Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression.
Cell Metab
; 36(7): 1550-1565.e9, 2024 Jul 02.
Article
in En
| MEDLINE
| ID: mdl-38718793
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pituitary Gland
/
Unfolded Protein Response
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Non-alcoholic Fatty Liver Disease
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X-Box Binding Protein 1
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Liver
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Mice, Inbred C57BL
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Obesity
Limits:
Animals
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Female
/
Humans
/
Male
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2024
Document type:
Article
Affiliation country:
United States