Defective medium-chain fatty acid β-oxidation in the liver alters the fat preference and induces hepatic steatosis and glucose intolerance

Long-chain triglycerides (LCTs) exert obesogenic effects, whereas medium-chain triglycerides (MCTs) exert antiobesity effects. To date, most studies examining the distinct effects of MCTs and LCTs have been conducted under extreme conditions using high-fat diets (45-60 kcal% fat). In this study, we aimed to investigate the health effects of varying MCT/LCT intake ratios in 30 kcal% high-fat diets, using liver-specific medium-chain acyl-CoA dehydrogenase (MCAD)-deficient (MCAD^L-/-) mice. Since this fat level more closely resembles the human diet without causing overeating, it allows for a purer assessment of the metabolic effects of the MCT/LCT intake ratios compared with the results of studies using extreme high-fat conditions. We fed MCAD^L-/- mice 30 kcal% fat MCT and LCT diets for 12 wk. Notably, MCAD^L-/- mice consumed the LCT diet more than the MCT diet, without any difference in the total caloric intake. Despite no difference in body weight, MCAD^L-/- mice exhibited impaired glucose tolerance and elevated hepatic triacylglycerol and cholesterol levels. Moreover, lipid droplet size and gene expression levels of some inflammatory markers increased in the adipose tissues of MCAD^L-/- mice. Overall, these results suggest that the intact metabolism of medium-chain fatty acids in the liver is crucial for dietary fat preference regulation. Furthermore, antiobesity effects of MCTs are observed even when the percentage of MCT intake is increased without altering the total fat intake.<b>NEW & NOTEWORTHY</b> Medium-chain triglycerides (MCTs) exert antiobesity effects; however, whether these antiobesity effects are observed when the MCT/long-chain triglyceride intake is altered using a high-fat diet (30 kcal% fat) remains unclear. This study found that impaired medium-chain fatty acid metabolism in the liver reduced MCT preference, without altering the total fat intake, resulting in metabolic dysfunction. Therefore, increasing the MCT ratio in dietary fats possibly reduces the risk of obesity.