Effects of dietary obesity in fathers on gene expression of fat in the female offspring (mRNA data)

The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed ß-cell ‘dysfunction’ in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet altered the expression of 211 pancreatic islet genes in adult female offspring (P < 0.001); genes belonged to 8 functional clusters, including calcium ion binding, primary metabolic processes and ATP binding, and organ/system development. Broader KEGG pathway analysis of 2014 genes differentially expressed at the P < 0.01 level further demonstrated involvement of insulin and calcium signaling, and MAPK pathways. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies.全球范围内，各年龄层与性别人群的肥胖患病率均呈上升态势。青少年群体肥胖负担的加重，会促使2型糖尿病提早发病。父母一方罹患肥胖，是儿童肥胖的独立危险因素。尽管饮食诱导的母体肥胖对子代的不良影响已得到广泛证实，但父代肥胖的贡献程度尚不明确，而非遗传因素在致病通路中的作用同样未明。本研究证实，父代高脂饮食可使其F1代雌性子代出现β细胞功能障碍。对斯普拉格-道利（Sprague Dawley）雄鼠实施长期高脂饮食喂养，可导致其体重升高、脂肪堆积、糖耐量受损及胰岛素敏感性下降。与对照组相比，其子代雌性个体在出生首日体重更低，青春期生长速率加快，且在未出现肥胖或脂肪堆积增加的情况下，即表现出胰岛素分泌受损与糖耐量异常。父代高脂饮食会改变成年雌性子代体内211个胰岛基因的表达（P < 0.001）；这些基因可划分为8个功能簇，涵盖钙离子结合、初级代谢过程、ATP结合以及器官/系统发育等功能类别。对P < 0.01水平下差异表达的2014个基因进行更广泛的京都基因与基因组百科全书（KEGG）通路分析，进一步证实胰岛素信号通路、钙离子信号通路及丝裂原活化蛋白激酶（MAPK）通路均参与其中。本研究是首个在哺乳动物中报道父代高脂饮食所致代谢后遗症通过非遗传方式跨代传递至子代的研究。上述发现证实了父代在子代代谢编程中的作用，并为后续相关研究提供了理论框架。