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Recent advances in the relationship between obesity, inflammation, and insulin resistance

Recent advances in the relationship between obesity,

in?ammation,and insulin resistance

Jean-Philippe Bastard1,Mustapha Maachi1,Claire Lagathu1,Min Ji Kim1,Martine Caron1,

Hubert Vidal2,Jacqueline Capeau1,Bruno Feve3

1Inserm U680,Facultéde Médecine Pierre et Marie Curie,site Saint-Antoine,UniversitéPierre et Marie Curie,Paris6et Service de Biochimie et Hormonologie,H?pital Tenon,AP-HP,4rue de la Chine,75970Paris cedex20,France

2UMR Inserm-U449;INRA U-1235;Facultéde Médecine https://www.sodocs.net/doc/483076660.html,ennec,UniversitéClaude Bernard-Lyon1,69372Lyon Cedex08,France

3Inserm U693,UniversitéParis11et service d’Endocrinologie,CHU de Bicêtre,63rue Gabriel Péri,94270Le Kremlin-Bicêtre,France

Correspondence:J.P.Bastard

Accepted for publication January26,2006

ABSTRACT.It now appears that,in most obese patients,obesity is associated with a low-grade in?ammation of white adipose tissue(WAT)resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance,impaired glucose tolerance and even diabetes.WAT is the physiological site of energy storage as lipids.In addition,it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes.In obesity,WAT is characterized by an increased production and secretion of a wide range of in?ammatory molecules including TNF-a and interleukin-6(IL-6),which may have local effects on WAT physiology but also systemic effects on other organs.Recent data indicate that obese WAT is in?ltrated by macrophages,which may be a major source of locally-produced pro-in?ammatory cytokines. Interestingly,weight loss is associated with a reduction in the macrophage in?ltration of WAT and an improvement of the in?ammatory pro?le of gene expression.Several factors derived not only from adipocytes but also from in?ltrated macrophages probably contribute to the pathogenesis of insulin resistance.Most of them are overproduced during obesity,including leptin,TNF-a,IL-6and resistin.Conversely,expression and plasma levels of adiponectin,an insulin-sensitising effector,are down-regulated during obesity.Leptin could modulate TNF-a production and macrophage activation.TNF-a is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species.However,its actual involvement in glucose metabolism disorders in humans remains controversial.IL-6production by human adipose tissue increases during obesity.It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications.Both TNF-a and IL-6can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway.In rodents,resistin can induce insulin resistance,while its implication in the control of insulin sensitivity is still a matter of debate in humans.Adiponectin is highly expressed in WAT,and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance,type2diabetes and coronary heart disease.Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle.In addition,adiponectin counteracts the pro-in?ammatory effects of TNF-a on the arterial wall and probably protects against the development of arteriosclerosis.In obesity,the pro-in?ammatory effects of cytokines through intracellular signalling pathways involve the NF-j B and JNK systems.Genetic or pharmacological manipulations of these effectors of the in?ammatory response have been shown to modulate insulin sensitivity in different animal models.In humans,it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-in?ammatory properties.Thus,it can be considered that obesity corresponds to a sub-clinical in?ammatory condition that promotes the production of pro-in?ammatory factors involved in the pathogenesis of insulin resistance.

Keywords:adipocyte,macrophage,obesity,diabetes,visceral adipose tissue,adipokines

It is now well established that obesity is an independent risk factor for type2diabetes,dyslipidemia,and cardio-vascular diseases(CVD).There is also strong evidence that,for a given adiposity,there is a large heterogeneity in the metabolic and cardiovascular risk mainly linked to the location of excessive adipose tissue.Visceral adipose tissue accumulation is an important predictive factor of lipid,glucose or atherogenic disturbances, while location of adipose tissue in the lower part of the body is not associated with increased alterations at the metabolic level.Since the description of the metabolic syndrome in the eighties by Reaven[1],the awareness of its deleterious consequences and the dramatic rise in the prevalence of obesity led physicians and public health Eur.Cytokine Netw.,V ol.17n°1,March2006,4-12

services to consider it the major health problem linked to related morbidities.

This review will mainly focus on the mechanisms by which excess adipose tissue can lead to insulin resistance and type2diabetes,and promote the onset of CVD.

