Dataset Information

FoxO6-mediated IL-1? induces hepatic insulin resistance and age-related inflammation via the TF/PAR2 pathway in aging and diabetic mice.

ABSTRACT: FoxO has been proposed to play a role in the promotion of insulin resistance, and inflammation. FoxO is a pro-inflammatory transcription factor that is a key mediator of generation of inflammatory cytokines such as IL-1? in the liver. However, the detailed association of FoxO6 with insulin resistance and age-related inflammation has not been fully documented. Here, we showed that FoxO6 was elevated in the livers of aging rats and obese mice that exhibited insulin resistance. In addition, virus-mediated FoxO6 activation led to insulin resistance in mice with a notable increase in PAR2 and inflammatory signaling in the liver. On the other hand, FoxO6-KO mice showed reduced PAR2 signaling with a decrease in inflammatory cytokine expression and elevated insulin signaling. Because FoxO6 is closely associated with abnormal production of IL-1? in the liver, we focused on the FoxO6/IL-1?/PAR2 axis to further examine mechanisms underlying FoxO6-mediated insulin resistance and inflammation in the liver. In vitro experiments showed that FoxO6 directly binds to and elevates IL-1? expression. In turn, IL-1? treatment elevated the protein levels of PAR2 with a significant decrease in hepatic insulin signaling, whereas PAR2-siRNA treatment abolished these effects. However, PAR2-siRNA treatment had no effect on IL-1? expression induced by FoxO6, indicating that IL-1? may not be downstream of PAR2. Taken together, we assume that FoxO6-mediated IL-1? is involved in hepatic inflammation and insulin resistance via TF/PAR2 pathway in the liver.

SUBMITTER: Kim DH

PROVIDER: S-EPMC6454229 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FoxO6-mediated IL-1β induces hepatic insulin resistance and age-related inflammation via the TF/PAR2 pathway in aging and diabetic mice.

Kim Dae Hyun DH Lee Bonggi B Lee Jaewon J Kim Mi Eun ME Lee Jun Sik JS Chung Jae Heun JH Yu Byung Pal BP Dong H Henry HH Chung Hae Young HY

Redox biology 20190403

FoxO has been proposed to play a role in the promotion of insulin resistance, and inflammation. FoxO is a pro-inflammatory transcription factor that is a key mediator of generation of inflammatory cytokines such as IL-1β in the liver. However, the detailed association of FoxO6 with insulin resistance and age-related inflammation has not been fully documented. Here, we showed that FoxO6 was elevated in the livers of aging rats and obese mice that exhibited insulin resistance. In addition, virus-m ...[more]

PMID: 30974318

Similar Datasets

Project description:Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1β-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1β is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1β has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1β overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1β itself on IL-1β expression in microglial, macroglial (astrocytes and Müller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1β in isolated retinal vessels and on the temporal pattern of IL-1β upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1β was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, α2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1β expression in retinal endothelial cells but not in macroglia and microglia. IL-1β induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1β overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1β expression as compared to non-diabetic rats. Retinal expression of IL-1β increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1β in diabetes; and to IL-1β itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1β overexpression. Interrupting the vicious circle triggered by IL-1β autostimulation could limit the progression of diabetic retinopathy.

Dataset Information

FoxO6-mediated IL-1? induces hepatic insulin resistance and age-related inflammation via the TF/PAR2 pathway in aging and diabetic mice.

Publications

FoxO6-mediated IL-1β induces hepatic insulin resistance and age-related inflammation via the TF/PAR2 pathway in aging and diabetic mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets