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-alpha), interleukin (IL-6), IL-1beta and resistin, which in turn activates the c-Jun-N-terminal kinase (JNK) and NF-kappaB 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-kappaB, 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.

Figure 1

In the human body, carbon monoxide is formed at a rate of 16.4 μmol/h and daily production can reach 500 μM (Piantadosi, Antioxid Redox Signal, 2002, 4:259-70). About 86% comes from HO-catalyzed degradation of heme while 14% from lopid peroxidation xenobiotics and other sources.

Figure 2

Schematic representation illustrating the protective role of the HO system in glucose metabolism. Inflammatory and oxidative mediators like NF-κB, JNK, TGF-α, IL1β and IL-6 are amongst the pathophysiological factors that impair insulin signalling. Generally these substances stimulate oxidative/inflammatory events destroying tissue. Conversely, other factors including cytokines and inflammatory/oxidative transcription factors like NF-κB, JNK stimulate a variety of different pathophysiological pathways to further aggravate oxidative/inflammatory insult, creating a vicious cycle of intense inflammation that would severely damage tissue and compromise many physiological functions including glucose metabolism. However, the HO system suppresses these inflammatory/oxidative mediators and pro-inflammatory cytokines to enhance insulin signalling and improve glucose metabolism.