The Saban Research Institute, Developmental Neuroscience Program, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, Lille, France.
PLoS Biol. 2020 Mar 12;18(3):e3000296. doi: 10.1371/journal.pbio.3000296. eCollection 2020 Mar.
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.
肥胖症和相关的 II 型糖尿病患病率的稳步上升是一个主要的健康问题，尤其是在儿童中。母体肥胖是导致后代代谢紊乱的一个危险因素。内质网（ER）应激已成为涉及成年个体瘦素抵抗和 2 型糖尿病的关键机制。在这里，我们使用母体肥胖的小鼠模型来研究早期 ER 应激在这种代谢性疾病的营养编程中的重要性。肥胖母鼠的后代表现出葡萄糖不耐受，并出现体重增加、肥胖和食物摄入增加。此外，母体肥胖破坏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。来自肥胖母亲的新生儿的下丘脑中 ER 应激相关基因上调。用 ER 应激缓解药物牛磺熊脱氧胆酸对新生儿进行治疗，可改善代谢和神经发育缺陷，并逆转肥胖母鼠后代的瘦素抵抗。
