obesity has become a huge burden worldwide . according to the 2013 korea national health and nutrition examination survey , one in three korean adults are obese and more than half are considered to be at least overweight , implying that korea is not an exception to this worldwide pandemic . environmental factors such as unhealthy dietary habits , sedentary lifestyle and socioeconomic influences are considered as the major contributors . in the past several decades , evidence suggests that obesity is a state of chronic , low - grade inflammation . one of the earliest evidence demonstrated the expression of proinflammatory cytokine , tumor necrosis factor  ( tnf- ) , in rodent adipose tissue during the development of obesity and the attenuation of insulin resistance followed by neutralization of tnf- . this study supports the role of inflammation in obesity and regulation of its complications by inflammatory mediators . thereafter , significant advances in understanding the complex role of immune - metabolism have been accomplished , and obesity is now known to be associated with proinflammatory cytokine secretion , immune cell infiltration , and disrupted function of tissues involved in glucose homeostasis , leading to insulin resistance . nitric oxide ( no ) is an endogenous signaling molecule produced by nitric oxide synthase ( nos ) . no is involved in various physiologic processes such as the regulation of synaptic transmission , vasodilation , leukocyte - endothelial interactions , immune function , and angiogenesis . besides these pleiotropic effects , no has recently emerged as an important regulator of energy metabolism . for example , no bioavailability reflected by nos activity is decreased in animal models of diet - induced obesity ( dio )   and in obese and insulin - resistant patients . the reduction of no content occurs early in the course of developing insulin resistance , followed by vascular and peripheral tissue ( such as liver , muscle , and adipose ) inflammation and insulin resistance during dietary excess . furthermore , genetic deletion of endothelial nitric oxide synthase ( enos ) is associated with insulin resistance even in the absence of high - fat ( hf ) stimuli . conversely , interventions to increase no output has remarkable effects on obesity and insulin resistance in both animal and human studies , implying that anti - inflammatory and anti - obesity properties of no might serve as a potential therapeutic approach against obesity and its related metabolic outcomes . vasodilatory - stimulated phosphoprotein ( vasp ) is a 40 kda protein associated with cell adhesion and modulation of cytoskeletons   and found in various cell types , but is highly expressed in vascular endothelial cells , smooth muscle cells , fibroblasts , and platelets . recently , a growing body of evidence suggests that vasp as a downstream mediator of no signal transduction pathway exerts anti - obesity effects by improving inflammation and insulin resistance in various tissues involved in glucose metabolism . therefore , in this review , we evaluate the current evidence supporting the protective effect of no / cyclic guanosine monophosphate ( cgmp)/vasp signaling pathway against obesity and possibly , type 2 diabetes mellitus . the enos is mainly expressed in endothelial cells and generates enos - derived no . in cardiovascular tissues , enos - derived no is known to exert vasodilatory , anti - inflammatory , and anti - proliferative effects   via cgmp - dependent protein kinase ( pkg ) by increasing cgmp levels . the no / cgmp - induced pkg activation in various cell types exerts diverse biological function by modulating its multiple downstream effectors . for example , pkg interacts with vasp   and survival molecules such as the apoptosis - regulating protein bad , the oncogenic tyrosine kinase c - src , and the transcription factor cyclic adenosine monophosphate ( camp)-responsive element binding protein ( creb )   to regulate cell migration , survival , and proliferation . on the other hand , pkg - mediated activation of the mitogen - activated protein kinase ( mapk ) family regulates angiogenesis in vascular endothelial cells   and the contractile function of myocardial fibers   and vascular smooth muscle cells ( fig . implication of modulating vasp in cancerous or neural cells has been widely studied due to its role in cell adhesion , migration , and proliferation . however , recently , phosphorylation of vasp by pkg on a specific serine residue ( ser-239 ) has been found to improve inflammation and insulin resistance in various peripheral organs such as the adipose tissue , the liver , and the vasculature . in visceral adipose tissue , nutrient excess leads to the infiltration of macrophages via the production of monocyte chemoattractant protein 1 ( mcp-1 ) , a key mediator recruiting macrophage precursors into the adipose tissue . subsequent release of proinflammatory cytokines such as interleukin 6 ( il-6 ) and tnf- results in impaired insulin signaling . hence , improving obesity - induced insulin resistance by regulating inflammatory signaling has been of great interest as it can serve as a potential therapeutic target . based on the anti - inflammatory role of endothelial no signaling in the vasculature and the decline of vascular no levels early in the course of dio , handa et al .   