A recent study published in Cell Metabolism identifies a new mechanism by which obesity affects pituitary function through disrupting the unfolded protein response (UPR), and the resultant endocrine defects leading to maladptive hepatic UPR and progression of nonalcoholic fatty liver disease (NAFLD, also known as metabolic dysfunction-associated steatotic liver disease).

Hormone secretion from the pituitary is carried out by specialised secretory cells, which require a functional endoplasmic reticulum (ER) for their endocrine output. Upon stress, cells initiate the UPR to regulate ER stress and restore ER homeostasis. An impaired UPR in secretory endocrine cells can result in reduced hormone secretion, as occurs in insulin-secreting pancreatic β-cells during diabetes mellitus. “However, to our best knowledge, no published studies have characterized the pituitary UPR functional significance in the context of obesity,” says Yang. Thus, the researchers set out to address these knowledge gaps, using a variety of approaches to study human tissue and genetic mouse models.

最近发表在《细胞代谢》杂志上的一项研究发现了一种新机制，肥胖通过破坏未折叠蛋白反应 (UPR) 来影响垂体功能，由此产生的内分泌缺陷导致肝脏 UPR 适应不良和非酒精性脂肪性肝病 (NAFLD，也称为代谢功能障碍相关的脂肪肝病）。

垂体的激素分泌是由专门的分泌细胞进行的，这些细胞需要功能性内质网（ER）来进行内分泌输出。在应激时，细胞启动 UPR 来调节 ER 应激并恢复 ER 稳态。分泌内分泌细胞中的 UPR 受损会导致激素分泌减少，就像糖尿病期间分泌胰岛素的胰腺 β 细胞中发生的情况一样。 “然而，据我们所知，尚无已发表的研究描述垂体 UPR 在肥胖背景下的功能意义，”杨说。因此，研究人员着手解决这些知识差距，使用各种方法来研究人体组织和遗传小鼠模型。