Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.

肥胖会改变控制肝脏免疫代谢稳态的垂体激素水平，其失调会导致非酒精性脂肪肝（NAFLD）。然而，肥胖对垂体内稳态的影响在很大程度上尚不清楚。在这里，我们发现肥胖小鼠和人类的垂体中未折叠蛋白反应（UPR）减弱，但炎症特征升高。此外，我们发现肥胖会使垂体发炎，导致垂体肌醇需求酶 1α (IRE1α)-X-box 结合蛋白 1 (XBP1) UPR 分支受损，这对于预防垂体内分泌缺陷和 NAFLD 进展至关重要。有趣的是，垂体 IRE1 缺失会导致甲状腺功能减退，并抑制肝脏中甲状腺激素受体 B (THRB) 介导的Xbp1激活。相反，激活肝脏 THRB-XBP1 轴可改善垂体 UPR 缺陷小鼠的 NAFLD。我们的研究为肥胖引起的垂体内细胞缺陷以及垂体-肝脏 UPR 通讯在 NAFLD 进展中的病理生理学作用提供了第一个证据和机制。