Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate

Abstract

The prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance. Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability, is one of the main causes of type 2 diabetes. The hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of several genes of the metabolic pathways including proinflammatory adipokines, endothelial NO synthase (eNOS), and insulin signaling components. It seems that adipose tissue hypoxia and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity-related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production of reactive oxygen species (ROS) and decreases the production of NO. Nitrate can restore NO depletion and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity/diabetes, the combined effects have not been investigated yet. This review discusses some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity/diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.

Figure 1

Insulin resistance in obesity. Obesity is associated with hypoxia, inflammation, and lipolysis. These conditions can lead to insulin resistance by impairment of insulin receptor substrate (IRS)/phosphatidyl inositol-3 kinase (PI3K)/AKT pathway. The c-Jun amino-terminal kinase (JNK), Toll-like receptors (TLRs), Akt substrate of 160 kDa (AS160), and AKT/serine (Ser)-1177 are the sensing points that hypoxia and inflammatory factors can inhibit insulin signaling. It should be noted that not all the above signaling occurs in every cell. GLUT: Glucose transporter; IKKB: IκB kinase β; IR: Insulin receptor; mTORC: Mammalian target of rapamycin complex; PDK1: 3-Phosphoinositide-dependent protein kinase 1; Ser307: Serine 307; TNF-α-R: Tumor necrosis factor-α receptor; Tyr P: Phosphorylated tyrosine.

Figure 2

Hypoxia-inducible factor-1α (HIF-1α) responses to hypoxia. HIF-1α acts through up-/downregulation of ~1300 genes including glucose transporters (GLUTs), adipokines, and cytokines. CBP/p300: cAMP response element-binding protein- (CREB-) binding protein (CBP) and p300; Dehydro-Asn803: Dehydroxylated asparagine 803; Dehydro-P402 and P564: Dehydroxylated proline 402 and proline 564; FIH: Factor-inhibiting hypoxia-inducible factor; HRE: Hypoxia-response element; PHD: Prolyl hydroxylase domain enzymes; VEGF: Vascular endothelial growth factor.

Figure 3

Hypoxia-inducible factor-1α (HIF-1α) degradation/stabilization. Inhibition of prolyl hydroxylase domain (PHD) enzymes by hypoxia and nitric oxide (NO) leads to stabilization of HIF-1α. Hypoxia upregulates the arginase enzyme; thus, the substrate of NO synthase (NOS), arginine, is reduced and NO production is decreased. Furthermore, hypoxia can induce production of ROS (superoxide anion). The bioavailability of ROS and NO is regulated by each other. HIF-1α upregulates inducible NOS (iNOS), which produces NO. NO inhibits PHD and stabilizes HIF-1α; NO can also contribute to angiogenesis through vascular endothelial growth factor (VEGF), which is upregulated by HIF-1α. Asn: Asparagine; Pro: Proline; pVHL: Von Hippel-Lindau tumor suppressor protein.