title: Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co-morbid with insulin-resistant type-2 diabetes.
abstract: OBJECTIVE
  Visceral adiposity and impaired glucose metabolism are common patho-physiological features in patients co-morbid with obesity and type-2 diabetes. We investigated the effects of the heme-oxygenase (HO) inducer hemin and the HO blocker stannous-mesoporphyrin (SnMP) on glucose metabolism, adipocyte hypertrophy and pro-inflammatory cytokines/mediators in Zucker diabetic fatty (ZDF) rats, a model characterized by obesity and type-2 diabetes.
  
  
  METHODS
  Histological, morphological/morphometrical, Western immunoblotting, enzyme immunoassay, ELISA and spectrophotometric analysis were used.
  
  
  RESULTS
  Treatment with hemin enhanced HO-1, HO activity and cGMP, but suppressed retroperitoneal adiposity and abated the elevated levels of macrophage-chemoattractant protein-1 (MCP-1), ICAM-1, tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-1β, NF-κB, c-Jun-NH2-terminal-kinase (JNK) and activating-protein (AP-1), with parallel reduction of adipocyte hypertrophy. Correspondingly, important proteins of lipid metabolism and insulin-signalling such as lipoprotein lipase (LPL), insulin-receptor substrate-1 (IRS-1), GLUT4, PKB/Akt, adiponectin, the insulin-sensitizing and anti-inflammatory protein and adenosine-monophosphate-activated protein kinase (AMPK) were significantly enhanced in hemin-treated ZDF rats.
  
  
  CONCLUSIONS
  Elevated retroperitoneal adiposity and the high levels of MCP-1, ICAM-1, TNF-α, IL-6, IL-1β, NF-κB, JNK and AP-1 in untreated ZDF are patho-physiological factors that exacerbate inflammatory insults, aggravate adipocyte hypertrophy, with corresponding reduction of adiponectin and deregulation of insulin-signalling and lipid metabolism. Therefore, the suppression of MCP-1, ICAM-1, TNF-α, IL-6, IL-1β, NF-κB, JNK, AP-1 and adipocyte hypertrophy, with the associated enhancement of LPL, adiponectin, AMPK, IRS-1, GLUT4, PKB/Akt and cGMP in hemin-treated ZDF are among the multifaceted mechanisms by which the HO system combats inflammation to potentiate insulin signalling and improve glucose and lipid metabolism. Thus, HO inducers may be explored in the search of novel remedies against the co-morbidities of obesity, dysfunctional lipid metabolism and impaired glucose metabolism.
authors.affiliation: Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: J F
authors.initials: JF
authors.lastname: Ndisang
authors.forename: A
authors.initials: A
authors.lastname: Jadhav
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D006427:Hemin / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000517:prevention & control; D006984:Hypertrophy; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000009:adverse effects; D009765:Obesity / Q000150:complications*; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052242:Adiponectin; C499920:Adipoq protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D008665:Metalloporphyrins; C518404:stannous mesoporphyrin; D006427:Hemin; D051547:Heme Oxygenase-1
keywords: adiponectin; heme oxygenase; inflammatory cytokines; visceral adiposity