made an attempt to unravel the role of no / cgmp / vasp signaling pathway in the pathogenesis of obesity - associated inflammation in adipose tissue . in this study , hf feeding significantly reduced phospho - enos and phospho - vasp in white adipose tissue , compared to mice fed a low - fat ( lf ) diet . genetic deficiency of enos induced increased expression of proinflammatory cytokines in adipose tissue of enos mice ; however , a lf diet could not prevent adipose tissue inflammation in these mice , further reflecting the significance of endothelial no signaling in attenuating adipose tissue inflammation . by contrast , administration of sildenafil , a drug that increases signaling downstream of vascular no , prevented hf diet - induced proinflammatory gene expression and adipose tissue macrophage infiltration while improving insulin sensitivity in wild type ( wt ) mice . because the authors hypothesized that vasp , a downstream target of the no / cgmp pathway , is crucial to the anti - inflammatory effects of no signaling pathway on adipose inflammation , they used vasp and wt littermate mice fed an lf and hf diet . as expected , in vasp mice , levels of mrna encoding proinflammatory cytokines mcp-1 , il-6 , and tnf- the recapitulation of the effect of enos deficiency to increase adipose tissue inflammation in vasp - null mice suggests that vasp must be present for no / cgmp signaling pathway to exert its anti - inflammatory effect in adipose tissue . it is highly vascularized receiving 20% of cardiac output , and hepatic sinusoidal endothelial cells make up half of nonparenchymal cells of the liver . sinusoidal endothelial cells have shown to express enos and produce no basally , regulating hepatic vascular resistance . in a dio setting , reduced vascular no levels were followed by enhanced liver nuclear factor-b ( nf-b ) signaling and impaired insulin - mediated phosphorylation of akt , highlighting the possible role of no signaling in regulation of hepatic insulin resistance and inflammation . macrophages are myeloid - derived mononuclear cells that are a critical component of the innate immune response . they are more enriched in the areas that are exposed to pathogens , toxins and tissue damages such as the lung and the liver . accumulating evidence supports a role for tissue macrophages in a broad spectrum of inflammatory conditions , and the number and activity of macrophages are associated with insulin resistance and metabolic deterioration in states of over nutrition such as obesity . kupffer cells , the liver - specific macrophages , reside on the luminal side of the sinusoidal endothelium , and are mainly involved in scavenging , host immunity and immune tolerance in the liver . recent studies demonstrated that increased kupffer cell activity is responsible for hepatic insulin resistance , and that depletion of kupffer cells attenuated the development of hepatic steatosis and hepatic insulin resistance , both of which suggest an important early role of kupffer cells in diet - induced alterations in hepatic insulin resistance . questioned whether endothelial no signaling contributes to the effect of hf feeding to induce inflammatory activation of kupffer cells and associated hepatic insulin resistance . in the study , proinflammatory activation of kupffer cells was induced both in wt mice fed hf diet and in genetically enos - deficient mice , highlighting the protective effect of no signaling in hepatic inflammation and insulin resistance . similarly , targeted deletion of vasp in vivo , a key downstream target of endothelially derived no , predisposed to hepatic and kupffer cell inflammation regardless of diet , whereas agent - enhanced vasp signaling reversed the inflammatory activity and insulin resistance in vasp - deficient hepatocytes and macrophages in vitro . subsequently , tateya et al . have also demonstrated that no / vasp signaling increases hepatic fatty acid oxidation by activating ampk in mice models , suggesting that direct activation of vasp could be a potential therapeutic target of hepatic steatosis . the mechanism through which endothelial no / cgmp / vasp signaling