A human-like fat diet is sufficient to induce transgenerational obesity

The prevalence of obesity has steadily increased since decades. In the meantime, in line with the exposition of populations of from industrialized countries have been exposed to fat-rich diet with high exaggerated ù6/ù3 ratio of ù6- over ù3-polyunsaturated fatty acids. To assess the contribution of dietary fatty acids, male and female mice fed a human-like fat diet were mated randomly and maintained after breeding on the same diet for successive generations. Offspring showed over 4 generations a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in energy intake. Transgenerational alterations in adipokine levels were accompanied by hyperinsulinemia. When switched to a standard diet, the obese phenotype (termed revHF4) reversed partially. Offspring of revHF4 mice exhibited higher birth weight and faster gain weight compared to control mice. Gene expression analyses of the stromal vascular fraction of adipose tissue over generations revealed i) underexpression of genes favoring angiogenesis and controlling oxidative stress and ii) overexpression of genes involved in inflammation, and in adipogenesis .and in insulin resistance. Thus, under conditions of genome stability, our results show that metabolic imprinting induced by a human-like fat diet is accompanied by a gradual fat mass enhancement, in accordance with the increasing prevalence of obesity observed in humans over generations. 2 independent experiments. Experiment 1 = 12 microarrays, corresponding to the 6 possible comparisons between STD, HF0, HF3 and HF4, in dye-swap. Experiment 2 = 22 microarrays, corresponding to the 6 possible comparisons between HF0, HF1, HF3 and HF4, in dye-swap, plus a dye-swap comparison between HF0 and STD (2 times), HF1 and HF1-REV (one time), HF3 and HF3-REV (one time), HF4 and HF4-REV (one time). (HF0 = outcome of STD, fed with a high fat diet. STD = fed with a normal diet. HF1 = outcome of HF0, fed with a high fat diet. HF1-REV = outcome of HF0, fed with a normal diet. HF3 = outcome of HF2, fed with a high fat diet. HF3-REV = outcome of HF2, fed with a normal diet. HF4 = outcome of HF3, fed with a high fat diet. HF4-REV = outcome of HF3, fed with a normal diet).