Elevated Endoplasmic Reticulum Stress Response Contributes to Adipose Tissue Inflammation in Aging

Adipose tissue inflammation has been linked to age-related metabolic diseases. However, the underlying mechanisms are poorly understood. Adipose tissue inflammation and insulin resistance in diet associated obesity has been correlated with aberrant endoplasmic reticulum ( ER) stress. This study was undertaken to test our hypothesis that increased ER stress response contributes to age-associated adipose tissue inflammation. We found elevated ER stress response in adipose tissue of old ( 18-20 months) compared to young ( 4-6 months) mice. Elevated ER stress markers BIP ( GRP78), CHOP, cleaved-ATF-6, phospho-IRE1 alpha, and XBP- 1 were observed in old compared to young adipose tissue stromal cells. Additionally, old adipose tissue stromal cells were more sensitive to an ER stress inducer, thapsigargin. Similar experiments with adipose tissue macrophages showed elevated Chop and Bip expression in old adipose tissue macrophages when induced with thapsigargin. Treatment of chemical chaperone 4- phenyle- butyric acid alleviated ER stress in adipose tissue stromal cells and adipose tissue macrophages and attenuated the production of IL- 6 and MCP- 1 by adipose tissue stromal cells, and TNF-alpha by adipose tissue macrophages from both young and old mice. Finally, old mice fed with 4- phenyle- butyric acid have reduced expression of ER stress and inflammatory cytokine genes. Our data suggests that an exaggerated ER stress response in aging adipose tissue contributes to age- associated inflammation that can be mitigated by treatment with chemical chaperones.