biostudies-literatureQian QBLRD VANIDDK NIH HHSNHLBI NIH HHSNIH1550-1565.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC11222033biostudies-literatureUnknown36(7)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 Cell metabolismObesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.PMC11222033R01 DK108835I01 BX004249R01 DK126817P30 DK054759IK6 BX006040R01 HL162773Ding WXRahmouni KCao HYang LZhang ZDavis SWHotamisligil GSQian QNorris AWLi MfalseObesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.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 2024-01-01T00:00:00Z2024 Jul2026-06-02T20:29:34.11Z2026-04-20T03:10:09.456ZS-EPMC112220333871879310.1016/j.cmet.2024.04.014