Abstract 19686: Perturbations in Redox Homeostasis in Visceral Fat Due to Decreases in HO-1, Adiponectin and pAMPK Adversely Effects Vascular Function in Obese Mice.
Redox homeostasis and the expression of antioxidant genes in visceral fat influence adiponectin release and inflammatory cytokines, TNFα and IL-6 levels. The redox state of visceral fat may also be a determining factor in insulin resistance, glucose intolerance and vascular dysfunction.
Aim: To examine the expression of stress response genes in visceral fat including glutathione s. transferase 1, (GST1), NAD (P) H-1 dehydroxygenase quinine 1 (Nq1), thioredoxin reductase 1 (TxR1) and heme oxygenase-1 (HO-1) in fat tissues of obese mice to assess upregulation of these genes affected insulin sensitivity and inflammatory cytokine levels.
Methods: Male lean and obese (ob/ob) mice (11 weeks old) were treated with either cobalt protoporphyrin (CoPP), i.p., 3 mg/kg or vehicle solution for 6 weeks. Serum levels of adiponectin, IL-1β, IL-6 were determined. Visceral fat GST1, Nq1, TxR1 and HO-1 levels were measured. Insulin resistance and glucose tolerance, adipocyte cell size and visceral and subcutaneous fat were measured.
Results: Visceral fat TxR1, Nq1, GST1 and mRNA were increased (p<0.01), in ob/ob mice when compared to age matched lean control animals. In contrast, HO-1 and adiponectin protein levels were decreased in fat of obese when compared to fat of lean mice, (p<0.01). The decrease of HO-1 levels suggests that radical scavenging activity was significantly compromised in obese mice. Upregulation of HO-1 in visceral fat increased insulin sensitivity (p<0.01, vascular pAMPK (p<0.05) and vascular response to acetylcholine (p<0.05) and prevented weight gain (p<0.01). Immunohistochemistry of visceral fat showed that HO-1 and adiponectin protein levels were increased by CoPP (p<0.001). Conversely, inhibition of HO activity reversed these beneficial effects.
Conclusion: These results provide the first in vivo evidence of an increase of redox stress in obese mice due to a decrease in HO-1, even in presence of excess of NrF2 response genes (TxR1, Nq1, and GST1). We believe that high levels of HO-1 contribute to both the maintenance of redox homeostasis of visceral fat and the prevention of inflammation leading to decreased insulin resistance and vascular dysfunction.
- © 2010 by American Heart Association, Inc.