Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring
Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring
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DOI：
10.1038/nature09491
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发表时间：
2010-10-21
期刊：
影响因子：
64.8
通讯作者：
Morris, Margaret J.
中科院分区：
文献类型：
--
作者：
Ng, Sheau-Fang;Lin, Ruby C. Y.;Morris, Margaret J.
全球肥胖率在大多数年龄段的男女中都在增加。这导致了2型糖尿病及其相关流行病的早期出现(1，2)。父母中任何一方肥胖是儿童肥胖的独立危险因素(3)。虽然饮食引起的母亲肥胖对后代肥胖和新陈代谢的不利影响已经得到了很好的证实(4)，但肥胖父亲的贡献程度尚不清楚，特别是非遗传因素在原因途径中的作用。在这里，我们展示了父亲的高脂饮食(HFD)暴露导致大鼠F-1雌性后代的β细胞‘功能障碍’。长期摄入高脂饮食会导致体重增加、肥胖、糖耐量受损和胰岛素敏感性下降。与对照组相比，她们的雌性后代很早就出现了胰岛素分泌受损和糖耐量受损，并随着时间的推移而恶化，并且肥胖正常。父本HFD改变了成年雌性后代642个胰岛基因的表达(P<；0.01)；这些基因属于13个功能簇，包括阳离子和ATP结合、细胞骨架和细胞内转运。对2,492个差异表达基因的更广泛的通路分析(P<；0.05)表明，钙、MAPK和Wnt信号通路参与了细胞凋亡和细胞周期。IL13RA2基因发生低甲基化，表达差异最大(1.76倍)。这是首次在哺乳动物中发现一种HFD的代谢后遗症从父亲传给后代的非遗传性代际传播。
The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic(1,2). Having either parent obese is an independent risk factor for childhood obesity(3). Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established(4), the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs beta-cell 'dysfunction' in rat F-1 female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.