Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression

Qingwen Qian; Mark Li; Zeyuan Zhang; Shannon W Davis; Kamal Rahmouni; Andrew W Norris; Huojun Cao; Wen-Xing Ding; Gökhan S Hotamisligil; Ling Yang

doi:10.1016/j.cmet.2024.04.014

Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression

Cell Metab. 2024 May 3:S1550-4131(24)00134-7. doi: 10.1016/j.cmet.2024.04.014. Online ahead of print.

Authors

Affiliations

¹ Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
² Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208, USA.
³ Department of Neuroscience and Pharmacology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
⁴ Division of Endocrinology and Diabetes, Department of Pediatrics, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
⁵ Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA 52242, USA.
⁶ Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
⁷ Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
⁸ Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: ling-yang@uiowa.edu.

PMID: 38718793
DOI: 10.1016/j.cmet.2024.04.014

Abstract

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.

Keywords: IRE1; NAFLD; UPR; obesity; pituitary gland; thyroid hormone.