A recent and striking discovery is that obesity is associated with a low-grade in?ammation process in adipose tissue, the pathophysiological mechanisms of which remained poorly understood,underlining the relationship between fat cells and the immune system.Another physiological and pathological aspect that has generated a considerable sum of experimental and clinical work during the last decade is that adipocytes have the capacity to synthesize and secrete several factors collectively called adipokines. Some of them appear to play an important role in obesity-associated insulin resistance and cardiovascular complica-tions[2,3].

Therefore,it must also be kept in mind that at the tissue level,obesity is not an exclusively adipocyte disease,but also involves other cell types that reside in WAT.This concept helps us to understand the pathophysiological mechanisms at the root of insulin resistance and type2 diabetes.

ADIPOSE TISSUE INFLAMMATION DURING OBESITY:A LINK WITH COMPONENTS

OF THE METABOLIC SYNDROME

Obesity is associated with a chronic in?ammatory re-sponse,characterized by abnormal adipokine production, and the activation of some pro-in?ammatory signalling pathways,resulting in the induction of several biological markers of in?ammation[4-9].Conversely,a reduction in body weight is accompanied by a decrease or even a normalization of these biological parameters[10-13].This association is meaningful,and several animal models sug-gest that these in?ammatory processes have a causal rela-tionship with obesity and its co-morbidities such as insulin resistance,type2diabetes and CVD.

The role of fat cells in metabolic dysfunctions has long been considered,but their potential role in an in?amma-tory process is a new concept.However,recently,several ?ndings have converged to indicate that adipocytes share with immune cells certain properties such as complement activation[14]and pro-in?ammatory cytokine production [4].Fat cell precursors also share features with macroph-ages.Preadipocytes have the capacity for phagocytosis in response to several stimuli[15,16].Moreover,numerous genes that code for transcription factors,cytokines,in?am-matory signalling molecules,and fatty acid transporters are essential for adipocyte biology,and are also expressed and functional in macrophages[17-19].

A body of evidence suggests the presence of an overall, low-grade in?ammation in obesity,with altered levels of several circulating factors such as an increase in the plasma levels of C-reactive protein(CRP),tumor necrosis factor-a (TNF-a),interleukin-6(IL-6),and other biological mark-ers of in?ammation[2,3,20-25].In addition,there is a correlation in healthy individuals between body mass in-dex(BMI)and CRP levels[20].IL-6has been reported to increase liver CRP production[20,26].Interestingly,adi-pose tissue IL-6content is higher in obese patients display-ing an increased CRP level.Otherwise,there is at least a two-fold higher risk of type2diabetes within3-4years in obese individuals with higher CRP levels[27].

At the adipose tissue level,TNF-a has been shown to be over-expressed in WAT from different animal models of obesity,and is considered to be a molecule that makes a link between in?ammation and obesity.Recombinant TNF-a decreases insulin sensitivity,while TNF-a-or TNF-a receptor-null mice have an increased sensitivity in response to this hormone[4,28].Thus it is likely that overproduction of TNF-a by WAT from obese animal models contributes to insulin resistance.

Other adipose-speci?c molecules that are involved in the control of energy metabolism,also regulate immune re-sponses.For example leptin,in addition to its key role in food intake and energy expenditure also regulates immune processes.Leptin-de?cient mice or humans display an altered immune status[29-31].The reduction in leptin levels could be responsible for fast-associated immuno-suppression[32].

Adipose tissue macrophage in?ltration during obesity Large-scale studies of gene expression using micro-array approaches have already highlighted that in WAT from rodent genetic models of obesity the expression of genes coding for proteins involved in in?ammatory processes was markedly altered[33].Unexpectedly,it was observed that these variations in gene expression in WAT were essentially related to a macrophage in?ltration in WAT of these obese mice[34,35].These locally present macroph-ages are responsible for the major part of the locally-produced TNF-a,and for an important part of the produc-tion of IL-6and inducible nitric oxide synthase(iNOS) [34].This macrophage in?ltration has also been reported in WAT of obese patients[34,36-40].

It is noteworthy that a reduction in body weight is accom-panied,not only by an improvement in the in?ammatory process and the co-morbidities,but also by a decrease in the expression of genes coding for in?ammation proteins [37].This phenomenon is already detectable with a small decrease in body weight.Three months following by-pass surgery,there is a signi?cant decrease in both macrophage in?ltration and in the steady state levels for mRNA in-volved in the in?ammatory response[38].Thiazolidinedi-ones are able to reproduce this kind of effect on WAT gene expression[35].

