insulin resistance ( ir ) is a complicated condition in which three primary metabolic tissues that are sensitive to insulin , skeletal muscle , liver , and white adipose tissue ( wat ) become less sensitive to insulin and its downstream metabolic actions under normal serum glucose concentrations . ir is closely associated with obesity , hypertension , hyperglycaemia , polycystic ovary syndrome , and metabolic syndrome ( see glossary ) [ 2 , 3 ] . as the key component of metabolic syndrome , the antilipolytic effect of insulin is decreased in insulin - resistant conditions , which may promote hepatic triglyceride synthesis . as we know , ffa could be taken up by organs and accumulated as ectopic fat , such as hepatic and cardiac lipids . and several factors are implicated in the pathology of obesity - related nafld , including complex interactions between glucose and lipid metabolism , genetic predisposition , environmental conditions , and modulation of the intestinal microbiota . ir encompasses a wide spectrum of disorders , such as defective insulin receptor signal transduction and mitochondrial function [ 7 , 8 ] , microvascular dysfunction [ 9 , 10 ] , and inflammation [ 1113 ] . obesity , characterized as a state of chronic low - grade inflammation caused by overnutrition , is a major cause of decreased insulin sensitivity , which makes obesity a major risk factor for ir [ 1416 ] . nafld is recognized as a typical feature of metabolic syndrome and manifested as a series of hepatic injuries including steatosis , nonalcoholic steatohepatitis ( nash ) , and even hepatocellular carcinoma . obesity causes lipid accumulation in adipocytes , which activates c - jun n - terminal kinase ( jnk ) and nuclear factor - kappa b ( nf-b ) signaling pathways and might subsequently increase the production of proinflammatory cytokines such as tumor necrosis factor - alpha ( tnf- ) and interleukin-6 ( il-6 ) [ 11 , 19 ] . in most cases , adipose tissue ( at ) is an important site of obesity - induced ir , and it can also affect the liver and muscle by releasing cytokines , including adipokines such as tnf- [ 11 , 18 ] . at consists of several cell types . among these , adipocytes and immune cells , such as macrophages and dendritic cells ( dcs ) , have attracted significant attention as contributors that link inflammation to ir . this review will focus on the relationship between inflammation and ir , and we analyze the mechanisms relating to how inflammatory cytokines , signaling pathways , and some other factors link inflammation to ir . tnf- is an adipose tissue - derived proinflammatory cytokine that causes insulin resistance by enhancing adipocyte lipolysis and increasing the serine / threonine phosphorylation of irs-1 ( insulin receptor substrate-1 ) [ 11 , 21 ] . several signaling pathways , including the ikk/nf-b pathway , are involved in the pathogenesis of ir ( see figure 1 ) [ 22 , 23 ] . it was reported that tnf- can increase glucose uptake in both visceral and subcutaneous adipocytes by activating the adenosine monophosphate activated protein kinase ( ampk ) pathway , whereas it triggers insulin resistance in visceral adipocytes by activating jnk1/2 . because of the depot - specific effects of tnf- on glucose uptake , approaches to treat ir by modulating tnf- signaling are ongoing . however , studies of therapies such as the tnf- superfamily member stweak ( soluble tumour necrosis factor - like weak inducer of apoptosis ) , which aims to block tnf signaling to treat ir , have demonstrated that tnf- plays a role in ir . interestingly , the plasma levels of tnf- are higher in males than in females , as well as in obese individuals compared with lean ones . this suggests that obese males are more likely to suffer from ir and related diseases such as cardiovascular disease . interleukin-1 ( il-1 ) is a proinflammatory cytokine whose secretion is regulated by inflammasome activity . il-1 contributes to ir by impairing insulin signaling in peripheral tissues and macrophages , which leads to the reduced insulin sensitivity of -cells and possible impaired insulin secretion [ 27 , 28 ] . the levels of il-1 in various cells such as endothelial cells and monocytes are increased during hyperglycemia . il-1 also plays a vital role in initiating and maintaining inflammation - induced organ dysfunction in type 2 diabetes mellitus ( t2 dm ) . il-1 might increase systemic inflammation and inhibit insulin action in the major insulin - target cells , such as macrophages . il-6 is secreted by multiple tissues , particularly adipose tissue , and is recognized as an inflammatory mediator that causes ir by reducing the expression of glucose transporter-4 ( glut-4 ) and insulin receptor substrate-1 ( irs-1 ) . these effects are exerted by the activation of the janus kinase - signal transducer and activator of transcription ( jak - stat ) signaling pathway ( see box 1 ) and increased the expression of suppressor of cytokine signaling 3 ( socs3 ) [ 32 , 33 ] ( see figure 1 ) . therefore , hybrid training can ameliorate insulin resistance by suppressing serum il-6 in skeletal muscle . il-6 also induces ir by blocking the phosphoinositide 3-kinase ( pi3k ) pathway and impairing glycogen synthesis by downregulating the expression of microrna-200s ( mir-200s ) and upregulating that of friend of gata 2 ( fog-2 ) [ 35 , 36 ] . it was suggested that ir in human skeletal muscle is related to il-6 stimulation , which induces toll - like receptor-4 ( tlr-4 ) gene expression by activating stat3   ( see figure 1 ) . leptin is a protein that is derived primarily from white adipose tissue ( wat ) . it suppresses appetite and increases energy expenditure by repressing anabolic neuronal circuits and activating catabolic neuronal circuits . furthermore , a state called leptin resistance , which was disputed lately by the concept of hypothalamic leptin insufficiency , is often observed in the obese individuals , and weight loss simultaneously reduces serum leptin levels . consistent with this , the stimulation of pi3k signaling by leptin is essential for modulating glucose metabolism and the function of pancreatic -cells [ 3142 ] . it is likely that an increased concentration of leptin , an anti - inflammatory cytokine , during inflammation in at is associated with leptin resistance in obese individuals . interestingly , leptin was recommended as a biomarker for in utero insulin resistance based on the link between maternal and fetal leptin and ir [ 43 , 44 ] . leptin is a potential treatment for ir because it improves glycometabolism , insulin sensitivity , and lipometabolism [ 45 , 46 ] . its levels reduce in obesity , ir , or t2 dm , where it acts as an anti - inflammatory cytokine , but increase in osteoarthritis ( oa ) and type 1 diabetes mellitus ( t1 dm ) , where it acts as a proinflammatory cytokine [ 39 , 47 ] . two receptors are involved in the glucose metabolism that links adiponectin to the amelioration of ir . adiponectin receptor 1 ( adipor1 ) is likely to reduce the expression of the genes that encode hepatic gluconeogenic enzymes and molecules involved in lipogenesis by activating ampk . in contrast , adiponectin receptor 2 ( adipor2 ) increases the expression of the genes that contribute to glucose consumption by activating peroxisome proliferator activated receptor - alpha ( ppar- ) signaling [ 48 , 49 ] . adipor1 and adipor2 are expressed at high levels in skeletal muscle and the liver , respectively [ 28 , 50 ] . in brief , adiponectin ameliorates hepatic insulin resistance by reducing glycogenesis and lipogenesis , as well as increasing glucose consumption . it is generated from adipocytes , whereas it is produced mostly by macrophages in humans . it was suggested that resistin participates in the pathogenesis of ir and that its levels might be elevated due to obesity and ir . resistin promotes ir by regulating the expression of proinflammatory cytokines , including tnf- and il-6 , in macrophages via an nf-b - dependent pathway . it also plays roles in inflammation and ir by binding directly to tlr4 receptors in the hypothalamus to activate jnk and mitogen - activated protein kinase ( mapk ) signaling pathways . monocyte chemoattractant protein-1 ( mcp-1 ) is a proinflammatory chemokine produced by adipocytes , macrophages , and endothelial cells , which might lead to the recruitment of macrophages , dcs , and memory t cells [ 11 , 54 ] . adipocytes and macrophages are the main source of proinflammatory cytokines . however , the expression of mcp-1 increases during adiposity , which might stimulate the recruitment of macrophages and dcs , which further increases the expression of cytokines to exacerbate inflammation - induced ir . the expression of mcp-1 increases during obesity , particularly in visceral fat areas , which might contribute to the pathogenesis of ir , particularly in the liver [ 54 , 55 ] . it plays a role in ir by regulating the inflammatory response , insulin sensitivity , lipid metabolism , macrophage polarization and infiltration , and the phosphorylation of extracellular signal - regulated kinase-1/2 ( erk-1/2 ) and p38 mapk . c - c motif chemokine receptor 2 ( ccr2 ) is a vital mcp-1 receptor . in adipose tissue of ccr2 knockout mice , macrophage content and inflammatory profile this suggests that mcp-1 plays a crucial role in the development of both inflammation and ir . nf-b is a transcription factor comprised of rel family proteins such as p65/rela , relb , c - rel , p50/p105 , and p52/p100 . it is involved in a series of pathological processes such as inflammation and innate and adaptive immune responses [ 58 , 59 ] . nf-b is sequestered in the cytoplasm bound to ib proteins in normal circumstances , which prevents the nuclear localization of nf-b . after stimulation with various pathogenic stimuli , such as those in obese individuals , the ikk complex that contains two subunits ( ikk and ikk ) is activated , which triggers the phosphorylation of ib on ser32 and 36 . this leads to the degradation of ib , exposes the nuclear localization sequence of nf-b , and triggers its translocation to the nucleus and the upregulation of target genes that encode inflammatory mediators such as tnf- , il-1 , and il-6 [ 20 , 58 ] ( see figure 2 ) . ikk deficiency in adipocytes completely prevented the free fatty acid- ( ffa- ) induced expression of tnf- and il-6 , whereas the activation of ikk inhibited the expression of anti - inflammatory cytokines such as leptin and adiponectin . according to this , in addition , treatments that inhibit nf-b always improve ir , which suggests that the nf-b pathway plays an important role in inflammation - associated ir . nf-b is also a vital intermediary that couples ir to the proinflammatory cytokine il-1 in ir - related diseases such as obesity and t2 dm . there are three different jnk isoforms ( jnk-1 , -2 , and -3 ) , which belong to mapk family . jnk contributes to inflammation and metabolic syndrome ( ms ) , obesity , and ir by regulating the production of proinflammatory cytokines , karyomitosis , and cellular apoptosis [ 6365 ] . jnk can also be stimulated by endoplasmic reticulum ( er ) stress , which leads to the serine phosphorylation of irs-1 ( see figure 2 ) . jnk plays a role in the phosphorylation of the c - jun component of activator protein ( ap-1 ) transcription factor , but there is no evidence of a direct relationship between this transcriptional pathway and jnk - reduced ir . jnk plays an important role in ir by inhibiting insulin secretion from pancreatic -cells via proinflammatory stimuli including il-1 . moreover , the excessive activation of jnk in peripheral insulin - sensitive tissues promotes ir . it was demonstrated that inhibiting jnk reduced the release of ir - related proinflammatory cytokines such as tnf- and mcp-1 [ 6870 ] . interestingly , jnk-1 deficiency in adipose tissue protects against hepatic steatosis and promotes glucose intolerance , insulin clearance , ir , and hepatic steatosis . in skeletal muscle , jnk-1 does not affect the development of obesity and ir [ 65 , 71 ] . however , jnk in isolated rat skeletal muscle plays a vital role during oxidant - induced ir because insulin - stimulated glucose transport activity was improved by the selective inhibition of jnk . taken together , these studies suggest that further studies are needed to analyze the effects of jnk in ir . the inflammasome consists of a large group of cytosolic protein complexes and plays roles in inflammation by regulating the secretion of il-1 and il-18 . therefore , it is important in innate immunity and metabolic syndromes such as obesity and ir [ 30 , 73 ] . nod - like receptor proteins ( nlrps ) , neutrophilic alkaline phosphatases ( nalps ) , apoptosis associated speck - like protein ( asc ) , and caspase-1 are the essential components of inflammasome complexes . inflammasome nlrp3 ( nucleotide - binding domain , leucine - rich - containing family , and pyrin domain - containing-3 ) , which links saturated ffas to chronic inflammation , is being studied extensively because it is highly sensitive to nonmicrobial stress . it can be activated by mitochondrial dysfunction . in addition , the reduced expression of nlrp3 in obesity results in enhanced insulin signaling , decreased inflammation , and improved insulin sensitivity [ 73 , 74 ] ( see figure 3 ) . caspase-1 is a cysteine protease that contributes to ir by counteracting the metabolic function of adipose tissue to impair insulin sensitivity and also mediates the infiltration of macrophages into adipose tissues [ 75 , 76 ] . it was reported that the elimination of asc and caspase-1 lowers the plasma levels of insulin , leptin , and resistin . moreover , asc deficiency might protect individuals against hfd - induced ir , hepatic steatosis , and adipocyte hypertrophy . taken together , these studies suggest that the inflammasome plays a vital role in obesity - induced ir and that it is an important therapeutic target for the treatment of ir . macrophages infiltrate and reside in adipose tissue , named atms , and usually play an important role in obesity - induced ir . there are two types of atm : classically activated ( m1 ) in obese animals and alternatively activated ( m2 ) in lean species . atms have an important role in the development of chronic inflammation , including obesity - induced inflammation , because they are the primary source of cytokine production . in addition , obesity might change the number of atms by increasing the triple positive cd11b + f4/80 + cd11 + atm subpopulation . . used cd206 rather than cd209 and cd301 as m2 markers by flow cytometry to demonstrate that ir might be regulated by the number of m1 atms and the m1  :  m2 ratio . in addition , intervention with pioglitazone could reduce