Obesity Disrupts Pituitary-Hepatic UPR Communication Leading to NAFLD Progression

Background and Research Objectives

In recent years, the incidence of non-alcoholic fatty liver disease (NAFLD) has increased significantly. Research suggests that obesity, a major risk factor for NAFLD, disrupts hepatic immunometabolic homeostasis by affecting systemic hormone, inflammation, and metabolic balance. However, the impact of obesity on pituitary homeostasis itself and its specific mechanisms in NAFLD progression remain unclear. Given that the pituitary gland is a crucial endocrine organ playing a significant role in systemic hormone, inflammation, metabolic, and energy homeostasis, the authors hypothesized that obesity’s effect on the pituitary might further exacerbate the development of NAFLD. Therefore, this paper aims to explore how obesity affects the pituitary’s unfolded protein response (UPR) and how this impact leads to hepatic UPR defects, ultimately contributing to NAFLD progression.

Research Source and Author Information

This paper, titled “Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression,” is authored by Qingwen Qian, Mark Li, Zeyuan Zhang, and others, and was published in “Cell Metabolism” on July 2, 2024. The leading authors are affiliated with prestigious research institutions such as the University of Iowa Carver College of Medicine, University of South Carolina, University of Kansas Medical Center, and Harvard T.H. School of Public Health in the United States.

Research Methods and Steps

Research Process

1. RNA Sequencing Analysis: Using RNA sequencing (RNA-seq), researchers analyzed the pituitary transcriptome variations in lean and obese mice under normal diet and high-fat diet (HFD) conditions during fasting and refeeding. Results showed that refeeding significantly altered the pituitary transcriptome in normal mice but was notably weakened in HFD mice.

2. Immunofluorescence Analysis: Through immunofluorescence (IF) analysis, the expression levels of Ire1a and Xbp1 proteins in the pituitaries of lean and obese mice were compared. Results indicated that obesity significantly suppressed Ire1a and Xbp1 expression in the pituitary but did not affect other UPR branches like Perk.

3. Human Sample Analysis: Further RNA sequencing and IF analysis corroborated the differences in IRE1a and XBP1 expression in the pituitaries between obese and lean patients, consistently showing that obesity suppresses pituitary UPR signaling pathways.

4. ER Stress Measurement: ER function in the pituitary was assessed using ATF6LD-cLUC secretion reporter gene and UPRE-LUC reporter gene. The results demonstrated that obesity increased ER stress (mediated by increased ATF6LD-cLUC secretion) but suppressed adaptive UPR (decreased UPRE activity).

5. Single-cell RNA Sequencing Analysis: Single-cell RNA sequencing (scRNA-seq) of the pituitary in lean and obese mice revealed that obesity did not significantly alter the anterior pituitary cell composition but increased macrophage infiltration and pro-inflammatory macrophage-associated gene expression.

6. Experimental Intervention: By acutely depleting pituitary macrophages in obese mice using clodronate, its impact on pituitary UPR signaling and hormone secretion was assessed. Results showed that macrophage depletion significantly increased pituitary XBP1 and sXBP1 expression in obese mice, improving hormone secretion.

Experiments and Data Analysis

1. Pituitary and Hepatic UPR Experiment: By generating a pituitary IRE1a knockout mouse model (Ire1 Pko), the role of pituitary IRE1 in NAFLD progression was investigated. RNA-seq analysis showed that pituitary IRE1a deficiency significantly downregulated the expression of hepatic fibrosis and steatosis-related genes.

2. Liver Histology Analysis: Oil Red O staining and hepatic triglyceride (TG) content measurement revealed increased hepatic steatosis and TG content in pituitary IRE1a-deficient mice.

3. Hormone and Metabolic Function Testing: The impact of pituitary IRE1 deficiency on systemic metabolic levels, energy expenditure, and hormone secretion in mice was evaluated. IRE1-deficient mice exhibited increased fat mass and decreased energy expenditure, with significantly impaired liver function.

4. Liver-specific THRB Agonist Treatment: Using the liver-specific thyroid receptor β (THRB) agonist MGL-3196 to treat obese mice showed significant improvement in glucose intolerance and hepatic steatosis in obese mice.

5. sXBP1 Overexpression Experiment: Adenovirus-mediated overexpression of hepatic sXBP1 in IRE1 Pko mice significantly improved these mice’s systemic glucose homeostasis and hepatic steatosis.

Research Results and Significance

Key Findings

1. Obesity significantly inhibited the pituitary Ire1a-Xbp1 UPR signaling pathway.
2. In the pituitaries of obese and human obese patients, UPR signaling pathway-related gene expression was significantly downregulated.
3. Macrophage infiltration and pro-inflammatory gene expression were significantly increased.
4. Ire1 deficiency led to reduced pituitary hormone secretion, disrupted systemic thyroid hormone (TH) homeostasis, and resulted in physiological and liver pathological changes.

Research Conclusions

Obesity disrupts pituitary UPR signaling, interrupting pituitary-hepatic UPR communication, thereby exacerbating NAFLD progression. Therapeutically restoring UPR signaling in the pituitary and liver, such as with MGL-3196 to activate liver THRB, can significantly improve obesity-related metabolic disorders. Strategies targeting pituitary UPR function might offer a novel therapeutic approach to alleviate obesity-related metabolic diseases, including NAFLD.

Research Highlights

1. This study is the first to reveal obesity’s impact on pituitary UPR signaling pathways and its critical role in NAFLD progression.
2. Introduces a new cross-organ UPR communication mechanism, emphasizing the important regulatory role of pituitary hormones in hepatic UPR regulation.
3. Systematically validated the molecular mechanism by which obesity interrupts pituitary-hepatic UPR communication through various innovative experimental methods and models.

Research Value

This study not only provides new insights into the pathological mechanisms of obesity and NAFLD but also offers scientific bases for developing new medical interventions. Improving pituitary and hepatic UPR pathway function could potentially mitigate and reverse the progression of obesity-related metabolic diseases.

Additional Information

The authors provide a detailed description of the experimental methods used in the study, including RNA sequencing, immunofluorescence, single-cell RNA sequencing, and electron microscopy, ensuring the reliability and credibility of the data and research findings. The study was supported by multiple scientific funds and institutions, and all authors declared no conflicts of interest, ensuring the fairness and scientific integrity of the research.