Role of Heme Oxygenase in Inflammation, Insulin-Signalling, Diabetes and Obesity

Abstract

Diabetes and obesity are chronic conditions associated with elevated oxidative/inflammatory activities with a continuum of tissue insults leading to more severe cardiometabolic and renal complications including myocardial infarction and end-stage-renal damage. A common denominator of these chronic conditions is the enhanced the levels of cytokines like tumour necrosis factor-alpha (TNF-α), interleukin (IL-6), IL-1β and resistin, which in turn activates the c-Jun-N-terminal kinase (JNK) and NF-κB pathways, creating a vicious cycle that exacerbates insulin resistance, type-2 diabetes and related complications. Emerging evidence indicates that heme oxygenase (HO) inducers are endowed with potent anti-diabetic and insulin sensitizing effects besides their ability to suppress immune/inflammatory response. Importantly, the HO system abates inflammation through several mechanisms including the suppression of macrophage-infiltration and abrogation of oxidative/inflammatory transcription factors like NF-κB, JNK and activating protein-1. This review highlights the mechanisms by which the HO system potentiates insulin signalling, with particular emphasis on HO-mediated suppression of oxidative and inflammatory insults. The HO system could be explored in the search for novel remedies against cardiometabolic diseases and their complications.

Ischemic Stroke and Glucose Intolerance: a Review of the Evidence and Exploration of Novel Therapeutic Targets

“…Adipokines mainly consist of adiponectin, leptin, TNF-α, and resistin (57), and they play an important function in regulating glucose metabolism. For example, TNF-α and resistin activate the c-Jun N-terminal kinase and nuclear factor-κB pathways and exacerbate insulin resistance, type-2 diabetes, and related complications (58).…”

The Heme Oxygenase System Selectively Enhances the Anti-Inflammatory Macrophage-M2 Phenotype, Reduces Pericardial Adiposity, and Ameliorated Cardiac Injury in Diabetic Cardiomyopathy in Zucker Diabetic Fatty Rats

“…In general, obesity and insulin resistance are closely associated with a state of low-grade inflammation because of incessant activation of a wide variety of inflammatory mediators, including nuclear factor kB (NF-kB), tumor necrosis factor a (TNF-a), and c-Jun-N-terminal kinase (cJNK) (Feinstein et al, 1993;Hotamisligil et al, 1993;Hotamisligil and Spiegelman, 1994;Uysal et al, 1997;Permana et al, 2006;Tuncman et al, 2006;Sabio et al, 2008;Tilg and Moschen, 2008;Fernandez-Veledo et al, 2009;Karalis et al, 2009;Scazzocchio et al, 2009;Ndisang, 2010). Moreover, NF-kB stimulates TNF-a, interleukin (IL)-6, and IL-1b, which in turn may activate cJNK to create a vicious cycle that may aggravate insulin resistance and tissue damage (Ndisang, 2010). These destructive processes may be further exacerbated by macrophage infiltration, an event characterized by elevated levels of ED-1 (ED-1 is the primary antibody for activated macrophage) (Bazan et al, 2012).…”

Targeting heme oxygenase-1 in early diabetic nephropathy in streptozotocin-induced diabetic rats

“…The mechanisms underlying the renoprotective effect of CoPP in diabetic rats are complex, challenging, and not fully understood. Substantial evidence indicates that HO-1 provides the provenance of pathways that can interrupt virtually all major mechanisms of diabetic kidney injury, including reduction of the high blood glucose that represents the central core of DN (32,36,38).…”

“…1), which would greatly improve glucose metabolism, through enhanced adenosine monophosphate-activated protein kinasedependent glucose transporter 4 (GLUT4) expression and translocation (15). The antidiabetic effect observed with CoPP could be due to potentiation of insulin-sensitizing pathways (22) through HO upregulation similarly to increases in the activity of other factors which also promote insulin signaling such as adiponectin (22,(37)(38)(39)(40), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (36), and peroxisome proliferatoractivated receptor α (36).…”

“…Moreover, TNF-α induces insulin resistance by reducing the expression and translocation of GLUT4 by inhibiting the phosphatidylinositol 3 kinase/protein kinase B and peroxisome proliferator-activated receptor γ signaling (36).…”