AIMS/HYPOTHESIS Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. METHODS Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. RESULTS Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05). CONCLUSIONS/INTERPRETATION Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.

中文翻译：

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暴露于母体肥胖程序小鼠后代胰岛的性别差异。

目的/假设 妊娠期肥胖会增加后代 2 型糖尿病的风险。鉴于目前许多人群中近一半的育龄妇女超重/肥胖，因此我们必须提高对子宫内/早期生活环境对后代胰岛功能影响的理解。虽然许多实验研究已经检查了母体肥胖对后代胰岛结构和/或功能的影响，但以前没有描述这些变化是否独立于其他混杂的风险因素，如肥胖、产后高脂肪喂养和衰老. 因此，我们旨在研究暴露于母体肥胖对年轻、耐葡萄糖的雄性和雌性后代的后代胰岛的影响。方法 雌性 C57BL/6J 小鼠在怀孕和哺乳之前和整个怀孕和哺乳期间随意喂食食物或致肥胖饮食。后代断奶后开始吃食物并一直保持这种饮食直到研究结束。在 7 周龄时对雄性和雌性后代进行 IPGTT。在 8 周龄时，从后代中分离出胰岛，用于测量胰岛素分泌和含量、线粒体呼吸、ATP 含量、活性氧水平、β 和 α 细胞质量、颗粒和线粒体密度（通过透射电子显微镜）和 mRNA分别通过实时 RT-PCR 和蛋白质印迹法进行蛋白质表达。结果无论母体饮食和后代性别如何，葡萄糖耐量相似。然而，血糖较低 (p < 0.001) 和血浆胰岛素较高 (p < 0. 05) 在给予葡萄糖后 15 分钟在肥胖水坝的雌性后代中。这与这些后代更高的葡萄糖（p <0.01）和亮氨酸/谷氨酰胺刺激（p <0.05）胰岛素分泌有关。此外，与同性对照相比，肥胖水坝的雌性后代线粒体呼吸（p < 0.01）和密度（p < 0.05）增加。电子传递链的线粒体和核编码成分、在刺激 - 分泌偶联中起关键作用的 L 型 Ca2+ 通道亚型 [Cacna1d (p < 0.05)] 和雌激素受体 α (p < 0.05) 的表达也这些肥胖水坝的雌性后代的胰岛增加。此外，切割的 caspase-3 表达和 BAX:Bcl-2 降低 (p < 0.05)，反映了对细胞凋亡的敏感性降低。相反，在雄性后代中，葡萄糖和亮氨酸/谷氨酰胺刺激的胰岛素分泌在治疗组之间具有可比性。然而，线粒体呼吸受损，其特征是 ATP 合成驱动的呼吸减少 (p < 0.05) 和非耦合呼吸增加 (p < 0.01)，停靠的胰岛素颗粒减少 (p < 0.001)，Cacna1c (p < 0.001) 和 Cacna1d 减少(p < 0.001) 和增加的 cleaved caspase-3 表达 (p < 0.05)。结论/解释 母体肥胖会影响后代胰岛功能的性别差异。雌性而非雄性后代的胰岛似乎已准备好应对营养丰富的产后环境，这可能反映了未来 2 型糖尿病风险的差异。线粒体呼吸受损，其特征是 ATP 合成驱动的呼吸减少 (p < 0.05) 和非耦合呼吸增加 (p < 0.01)，停靠的胰岛素颗粒减少 (p < 0.001)，Cacna1c (p < 0.001) 和 Cacna1d (p < 0.001) 减少并增加裂解的 caspase-3 表达（p < 0.05）。结论/解释 母体肥胖会影响后代胰岛功能的性别差异。雌性而非雄性后代的胰岛似乎已准备好应对营养丰富的产后环境，这可能反映了未来 2 型糖尿病风险的差异。线粒体呼吸受损，其特征是 ATP 合成驱动的呼吸减少 (p < 0.05) 和非耦合呼吸增加 (p < 0.01)，停靠的胰岛素颗粒减少 (p < 0.001)，Cacna1c (p < 0.001) 和 Cacna1d (p < 0.001) 减少并增加裂解的 caspase-3 表达（p < 0.05）。结论/解释 母体肥胖会影响后代胰岛功能的性别差异。雌性而非雄性后代的胰岛似乎已准备好应对营养丰富的产后环境，这可能反映了未来 2 型糖尿病风险的差异。001) 和增加的 cleaved caspase-3 表达 (p < 0.05)。结论/解释 母体肥胖会影响后代胰岛功能的性别差异。雌性而非雄性后代的胰岛似乎已准备好应对营养丰富的产后环境，这可能反映了未来 2 型糖尿病风险的差异。001) 和增加的 cleaved caspase-3 表达 (p < 0.05)。结论/解释 母体肥胖会影响后代胰岛功能的性别差异。雌性而非雄性后代的胰岛似乎已准备好应对营养丰富的产后环境，这可能反映了未来 2 型糖尿病风险的差异。