Obesity Disrupts Pituitary UPR Leading to NAFLD

Obesity is the major risk factor for nonalcoholic fatty liver disease (NAFLD), for which effective cures are lacking. Despite the notion that obesity is associated with aberrant levels and action of pituitary hormones that are essential for maintaining hepatic metabolic and inflammatory states, the intrinsic pituitary endocrine abnormalities and their systemic consequences are incompletely defined. By characterizing the impact of diet-induced obesity (DIO) on the pituitary whole tissue and single cell transcriptome, we demonstrated that obesity disrupts pituitary endoplasmic reticulum (ER) homeostasis by suppressing the inositol-requiring enzyme- (IRE1)-mediated adaptive unfolded protein response (UPR). We further showed that defective pituitary UPR by IRE1-deletion in the anterior pituitary strikingly augmented obesity-associated systemic metabolic abnormalities, particularly the NAFLD-associated pathologies. Conversely, enhancing the adaptive UPR in the anterior pituitary, by genetic gain-of-function of spliced X-box binding protein 1 (sXBP1), ameliorated the systemic and hepatic metabolic defects observed in mice with pituitary IRE1 deletion. Intriguingly, disruption of the UPR in the pituitary resulted in impaired hepatic UPR, which was in part due to a defective thyroid hormone receptor (THR)-mediated activation of hepatic Xbp1. In contrast, activation of the hepatic THR signaling improved obesity-associated glucose intolerance and attenuated the impaired hepatic ER homeostasis in anterior pituitary-IRE1 deficient mice. Together, our study provides the first insight into disruption of endocrine signaling-mediated inter-organ UPR communication drives obesity-associated hepatic pathologies. Unraveling these connections might uncover new therapeutic targets for NAFLD and other obesity-associated diseases.