Effects of dietary obesity in fathers on gene expression of islets in the female offspring (miRNA 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 β-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，各年龄层与性别的肥胖（obesity）患病率均呈上升态势。青少年群体肥胖负担的不断加重，会促使2型糖尿病（type 2 diabetes）提早发病。父母一方罹患肥胖，是儿童肥胖的独立危险因素。尽管饮食诱导的母代肥胖对子代的有害影响已得到充分证实，但肥胖父代的贡献程度尚不明确，非遗传因素在致病通路中的作用亦尚未明晰。 本研究证实，父代高脂饮食（high fat diet）会诱导其子一代（F1）雌性后代出现β细胞功能障碍（β-cell dysfunction）。对斯普拉格-道利（Sprague Dawley）大鼠父代长期饲喂高脂饮食，可使其体重、体脂含量升高，糖耐量受损与胰岛素敏感性下降。与对照组相比，其子一代雌性后代在出生后第1日体重更低，青春期生长速率更快，且虽未出现肥胖或体脂升高的情况，但存在胰岛素分泌受损与糖耐量异常的问题。 父代高脂饮食会改变成年雌性后代体内211个胰岛基因（pancreatic islet genes）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个基因进行更全面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、钙信号通路以及丝裂原活化蛋白激酶（MAPK）通路均参与该调控过程。 本研究是首个在哺乳动物中报道的、由父代向子代传递高脂饮食代谢后遗症的非遗传跨代传递研究。上述发现证实了父代在子代代谢编程中的关键作用，并为后续相关研究提供了理论框架。