Diabetes Metab J.  2017 Apr;41(2):89-95. 10.4093/dmj.2017.41.2.89.

Role of NO/VASP Signaling Pathway against Obesity-Related Inflammation and Insulin Resistance

• Kang YM
• Kim F
• Lee WJ

• KMID: 2376770
• DOI: http://doi.org/10.4093/dmj.2017.41.2.89

Abstract

Obesity has quickly become a worldwide pandemic, causing major adverse health outcomes such as dyslipidemia, type 2 diabetes mellitus, cardiovascular disease and cancers. Obesity-induced insulin resistance is the key for developing these metabolic disorders, and investigation to understand the molecular mechanisms involved has been vibrant for the past few decades. Of these, low-grade chronic inflammation is suggested as a critical concept in the development of obesity-induced insulin resistance, and the anti-inflammatory effect of nitric oxide (NO) signaling has been reported to be linked to improvement of insulin resistance in multiple organs involved in glucose metabolism. Recently, a body of evidence suggested that vasodilatory-stimulated phosphoprotein (VASP), a downstream mediator of NO signaling plays a crucial role in the anti-inflammatory effect and improvement of peripheral insulin resistance. These preclinical studies suggest that NO/VASP signaling could be an ideal therapeutic target in the treatment of obesity-related metabolic dysfunction. In this review, we introduce studies that investigated the protective role of NO/VASP signaling against obesity-related inflammation and insulin resistance in various tissues.

Keyword

Adipose tissue; Chronic inflammation; Endothelium, vascular; Insulin resistance; Liver; Macrophages; Nitric oxide; Obesity; Vasodilator-stimulated phosphoprotein

MeSH Terms

Adipose Tissue
Cardiovascular Diseases
Diabetes Mellitus, Type 2
Dyslipidemias
Endothelium, Vascular
Glucose
Inflammation*
Insulin Resistance*
Insulin*
Liver
Macrophages
Metabolism
Nitric Oxide
Obesity
Pandemics
Glucose
Insulin
Nitric Oxide

Figure

• 

  Fig. 1 Schematic illustration of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway and its downstream effects. Activated cGMP-dependent protein kinase (PKG) by NO/cGMP signaling exerts diverse biological function by modulating its multiple downstream effectors in various cell types. PKG interacts with vasodilatory-stimulated phosphoprotein (VASP) to regulate cell adhesion and migration, inflammation and insulin sensitivity, as well as with survival molecules to regulate cell survival, and proliferation. PKG also exerts its role in angiogenesis and smooth muscle contractility via mitogen-activated protein kinase (MAPK) family. sGC, soluble guanylyl cyclase; PDE, phosphodiesterase; c-Src, proto-oncogene tyrosine-protein kinase c-Src; CREB, cyclic adenosine monophosphate (cAMP)-responsive element binding protein; RhoK, rho-associated protein kinase.

• 

  Fig. 2 Proposed effect of vasodilatory-stimulated phosphoprotein (VASP) on insulin resistance and inflammatory signaling in multiple organs. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway activates VASP, which inhibits nuclear factor-κB (NF-κB) activation; thereby, further inhibiting downstream inflammatory processes and enhancing insulin sensitivity. The schematic end-result of NO/cGMP/VASP signaling suggests its role against cardiometabolic disorders such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular diseases. Adapted from Cheng et al. [16], with permission from The American Physiological Society. HF, high-fat; sGC, soluble guanylyl cyclase; PDE, phosphodiesterase; PKG, cGMP-dependent protein kinase; IRS1, insulin receptor substrate 1; p-AKT, phospho-Akt; p-eNOS, phospho-endothelial nitric oxide synthase.

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