The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams.

肥胖和相关二型糖尿病患病率的稳步上升是一个主要的健康问题，特别是在儿童中。母亲肥胖是导致后代代谢紊乱的危险因素。内质网 (ER) 应激已成为成人瘦素抵抗和 2 型糖尿病的关键机制。在这里，我们使用孕产妇肥胖小鼠模型来研究生命早期 ER 应激在这种代谢疾病的营养规划中的重要性。肥胖母鼠的后代出现葡萄糖不耐症，并表现出体重、肥胖和食物摄入量增加。此外，母亲肥胖扰乱了与新生儿高瘦素血症和瘦素抵抗相关的黑皮质素回路的发育。肥胖母亲所生新生儿的下丘脑中与内质网应激相关的基因上调。使用缓解内质网应激药物牛磺熊去氧胆酸进行的新生儿治疗可改善肥胖母鼠后代的代谢和神经发育缺陷，并逆转瘦素抵抗。