Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (pituitary scRNA seq). Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (pituitary scRNA seq)

Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity. Overall design: Pituitaries were collected from WT RD vs HFD, and IRE1 PKO vs IREfl RD male mice (4 hrs feeding following a 16-hrs fasting).

肥胖可改变调控肝脏免疫代谢稳态的垂体激素循环水平，此类激素的失调会引发非酒精性脂肪性肝病（NAFLD）。本研究借助饮食诱导肥胖小鼠与IRE1基因敲除小鼠（IRE1PKO）模型，发现肥胖小鼠垂体组织内的未折叠蛋白反应（unfolded protein response, UPR）受到抑制，但炎症特征显著上调。从机制层面，本研究证实：垂体IRE1α-XBP1未折叠蛋白反应通路分支，在肥胖状态下对于抵御垂体内分泌缺陷与非酒精性脂肪性肝病的进展至关重要。实验整体设计：分别采集野生型常规饲料组（WT RD）、高脂饲料组（HFD）雄性小鼠，以及IRE1基因敲除组（IRE1PKO）与IRE1 flox对照常规饲料组（IREfl RD）雄性小鼠的垂体组织；所有小鼠均先经历16小时禁食，随后喂食4小时后取材。