Microglial ER-Stress Response via IRE1a 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 Inositol-Requiring Enzyme 1a (IRE1a), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.Objective: To investigate the role of IRE1a in microglia in mediating HFD-induced metabolic dysfunction.Methods: Using novel conditional knockout mice (CX3CR1GFP(delta)IRE1 and TMEM119ER(delta)IRE1), we deleted IRE1a 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 IRE1a in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1a 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.Conclusion: Our findings reveal that IRE1a-mediated ER stress response in microglia drives hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating the critical role of microglial ER stress response in diet-induced obesity and metabolic diseases.