This increase in macrophage in?ltration could represent the cause and/or the consequence of the low-grade in?am-mation state associated with obesity[41,42].The cellular and molecular mechanisms responsible for this macroph-age in?ltration remain largely unknown.Although it has been suggested that macrophages present within WAT could derive from preadipocytes[16,43],some experi-ments have shown that macrophages probably originate mostly from bone marrow precursors[34].Leptin could promote macrophage diapedesis from blood?ow to WAT [39].The fat cell is also able to synthesize and secrete a chemokine,MCP-1(monocyte chemoattractant protein-1),a recruiting factor for circulating monocytes that is over-expressed in obesity[44].It has been proposed that factors secreted by the human,hypertrophied,mature adi-pocyte can activate endothelial cells present in WAT.

Obesity,in?ammation,and insulin resistance5

In turn,endothelial cells can favour monocyte adhesion and transmigration leading to macrophage in?ltration [39,45].

It is now generally considered that both over-production of pro-in?ammatory cytokines by WAT from obese animals or humans (especially by macrophages that reside in WAT),and the de?ciency in anti-in?ammatory adipokines could be involved in the pathophysiology of insulin resis-tance.

ADIPOKINES,INFLAMMATION AND INSULIN RESISTANCE

The name of adipokine is nowadays generally given to any protein that can be synthesized and secreted by adipocytes (?gures 1and 2)[46].Several studies have shown that adipokine production is altered in obesity,type 2diabetes and metabolic syndrome.This is observed for leptin,TNF-a ,IL-6,adiponectin and resistin and will be more extensively discussed in this review.Other adipokines such as angiotensinogen,PAI-1or the recently discovered vis-fatin are also important players in vessel and metabolism regulation but will not be discussed here.Leptin

Leptin,is the product of the ob gene.It is involved in the regulation of energy homeostasis [47]and is almost exclu-sively expressed and produced by WAT and more particu-larly by differentiated mature adipocytes [48].Circulating levels [49]and adipose tissue mRNA expression of leptin [50]are strongly associated with BMI and fat mass in obesity.Thus,leptin appears as a real marker of adipose tissue mass in lean humans where the subcutaneous frac-tion represents about 80%of total fat.Indeed,leptin

mRNA expression is higher in subcutaneous adipose tissue (SAT)than in visceral adipose tissue (V AT)in human [51].Although leptin acts mainly at the level of the central nervous system to regulate food intake and energy expen-diture,there is a relationship between leptin and the low-grade in?ammatory state in obesity,suggesting that leptin could exert peripheral biological effects as a function of its cytokine-like structure [48].Indeed,leptin receptors be-long to the cytokine class I receptor family,and several published works have reported that there is an increased in?ammatory response associated with the presence of hyperleptinemia without obesity [52,53],and that leptin is able to control TNF-a production and activation by mac-rophages [52].However,the underlying mechanisms have not been clearly identi?ed.TNF-a

TNF-a is a pro-in?ammatory cytokine produced by a variety of cell-types,but mainly by macrophages and lym-phocytes.It can be produced by adipose tissue although this production is weak in humans.Nonetheless,TNF-a is thought to play a major role in the pathophysiology of insulin resistance in rodents [4]through the phosphoryla-tion of the insulin receptor substrate-1(IRS-1)protein on serine residues.This could prevent its interaction with the insulin receptor beta subunit,and stop the insulin signal-ling pathway.Although clinical studies have shown that V AT is closely linked to insulin resistance,TNF-a mRNA expression was similar in SAT and V AT [54,55].

Moreover,TNF-a is weakly expressed either in subcuta-neous or in deep human adipose tissue depots and this expression is not always modi?ed in obesity [56].This corresponds with the evaluation of in vivo secretion,which showed that TNF-a production by subcutaneous abdomi-

Adipose tissue Insulin responsiveness

Liver insulin responsiveness Adipocytes Adiponectin

Macrophages

Resistin/FIZZ3

Leptin

TNF αIL-6

+--Muscle insulin responsiveness

Figure 1

Adipokine expression and secretion by adipose tissue in lean subjects.

