Consumption of a high‐fat diet, but not regular endurance exercise training, regulates hypothalamic lipid accumulation in mice

Key points ‘Lipotoxicity’ refers to the excessive accumulation of lipids in non‐adipose tissues that causes cellular dysfunction and, in severe cases, cell death. Lipotoxicity is often present in obesity. It is unknown whether lipotoxicity occurs in the hypothalamus of the brain, an area involved in the regulation of feeding behaviour and energy balance. We show that high‐fat feeding results in increased lipid content in the hypothalamus, including triacylglycerol, diacylglycerol and ceramide, which was not reduced with 6 weeks of exercise training. The obese leptin‐deficient ob / ob mouse fed a chow diet had normal hypothalamic lipid content. These data show that dietary lipids regulate hypothalamic lipid accumulation, which is not readily reversed by exercise training. Abstract Obesity is characterised by increased storage of fatty acids in an expanded adipose tissue mass and in peripheral tissues such as the skeletal muscle and liver, where it is associated with the development of insulin resistance. Insulin resistance also develops in the central nervous system with high‐fat feeding. The capacity for hypothalamic cells to accumulate/store lipids, and the effects of obesity remain undefined. The aims of this study were (1) to examine hypothalamic lipid content in mice with increased dietary fat intake and in obese ob / ob mice fed a low‐fat diet, and (2) to determine whether endurance exercise training could reduce hypothalamic lipid accumulation in high‐fat fed mice. Male C57BL/6 mice were fed a low‐ (LFD) or high‐fat diet (HFD) for 12 weeks; ob / ob mice were maintained on a chow diet. HFD‐exercise (HFD‐ex) mice underwent 12 weeks of high‐fat feeding with 6 weeks of treadmill exercise training (increasing from 30 to 70 min day −1 ). Hypothalamic lipids were assessed by unbiased mass spectrometry. The HFD increased body mass and hepatic lipid accumulation, and induced glucose intolerance, while the HFD‐ex mice had reduced body weight and improved glucose tolerance. A total of 335 lipid molecular species were identified and quantified. Lipids known to induce insulin resistance, including ceramide (22%↑), diacylglycerol (25%↑), lysophosphatidylcholine (17%↑), cholesterol esters (60%↑) and dihexosylceramide (33%↑), were increased in the hypothalamus of HFD vs . LFD mice. Hypothalamic lipids were unaltered with exercise training and in the ob / ob mice, suggesting that obesity per se does not alter hypothalamic lipids. Overall, hypothalamic lipid accumulation is regulated by dietary lipid content and is refractory to change with endurance exercise training.