TY - JOUR
T1 - EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels
AU - Sodhi, Komal
AU - Puri, Nitin
AU - Inoue, Kazuyoshi
AU - Falck, J R
AU - Schwartzman, Michal L.
AU - Abraham, Nader G.
N1 - Funding Information:
This work was supported by NIH grants DK068134 , HL55601 and HL34300 (NGA). All authors had full access to the data and take responsibility for its integrity. All authors have read and agree with the manuscript as written. We thank Jennifer Brown for her outstanding editorial assistance in the preparation of the manuscript.
PY - 2012/8
Y1 - 2012/8
N2 - Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFα and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3β and pAKT levels along with attenuation of adipose tissue levels of Bach 1 - the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity.
AB - Recent reports have shown interplay between EETs (epoxides) and the heme oxygenase (HO) system in attenuating adipogenesis in cell culture models; prompting an examination of the effectiveness of EET agonist on obesity and associated cardio-metabolic dysfunction. Patho-physiological effects of an EET agonist (NUDSA) were contrasted in the absence and in the presence of stannous mesoporphyrin (an HO inhibitor) in SD rats fed a high fat (58%, HF) for 16 weeks. Animals on HF diet exhibited enhanced oxidative stress, increased levels of inflammatory cytokines and decreased levels of adiponectin along with reduced vascular and adipose tissue levels of EETs, HO-1; as compared to control rats (11% dietary fat). Treatment with NUDSA not only reversed serum adiponectin and vascular and adipose tissue levels of EETs and HO-1, but also, decreased blood pressure, subcutaneous and visceral fat content and serum TNFα and IL-6 levels in rats on HF diet. Aortic endothelial function, peNOS expression and adipose tissue markers of energy homeostasis i.e. pAMPK, Sirt1 and FAS, impaired in rats fed a HF diet, were restored in animals treated with this EET agonist. That NUDSA enhanced HO-1 expression, was accompanied by increase in p-GSK-3β and pAKT levels along with attenuation of adipose tissue levels of Bach 1 - the transcriptional suppresser of HO-1 expression. Prevention of these beneficial effects of NUDSA, in animals on HF diet and concurrently exposed to NUDSA and SnMP, supports the role of EET-HO interaction in mediating such effects. Taken together, our findings suggest that the EETs stimulate HO-1 expression via suppression of Bach 1 and interplay of these two systems affords vascular and metabolic protection in diet induced obesity.
KW - Adiponectin
KW - Cytochrome P450
KW - HO-1
KW - Metabolic dysfunction
KW - Obesity
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U2 - 10.1016/j.prostaglandins.2011.12.004
DO - 10.1016/j.prostaglandins.2011.12.004
M3 - Article
C2 - 22209722
AN - SCOPUS:84864427972
SN - 1098-8823
VL - 98
SP - 133
EP - 142
JO - Prostaglandins and Other Lipid Mediators
JF - Prostaglandins and Other Lipid Mediators
IS - 3-4
ER -