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

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

Journal article

Peer reviewed

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 and Ling Yang

Cell metabolism, Vol.36(7), pp.1550-1565.e9

05/03/2024

DOI: 10.1016/j.cmet.2024.04.014

PMCID: PMC11222033

PMID: 38718793

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https://pmc.ncbi.nlm.nih.gov/articles/PMC11222033/pdf/nihms-1989928.pdfView

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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. [Display omitted] •Obesity impairs the IRE1α-sXBP1 UPR branch in the pituitary gland•The pituitary IRE1α-sXBP1 axis-regulated endocrine output protects against NAFLD•Obesity suppresses THRB-activated Xbp1 in the liver•The hepatic THRB-XBP1 axis improves NAFLD in mice with defective pituitary UPR NAFLD is associated with abnormal levels of pituitary-derived hormones. Qian et al. found that obesity impairs pituitary UPR-regulated endocrine outputs. Disruption of the pituitary UPR leads to defective hepatic UPR and NAFLD progression. These data demonstrate the pathological relevance of integrated organelle crosstalk across organs in the context of NAFLD.

Obesity

IRE1

NAFLD

pituitary gland

thyroid hormone

UPR

Details

Title: Subtitle: Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression
Creators: Qingwen Qian - University of Iowa
Mark Li - University of Iowa
Zeyuan Zhang - University of Iowa
Shannon W. Davis - University of South Carolina
Kamal Rahmouni - University of Iowa
Andrew W. Norris - University of Iowa
Huojun Cao - University of Iowa
Wen-Xing Ding - University of Kansas Medical Center
Gökhan S. Hotamisligil
Ling Yang - University of Iowa
Resource Type: Journal article
Publication Details: Cell metabolism, Vol.36(7), pp.1550-1565.e9
DOI: 10.1016/j.cmet.2024.04.014
PMID: 38718793
PMCID: PMC11222033
NLM abbreviation: Cell Metab
ISSN: 1550-4131
eISSN: 1932-7420
Publisher: Elsevier Inc
Language: English
Electronic publication date: 05/03/2024
Academic Unit: Molecular Physiology and Biophysics; Endocrinology and Diabetes; Anatomy and Cell Biology; Endodontics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Dental Research; Internal Medicine
Record Identifier: 9984625260302771

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