6J.-P.Bastard,et al.

nal adipose tissue was quantitatively negligible in lean and obese subjects [57].This suggests that adipose tissue is not directly implicated in the increased circulating TNF-a levels observed in obesity in human.It can be hypothesized that other mechanisms involving a systemic effect of leptin or of other adipokines may induce TNF-a secretion by other cell types such as macrophages.Nevertheless,the precise role of TNF-a in human obesity requires further investigation.Interleukin-6

Interleukin-6is produced by many cell types (?broblasts,endothelial cells,monocytes),and many tissues including adipose tissue.It is now well known that IL-6production by adipose tissue is enhanced in obesity [5,6].It is thought that 15to 30%of circulating IL-6levels derives from adipose tissue production in the absence of an acute in-?ammation [57].Secretion is higher in V AT than in SAT [5,58].Accordingly,IL-6mRNA expression is higher in V AT than in SAT [5].However,in adipose tissue,the greater proportion of IL-6is not produced by mature adipocytes but rather by cells of the stroma vascular frac-tion including preadipocytes,endothelial cells and monocytes-macrophages [5,58].Interleukin-6is a multi-functional cytokine acting on many cells and tissues.One of the main effects of IL-6is the induction of hepatic CRP production,which is now known to be an independent,major risk marker of cardiovascular complications [59].Interestingly,there is a strong relationship between IL-6protein content in adipose tissue and circulating levels of both IL-6and CRP [60].In addition,IL-6has been re-cently proposed to play a central role in the link between

obesity,in?ammation and coronary heart diseases [61].As V AT can produce higher IL-6amounts than SAT [5],this could partly explain the relationship between central fat depots and cardiovascular risk complications in human.Moreover,IL-6production by adipose tissue could directly affect liver metabolism by inducing VLDL secretion and hypertriglyceridaemia,since the V AT is closely connected to the liver by the venous portal system [62].

Recent studies have suggested that IL-6could be involved in insulin resistance and its complications [6,63].The IL-6receptor belongs to the cytokine class I receptor family involving JAK/STATs (Janus kinases/signal transducers and activators of transcription)signal transduction path-way [64].Janus kinase activation induces STAT phospho-rylation,dimerisation and translocation to the nucleus to regulate target gene transcription [64].It is now clearly established that a strong interaction occurs between cytok-ine and insulin signalling pathways,and generally leads to an impaired biological effect of insulin.Although the exact mechanisms have not yet been clearly elucidated,it could involve tyrosine phosphatase activation [65]or an interac-tion between suppressor of cytokine signalling (SOCS)proteins and the insulin receptor [66-68].Whatever the mechanisms involved,it has now been clearly demon-strated that cytokines such as TNF-a and IL-6are able to decrease insulin action [65-70].Therefore,in addition to the aggravation of the cardiovascular risk linked to in?am-mation,the chronic increase in circulating cytokine levels could contribute to insulin resistance.

Inflammation

Liver insulin resistance

Muscle insulin resistance

Adipocytes Adiponectin

CRP

++Macrophages

Resistin/FIZZ3

Leptin

TNF αIL-6

---

Figure 2

Adipokine expression and secretion by adipose tissue in insulin-resistant,obese subjects.

Obesity,in?ammation,and insulin resistance 7

Adiponectin

Adiponectin,having been discovered by several groups, has been attributed several different names:ACRP30 (adipocyte complement-related protein of30kDa)or adi-poQ in mouse and GBP28(gelatin-binding protein28)or APM1(adipose most abundant gene transcript1)in human [71].It is highly expressed in adipose tissue.Plasma levels of adiponectin,which constitutes0.01%of circulating proteins,are between5to30mg/L in lean control subjects while those of leptin are between2to8l g/L.The expres-sion of adiponectin mRNA is dependent on the adipose tissue localisation.It is lower in V AT than in SAT[72]. Adiponectin has several particularities which distin-guished it from others adipokines:1)circulating adiponec-tin levels are decreased in obese and/or type2diabetic patients and in patients with coronary heart diseases,2) there is a strong positive correlation between adiponectine-mia and insulin sensitivity,3)there is an inverse correla-tion between adiponectinemia and obesity and more par-ticularly with abdominal obesity and4)adiponectin may play a protective role against atherosclerosis and insulin resistance.The insulin-sensitive action of adiponectin may involve the activation of AMP activated protein kinase (AMPK),which is known to regulate cellular malonyl CoA concentrations by inhibiting acetyl CoA carboxylase [73].This inhibition results in a decreased level of intra-cellular malonyl CoA and a subsequent decreased lipogen-esis associated with increased mitochondrial fatty acid beta-oxidation.Adiponectin is also able to regulate liver glucose production by lowering mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase,two key enzymes of neoglucogenesis[71]. In addition to its insulin-sensitising effects,adiponectin may have a protective effect on the vascular wall by acting early at several steps of the atherogenesis process:

