Oral Abstracts

Abstract

Background:The hepatic immuno-metabolic response is tightly controlled by hormones released from pituitary endocrine cells that rely on an intact endoplasmic reticulum (ER) function . Although abnormal pituitary hormone levels are positively correlated with the incidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in rodents and humans, the molecular mechanisms underlying the cell autonomous defect of pituitary hormone production are incompletely resolved . Methods: This study has employed bulk and single-cell RNA-Sequencing analyses, cellular and molecular biological methods, chemical or genetic approaches for gain and loss function of genes of interest, and in vivo mouse metabolic profiling. Results: We found that obesity, the major risk factor for NAFLD, impairs pituitary ER homeostasis by suppressing the inositol-requiring enzyme-α (IRE1α)-mediated adaptive unfolded protein response (UPR). Furthermore, IRE1α deficiency in the anterior pituitary gland impaired pituitary hormone production, augmented obesityassociated systemic metabolic abnormalities as well as NASH progression. Intriguingly, disruption of the pituitary UPR resulted in impaired hepatic UPR signature which was in part due to a defective thyroid hormone receptor (THR)-mediated activation of X-box binding protein 1 (Xbp1). Using genetic gain-of sXBP1 function in the anterior pituitary approach, we further showed that ameliorating adaptive pituitary improved the disruption of hepatic and systemic metabolic homeostasis in IRE1α pituitary KO mice with diet-induced obesity . Notably, activation of the hepatic THR signaling, by using a liver-specific THR agonist (MGL-3196), significantly improved hepatic steatosis, insulin resistance, and the impaired hepatic ER homeostasis in obese mice with anterior pituitary-IRE1α deficiency. Lastly, in the liver, overexpression of sXBP1 improved the metabolic defects in IRE1α pituitary-deletion mice. Conclusion: Together, our study provides the first insight into how dysregulation of pituitary hormone-mediated inter-organ UPR communication drives obesity-associated pathologies . Such knowledge is expected to uncover new targets for developing therapies for NAFLD .