changes in CpG methylation, increased histone acetylation, and transcription factor binding accompanied this response, suggesting that acute epigenetic modifications play a role in the lipid-induced upregulation of these genes. These data provide the novel information that with severe obesity the metabolic inflexibility evident in response to lipid exposure may be linked with an inability to upregulate transcriptional regulators caused by differential epigenetic modifications.