1)modulation of endothelial adhesion molecules[74],

2)transformation of macrophages into foam cells[75]and

3)modulation of vascular smooth muscle cells prolifera-tion[76].Moreover,adiponectin may modulate the TNF-a-induced in?ammatory response,since it has been shown that adiponectin reduces TNF-a secretion of macrophages [77].This anti-TNF-a effect may partly explain the anti-in?ammatory and anti-atherogenic effect of adiponectin. By contrast both TNF-a and IL-6reduce human adipocyte mRNA expression of adiponectin[78],which is an addi-tional mechanism by which these two cytokines induce insulin resistance.

Two adiponectin receptors,adipoR1and adipoR2,local-ized on chromosomes1q32and12p13respectively,have been recently cloned[79].AdipoR1is predominantly ex-pressed in skeletal muscle while adipoR2is mainly ex-pressed in the liver.However,the physiological relevance and the transduction signal pathways of these two recep-tors remain to be determined.

Resistin

Steppan et al.have recently discovered resistin,also called FIZZ3(found in in?ammatory zones)or adipocyte se-creted factor(ADSF)while looking for new molecular targets of thiazolidinediones in adipocytes[80].They showed that circulating and adipose tissue resistin levels were increased in obese rodents but decreased under treat-ment with thiazolidinediones.Moreover,infusion of re-combinant resistin into lean control animals induced insu-lin resistance,while its immuno-neutralisation improved insulin sensitivity in insulin-resistant obese animals.

In cultured adipocytes,resistin reduced insulin-stimulated glucose transport,an effect which was reversed using an anti-resistin antibody.In addition,resistin inhibited adipo-cyte differentiation[81].These studies suggest that resistin could be a link between adipose tissue,obesity and insulin resistance.However,additional,contradictory studies have indicated a decreased mRNA gene expression in adipose tissue from various insulin-resistant rodent mod-els.Nevertheless,recombinant resistin caused major liver insulin resistance[82].

It was recently shown that resistin-knockout mice have lower fasting glycaemia and increased glucose tolerance and insulin sensitivity associated with a reduced liver glucose production[82].The lack of resistin could lead to the activation of AMPK and consequently to a decreased expression of genes involved in liver neoglucogenesis, suggesting that resistin could exert effects opposite to those of adiponectin.Finally,resistin-knockout mice un-der a high fat diet regimen became as obese and insulin-resistant as their wild type counterparts.However,fasting glycaemia was lower in resistin-knockout mice,suggest-ing the implication of resistin in the hyperglycaemia and insulin resistance observed in obesity.

With regards to resistin in humans,several discrepancies have been observed since some studies have shown that adipose tissue expresses resistin while others did not?nd its presence or detected only very low mRNA expression in this tissue.It is believed that the adipocyte is not the major cell type producing resistin in humans,which rather is produced by circulating monocytes and macrophages[82]. Finally,most of the studies found no correlation between plasma resistin levels,BMI and insulin resistance in hu-man.Nonetheless,the macrophage localization of resistin and its inter-relationship with adipocyte metabolism and function are currently under investigation. INFLAMMATORY PATHWAYS IN INSULIN RESISTANCE AND TYPE2DIABETES

A century ago,it was suggested that in?ammation could be involved in the pathophysiology of type2diabetes[83]. Although the molecular mechanisms involved are not clearly understood,it has been suggested that not only the pro-in?ammatory effects of cytokines,but also of reactive oxygen species and free fatty acids in obesity are mediated through speci?c intracellular signalling pathways,involv-ing the nuclear factor(NF)-j B,I j

B kinase,(IKK),Acti-vating Protein-1(AP-1)and c-Jun NH2-terminal kinase (JNK)signalling molecules.All these pathways could interact with insulin signalling via serine/threonine inhibi-tory phosphorylation of IRS.

Genetic or pharmacological manipulations of these differ-ent effectors of the in?ammatory response modulate insu-lin sensitivity in different animal models.Indeed,invalida-tion of these genes,which mediate in?ammatory responses,modulates insulin sensitivity.Heterozygous IKK-b+/-mice under high fat diet regimen or mated with

8J.-P.Bastard,et al.

ob/ob obese mice have lower glycaemia,an improvement in insulin sensitivity and insulin signalling as compared to IKK-b+/+mice[84,85].

