title: Treatment with heme arginate alleviates adipose tissue inflammation and improves insulin sensitivity and glucose metabolism in a rat model of Human primary aldosteronism.
abstract: Visceral adiposity and insulin resistance are common pathophysiological denominators in patients with primary aldosteronism. Although we recently reported the antidiabetic effects of heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX) deoxycorticosterone acetate (DOCA-salt) hypertensive rats, a model of human primary aldosteronism characterized by elevated endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer heme arginate and the HO blocker chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX DOCA-salt rats. UnX DOCA-salt rats were hypertensive but normoglycemic. Heme arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor κB (NF-κB), activating-protein (AP-1), c-Jun-NH2-terminal kinase (JNK), macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and 8-isoprostane. These were associated with reduced glycemia, increased insulin, and the insulin-sensitizing protein adiponectin, with corresponding reduction in insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of heme arginate, aggravating insulin resistance, suggesting a role for the HO system in insulin signaling. Importantly, the effects of the HO system on ET-1, NF-κB, AP-1, JNK, MCP-1, and ICAM-1 in visceral or retroperitoneal adiposity in UnX-DOCA-salt rats have not been reported. Because 8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete adiponectin and insulin levels, the suppression of oxidative/inflammatory mediators such as 8-isoprostane, NF-κB, AP-1, MCP-1, ICAM-1, and JNK, an inhibitor of insulin biosynthesis, may account for the potentiation of insulin signaling/glucose metabolism by heme arginate. These data indicate that although UnX DOCA-salt rats were normoglycemic, insulin signaling was impaired, suggesting that dysfunctional insulin signaling may be a forerunner to overt diabetes in primary aldosteronism.
authors.affiliation: Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5.
authors.forename: Ashok
authors.initials: A
authors.lastname: Jadhav
authors.forename: Joseph Fomusi
authors.initials: JF
authors.lastname: Ndisang
mesh_terms: D050154:Adiposity; D000818:Animals; D001120:Arginine / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006418:Heme / Q000494:pharmacology / Q000627:therapeutic use*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006929:Hyperaldosteronism / Q000188:drug therapy* / Q000201:enzymology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008652:Mesoporphyrins / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D019332:Endothelin-1; D020536:Enzyme Activators; D007328:Insulin; D008652:Mesoporphyrins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C427471:chromium mesoporphyrin; D018799:Intercellular Adhesion Molecule-1; D006418:Heme; D001120:Arginine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose; C048849:heme arginate
keywords: Adiponectin; DOCA salt hypertension; Endothelin-1; Free radicals; Heme oxygenase; Insulin sensitivity; Visceral adiposity