Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice
Background: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inosit...
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Elsevier
2025-05-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000353 |
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| author | L. Stilgenbauer Q. Chen D. Pungi N. James H. Jayarathne L. Koshko S. Scofield K. Zhang M. Sadagurski |
| author_facet | L. Stilgenbauer Q. Chen D. Pungi N. James H. Jayarathne L. Koshko S. Scofield K. Zhang M. Sadagurski |
| author_sort | L. Stilgenbauer |
| collection | DOAJ |
| description | Background: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive. Objectives: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction. Methods: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks. Results: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses. Conclusions: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases. |
| format | Article |
| id | doaj-art-2c99bcb07cdc4b3a881dc2c52f0bf603 |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-2c99bcb07cdc4b3a881dc2c52f0bf6032025-08-20T03:17:54ZengElsevierMolecular Metabolism2212-87782025-05-019510212810.1016/j.molmet.2025.102128Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in miceL. Stilgenbauer0Q. Chen1D. Pungi2N. James3H. Jayarathne4L. Koshko5S. Scofield6K. Zhang7M. Sadagurski8Department of Biological Sciences, Detroit, MI, USA; Institute of Environmental Health Sciences, Detroit, MI, USACenter for Molecular Medicine and Genetics, School of Medine, Detroit, MI, USADepartment of Pharmaceutical Science, Wayne State University, Detroit, MI, USA; Institute of Environmental Health Sciences, Detroit, MI, USAInstitute of Environmental Health Sciences, Detroit, MI, USADepartment of Biological Sciences, Detroit, MI, USADepartment of Biological Sciences, Detroit, MI, USA; Institute of Environmental Health Sciences, Detroit, MI, USADepartment of Biological Sciences, Detroit, MI, USA; Institute of Environmental Health Sciences, Detroit, MI, USACenter for Molecular Medicine and Genetics, School of Medine, Detroit, MI, USA; Corresponding author. Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 E Canfield St, Detroit, MI 48201, USA.Department of Biological Sciences, Detroit, MI, USA; Institute of Environmental Health Sciences, Detroit, MI, USA; Corresponding author. Department of Biological Sciences, Integrative Biosciences Center, Wayne State University, Room 2418 IBio, 6135 Woodward, Detroit, MI 48202, USA.Background: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive. Objectives: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction. Methods: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks. Results: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses. Conclusions: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.http://www.sciencedirect.com/science/article/pii/S2212877825000353Hypothalamic inflammationMicrogliaHypothalamusER stressUPRNeuroinflammation |
| spellingShingle | L. Stilgenbauer Q. Chen D. Pungi N. James H. Jayarathne L. Koshko S. Scofield K. Zhang M. Sadagurski Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice Molecular Metabolism Hypothalamic inflammation Microglia Hypothalamus ER stress UPR Neuroinflammation |
| title | Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice |
| title_full | Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice |
| title_fullStr | Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice |
| title_full_unstemmed | Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice |
| title_short | Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice |
| title_sort | microglial er stress response via ire1α regulates diet induced metabolic imbalance and obesity in mice |
| topic | Hypothalamic inflammation Microglia Hypothalamus ER stress UPR Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000353 |
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