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 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 (CX3CR1(GFPΔIRE1) and TMEM119(ERΔIRE1)), 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.