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.
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.
Department of Physiology and Pharmacology, The University of Toledo College of Medicine, Health Education Building, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA.
Komal
K
Sodhi
Nitin
N
Puri
Kazuyoshi
K
Inoue
John R
JR
Falck
Michal L
ML
Schwartzman
Nader G
NG
Abraham
D052242:Adiponectin / Q000097:blood; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D015777:Eicosanoids / Q000819:agonists* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005293:Ferritins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology; D008665:Metalloporphyrins / Q000494:pharmacology; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism*
C577139:2-(11-(nonyloxy)undec-8-enamido)succinic acid; D052242:Adiponectin; C577166:Bach 1 protein, rat; D050976:Basic-Leucine Zipper Transcription Factors; D015415:Biomarkers; D016207:Cytokines; D015777:Eicosanoids; D018836:Inflammation Mediators; D008665:Metalloporphyrins; D012097:Repressor Proteins; C518404:stannous mesoporphyrin; D001224:Aspartic Acid; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3