Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel.
Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel.
Sci Rep. 2024 Aug 27;14(1):19874. doi: 10.1038/s41598-024-70438-y.
Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.
肥胖对公共健康构成威胁，其流行程度已达到 epidemic proportions（ epidemic proportions 可直译为“ epidemic 程度”，但为了与前文的“肥胖”相呼应，此处翻译为“流行程度”）。我们的假设表明，这种流行的部分原因是它通过父系表观遗传机制在代际间传播。为了研究这种可能性，我们专注于研究 CpG 甲基化的父系传递。第一代雄性 Wistar 大鼠分别喂食高脂肪饮食（HF）或标准饮食，然后与喂食标准饮食的雌性大鼠交配。我们从这些雄性大鼠中收集精子。这些雄性大鼠的后代在标准饮食下饲养至 35 天，然后进行饮食挑战。饮食诱导肥胖（DIO）雄性大鼠将肥胖相关特征传递给雄性和雌性后代。我们观察到 HF 处理雄性大鼠的精子和其后代下丘脑弓状核（Arc）中 Pomc 启动子的显著 hypermethylation（ hypermethylation 可直译为“高甲基化”，但为了与前文的“肥胖”相呼应，此处翻译为“甲基化增加”）。然而，这些 Arc 甲基化的差异在生命后期会减少。这种 hypermethylation（ hypermethylation 可直译为“高甲基化”，但为了与前文的“肥胖”相呼应，此处翻译为“甲基化增加”）与 DNMT3B 表达的增加相关。进一步使用简化代表性重亚硫酸盐测序（RRBS）研究可能参与肥胖跨代传播的 Arc 中的基因，我们确定了 77 个差异甲基化区域（DMRs），突出了与神经元发育相关的途径。这些发现支持 CpG 甲基化作为将肥胖相关特征传递给后代的一种机制。