inflammation and ameliorate ir by upregulating the expression of il-10 , which might contribute to the reduction of m2 quantity . in another study , it was suggested that the mcp-1/ccr2 axis might contribute to a shift from m2 to m1 polarization , which is an important cause of ir as it leads to the production of inflammatory factors such as tnf- and il-6 . during obesity , dietary saturated fatty acids lead to the activation of tlr2 and tlr4 in atms , which is followed by the activation of interferon regulatory factor-3 ( irf3 ) , jnk , and nf-b and subsequent inflammatory signaling ( see figure 3 ) . c - reactive protein ( crp ) is an acute - phase protein synthesized by the liver . it is an inflammatory marker whose expression is increased significantly during inflammation , mainly due to its regulation by proinflammatory cytokines such as il-6 and tnf- [ 79 , 80 ] . in most clinical and scientific studies , crp is measured using high - sensitivity assays and is known as high - sensitivity crp ( hs - crp ) . it was suggested that increased hs - crp levels might be caused by an insufficient insulin - induced suppression of crp synthesis . moreover , crp might contribute to vascular inflammation by activating complement proteins and increasing the production of thrombogenic components bound to the membranes of injured vascular cells , which contributes to the development of ir . in addition , elevated crp expression is a potential risk factor and indicator for t2 dm . however , there is no apparent causality between serum crp , ir , and diabetes , which suggests that crp is more likely to be a downstream marker rather than an upstream effector that links inflammation to ir . nevertheless , hs - crp is closely associated with ir , and thus its expression should be assessed during investigations of ir . inflammation plays an important role in the development of ir via various cytokines and molecular pathways , and so inflammation should be targeted with appropriate interventions to prevent ir . because dietary fat might play a role in the production of inflammatory molecules by modifying the intestinal microbiota , which might result in an inappropriate immune reaction , it is important for individuals to develop good dietary and living habits . for example , the activation of ikk/nf-b signaling might increase the secretion of proinflammatory cytokines such as tnf- and il-1 , which might in turn stimulate ikk/nf-b signaling . therefore , both of the fluctuation of cytokines and the status of relevant signaling pathways should be taken into account during studies analyzing inflammation - related ir . most current studies of inflammation - related ir are performed in animals , which makes it challenging to apply these methods to humans to exert a curative effect of ir in the clinic . because the mechanisms that link inflammation to ir are not understood completely , additional well - designed clinical and laboratory studies are in demand to elaborate their relationship . the janus kinase - signal transducers and activators of transcription ( jak - stat ) signaling pathway are a cytokines - activated cascade involved in many important biological processes including the proliferation , differentiation , and apoptosis of the cells . this signaling pathway contains three components : tyrosine kinase associated receptor , janus kinase and signal transducer , and activator of transcription . to date , four members of jak kinase family have been identified including jak1 , jak2 , jak3 , and tyk2 , and the stat family consists of seven proteins ( stats 1 , 2 , 3 , 4 , 5a , 5b , and 6 ) . the signaling pathway is initiated through binding of ligands to membrane - bound receptors which may lead to receptor dimerization and then activate the jak kinases ; in turn , the activation of jak kinases phosphorylates the tyrosine residues with the receptors . as a result , stat proteins are phosphorylated by jak , then dimerize via their src - homology 2 ( sh2 ) domains , and translocate to the nucleus where they regulate transcription of specific target genes involved in multiple diseases including leukemia , rheumatoid arthritis , cancer , and diabetic nephropathy [ 88 , 89 ] .
obesity is now widespread around the world . 
 obesity - associated chronic low - grade inflammation is responsible for the decrease of insulin sensitivity , which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes . 
 the state of low - grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes . 
 obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways , both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action . 
 it has been suggested that specific factors and signaling pathways are often correlated with each other ; therefore , both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation - related insulin resistance . in this paper , we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies .