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 .
 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 . 
INTRODUCTION
NO/cGMP/VASP SIGNALING PATHWAY
NO/VASP SIGNALING IN ADIPOSE TISSUE
NO/VASP SIGNALING IN THE LIVER
NO/VASP SIGNALING IN VASCULAR ENDOTHELIUM
CONCLUSIONS