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

Abstract

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-IRE1α, 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-α 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.

Impaired autophagy activity is linked to elevated ER-stress and inflammation in aging adipose tissue

“…From our previous study [11] and present study we postulate that compromised chaperoning capacity, along with the diminished expression of autophagy associated components in aging results in accumulation of unfolded or misfolded proteins in the ER. This leads to the Unfolded Protein Response (UPR) or ER stress response.…”

“…Along with our current observations, exciting new data are now linking elevated ER stress response [11] with compromised autophagy and accumulation of senescent cell progenitors [49] as upstream molecular events in adipose tissue inflammation in aging. Our study identifies the interplay of autophagy activity and ER stress response in aging adipose tissue, however the molecular links between two of these pathways requires further investigations.…”

“…To investigate the role of autophagy in adipose tissue inflammation, we focused on the adipose tissue-derived SVFs, as this is the predominant source of pro-inflammatory cytokines [4, 11] in fat. We analyzed mRNA expression of key autophagy-associated genes Beclin1 , Atg3, Atg5, Atg7, Lc3a and Lc3b in SVFs derived from epididymal fat pads of young (4-6 months) and old (20 months) mice by RT-qPCR analysis.…”

“…These changes include the decline preadipocyte replication, decreased adipogenesis, increased susceptibility to lipotoxicity and increased pro-inflammatory cytokines, chemokines, extracellular matrix (ECM)-modifying protease and stress response element expression. We have recently demonstrated that elevated endoplasmic reticulum (ER) stress response contributes to greater inflammatory response [11] in aging adipose tissue SVFs. However, the molecular events that lead to its increased susceptibility to ER stress response in aging adipose tissue are poorly defined.…”

The beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging

“…A role of endoplasmic reticulum (ER) in aging and inflammation has been investigated. Elevated ER stress markers including GRP78/BiP, C/EBP homologous protein, and X-box binding protein-1 were observed in adipose tissue stromal cells taken from old mice compared with young mice, and inflammatory response to exogenous stressor was also greater in both adipose tissue stromal cells and macrophages taken from older mice [20].…”