肥胖和滥用药物代表了这千年的两个主要公共卫生问题，对我们的发病率，死亡率和健康支出产生了有害影响。根据WHO in 2016，大约19亿成年人超重，其中6.5亿人肥胖。此外，根据世界药物报告2018，，，，around 275 million people worldwide have been reported to have used an illicit drug at least once in 2016. Considering the financial and social burden, it is of the utmost importance that we better understand these disorders, while at the same time developing preventative and therapeutic solutions.

肥胖和药物成瘾都是多因素疾病，反映了基因与环境之间的复杂相互作用。虽然遗传因素无疑起着至关重要的作用，但仅凭它们不能解释近期肥胖或成瘾的戏剧性兴起。这引起了人们对理解表观遗传学作为基因环境相互作用的介体在这些疾病原因中的潜在作用的兴趣。

最近,“早期生活程序的概念ing’ has gained wide attention among obesity and addiction researchers as a key enabler of epigenetic modifications. Early life programming refers to the fact that environmental insults, such as stress, during critical periods of fetal development can induce irreversible physiological changes in the form of various diseases later in life.

在“早期生命计划”的背景下，许多最近的研究报告说，怀孕和泌乳期间的肥胖或营养不良对肥胖和相关代谢综合征的发展产生了重大影响。类似的工作还显示了妊娠对非法药物的接触与后代成瘾的易感性之间的联系。但是，迄今为止，关于孕产妇垃圾食品在怀孕和哺乳和对药物滥用的倾向之间的联系知之甚少。

We show that 9 weeks maternal high fat diet exposure induces obesogenic, and addictive-like phenotypes … over three generations in the absence of any further high fat diet exposure.

考虑肥胖和吸毒成瘾的增长及其共享功能，，，，in our current study we focused on exploring whether maternal overnutrition in mice during perinatal periods can increase the susceptibility to addiction and obesity in the progeny.我们的早期研究showed that maternal high-fat diet (HFD) in mice over a period of 9 weeks (3 weeks preconception, 3 weeks gestation and 3 weeks lactation) led to addictive-like behaviors and metabolic syndrome-like phenotypes in the first generation (F1). The addictive and metabolic phenotypes were associated with a hypodopaminergic mesolimbic reward system as a common underlying mechanism.

This observation has driven us to explore whether the observed addictive-like and obesogenic phenotypes can be transmitted across generations. And if yes, what is the underlying mechanism for such transgenerational inheritance? To be more specific, which epigenetic mark carries this information across generations?

为了回答这些问题，我们将出生的男性后代（F1）带到了9周的HFD和Chow-fed（对照）大坝（F0）。来自两组的F1雄性与幼稚的食喂女性交配，以产生第二代（F2）后代。同样，从HFD和Chow-fed祖先（F0）的F2男性后代开始产生第三代（F3）后代。

我们在这里表明，9周的母体HFD暴露会诱导肥胖（例如，体重增加，脂肪增加，胰岛素抵抗和脂质谱的改变），成瘾性表型（例如，酒精的消耗增加，对可卡因和苯丙胺的敏感性增强，增强了敏感性）以及在没有任何进一步的HFD暴露的情况下，在三代人中，中断奖励系统的低巴博金能状态。我们的发现证明了通过男性种系具有真正的转产遗传，因为该效应在不暴露的F3代中也持续存在。此外，在第三代情况下，出现了明显的性别依赖性效果，女性表现出上瘾的行为，而男性则表现出肥胖的表型。

While the present study was in a mouse model, this observation may help to increase awareness about healthy food habits during pregnancy and breastfeeding.

为了了解这种遗传的潜在机制，我们分析了F1和F2精子中的全局DNA甲基化模式。尽管HFD组的整个基因组甲基组在这两代人中都受到了巨大影响，但几代人都不能保守清晰的甲基化特征。这表明精子甲基团可能不构成观察到的表型的主要载体，这表明传播模式更为复杂。

Our findings highlight the long-term impact of maternal fat rich food intake during preconception, gestation and lactation on the development of obesity and addiction across multiple generations. Our work provides further insight into the role of early life nutrition in the causes of obesity and addiction. While the present study was in a mouse model, this observation may help to increase awareness about healthy food habits during pregnancy and breastfeeding to secure better health for the next generations.

Enjoyed this blog post? Read the full article inTranslational Psychiatry。