Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression
Description
Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on the 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 UPR. Mechanistically, we demonstrated that the pituitary inositol-requiring enzyme 1a (IRE1a)-X-box binding protein 1 (XBP1) UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and impaired 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 the pituitary-liver UPR communication in NAFLD progression.