Obesity is a growing societal scourge responsible for approximately 4 million deaths worldwide. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces a gradual enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a healthy overweight phenotype that is not reversed after 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

中文翻译：

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父亲多代接触致肥胖饮食会导致表观遗传易感性代谢异常

肥胖症是一种日益严重的社会祸害，全世界约有400万人死亡。最近的研究发现，饮食不平衡引起的父亲过多的体重会影响后代的代谢健康。这些报告主要采用单代男性暴露。然而，多代不平衡饮食喂养对子代代谢健康的影响仍然未知。在这里，我们表明，在小鼠中连续五代保持父系西方饮食喂养会导致几代人的脂肪量和相关代谢疾病逐渐增强。令人吃惊的是，这些多代西方饮食喂养的雄性的杂粮饮食后代形成了健康的超重表型，该表型在随后的四代中都没有逆转。机械上，将精子RNA显微注射到受精卵中的实验表明，精子RNA足以建立，但不能长期维持代谢病理的表观遗传。连续的父辈西方饮食喂养的几代人引起的进行性和永久性代谢失调可能会导致全球范围内的代谢性疾病流行。