exerts protective effect against inflammation and insulin resistance in kupffer cells has also been explored . using mice model with transgenic enos overexpression , this study demonstrated that the protective effect of no signaling against hf diet - induced hepatic inflammation and insulin resistance is associated with reduced proinflammatory m1 and increased anti - inflammatory m2 activation of kupffer cells . similar effects were induced by overexpression of vasp in macrophages , whereas vasp deficiency induced proinflammatory m1 macrophage activation . in attempt to determine whether vasp deficiency , specifically in the macrophage compartment , is sufficient to explain the hepatic inflammation and hepatic insulin resistance , transplantation of bone marrow from vasp - deficient donor mice into normal recipients was performed . as a result , the transplantation led to hepatic inflammation and insulin resistance resembling that induced in normal mice fed hf diet . taken together , no / vasp signal transduction inhibits proinflammatory m1 activation of the kupffer cells , and it can serve as a physiological determinant of macrophage polarization and a promising therapeutic target to prevent hepatic inflammation and insulin resistance . metabolic deterioration related to obesity is linked with cardiovascular diseases , and atherosclerosis is responsible for the vast majority of these cardiovascular events . thus , it is important to detect and delay the progression of atherosclerosis in its early stage . in recent years , it has become evident that insulin resistance and endothelial dysfunction play a central role in the pathogenesis of atherosclerosis . metabolic dysfunction causes lipid deposition and oxidative stress to the vessel wall , triggering an inflammatory reaction , and the release of chemoattractants and cytokines worsens the insulin resistance and endothelial dysfunction . within this context , therapies that improve vascular insulin resistance and inflammation would be ideal as it may reduce cardiovascular morbidity and mortality in clinical settings . reduced no bioavailability occurs within 1 week of hf feeding in mice , causing endothelial cell to be significantly more vulnerable to the inflammatory effects of excess nutrition . this further reduces no production , leading to a " vicious cycle " of increased vascular inflammation and reduced no levels . by contrast , increasing downstream no signaling in mice fed hf diet attenuates vascular inflammation ; thereby , breaking this vicious cycle and restoring vascular insulin sensitivity . investigated the role of vasp as a downstream mediator of the anti - inflammatory effect of no signaling in vascular tissue . compared to mice fed a lf diet , markedly reduced levels of vasp ser239 phosphorylation , a marker of vasp activation , were observed in aortic tissue of dio mice . hf feeding was associated with increased aortic inflammation , as measured by increased nf-b dependent gene expression , and reduced vascular insulin sensitivity ( including insulin - stimulated phosphorylation of enos and akt ) . these hf - diet - induced responses recapitulated in vasp mice , whereas overexpression of vasp in endothelial cells blocked inflammation and insulin resistance induced by palmitate , reflecting the protective effect against inflammatory signaling and insulin resistance in vasculature . these findings implicate that vasp can serve as a potential therapeutic target in the treatment of obesity - related vascular inflammation and insulin resistance . peripheral insulin resistance in obese state is crucial to the etiology of metabolic disorders such as type 2 diabetes mellitus , and thus , understanding the molecular mechanisms of insulin resistance in the organs involved in glucose homeostasis can provide further insights to the development of potential targeted therapy . the series of studies we have evaluated in this review commonly indicate that no / cgmp signaling limits obesity - related inflammation and insulin resistance in multiple organs , such as adipose tissue , liver , and vascular endothelium and also that vasp is a critical downstream mediator required for this protective effect of no / cgmp signaling ( fig . developing potential drugs that alter no signaling has been of caution due to its cytotoxic effect at high levels , generated by inducible nos . however , targeting downstream molecules of no - cgmp signaling pathway , such as soluble guanylyl cyclase or pkg could potentially overcome this drawback no - targeted therapeutic approach possesses . in this standpoint , vasp can be a promising therapeutic target to limit peripheral insulin resistance in obese state , although accumulation of more evidence is necessitated .