Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co‐morbid with insulin‐resistant type‐2 diabetes

Abstract

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. Histological, morphological/morphometrical, Western immunoblotting, enzyme immunoassay, ELISA and spectrophotometric analysis were used. 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. 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.