By contrast,tissue-speci?c,over-expression of IKK-b in liver and adipose tissue but not in skeletal muscle leads to systemic insulin resistance.Accordingly,selective inhibi-tion of the NF-j B function in liver and adipose tissue protects against insulin resistance in nutritional and ge-netic animal models of obesity[86].

JNK activity,which is mainly related to the JNK1isoform, is increased in obese mice.In response to a high fat diet or in the context of genetically obese rodents,JNK1-null animals gain less body weight and are less prone to altered insulin sensitivity[87].Liver-speci?c down-regulation of JNK signalling improves insulin responsiveness in animal models of type2diabetes[88].

The implication of in?ammation pathways is also sug-gested by the protective effect of some anti-in?ammatory compounds against obesity-associated insulin resistance. Aspirin not only inhibits IKK and JNK pathways[89,90], but also other serine/threonine kinases involved in TNF-a-induced insulin resistance.In addition,through its antioxi-dant properties,aspirin decreases NF-j B and AP-1activa-tion in response to oxidative stress[90].Salicylate reduces the severe insulin resistance observed in genetically obese rodents[84].In human species,high doses of salicylate improve insulin sensitivity of type2diabetic patients[91]. Nevertheless,the exact mechanisms by which aspirin modulates carbohydrate metabolism and insulin sensitiv-ity remain to be investigated[92].

Other drugs with well characterized anti-in?ammatory effects,such as thiazolidinediones and statins,also possess anti-diabetic properties.Thiazolidinediones have an insulin-sensitizing action that is possibly related,at least in part,to their ability to decrease adipocyte TNF-a produc-tion,or TNF-a effects on several target tissues,and by contrast to induce adiponectin expression[93].Statins modulate endothelial functions and trans-endothelial leu-kocyte migration,inhibit pro-in?ammatory cytokine se-cretion and interfere in the NF-j B pathway[94].Accord-ingly,pravastatin is known to reduce the risk of type2 diabetes.

CONCLUSION

During the last decade,understanding of the biology of adipose tissue and,in particular,its secretory functions have dramatically improved,and this has completely modi?ed our understanding of the pathophysiological link between the increase of fat mass,namely obesity,insulin resistance and cardiovascular complications.The adipok-ines produced by adipocytes or by adipose tissue-in?ltrating macrophages,are able to induce a low-grade in?ammation state that could play a central role in obesity and type2diabetes-related insulin resistance and cardio-vascular complications.New therapeutic approaches can thus be considered.However,further studies are necessary to better understand the regulation and biological func-tions of adipokines.New adipokines will be certainly discovered in the next few years,which will lead us to greater appreciation of the complexity of the cross-talk between metabolic tissues,and their alteration in human diseases.Acknowledgements.This work was supported by grants from INSERM and Universities Pierre et Marie Curie,Paris VI and Paris XI.

REFERENCES

1.Reaven GM.Banting lecture1988.Role of insulin resistance in

human disease.Diabetes1988;37:1595.

2.Das UN.Is metabolic syndrome X an in?ammatory condition?Exp

Biol Med(Maywood)2002;227:989.

3.Das UN.Obesity,metabolic syndrome X,and in?ammation.Nutri-

tion2002;18:430.

4.Hotamisligil GS,Shargill NS,Spiegelman BM.Adipose expres-

sion of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance.Science1993;259:87.

5.Fried SK,Bunkin DA,Greenberg AS.Omental and subcutaneous

adipose tissues of obese subjects release interleukin-6:depot dif-ference and regulation by glucocorticoid.J Clin Endocrinol Metab 1998;83:847.

6.Bastard JP,Maachi M,Tran Van Nhieu J,Jardel C,Bruckert E,

Grimaldi A,Robert JJ,Capeau J,Hainque B.Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro.J Clin Endocrinol Metab2002;87: 2084.

7.Samad F,Yamamoto K,Pandey M,Loskutoff DJ.Elevated expres-

sion of transforming growth factor-beta in adipose tissue from obese mice.Mol Med1997;3:37.

8.Samad F,Yamamoto K,Loskutoff DJ.Distribution and regulation

of plasminogen activator inhibitor-1in murine adipose tissue in vivo.Induction by tumor necrosis factor-alpha and lipopolysaccha-ride.J Clin Invest1996;97:37.

9.Sartipy P,Loskutoff DJ.Monocyte chemoattractant protein1in

obesity and insulin resistance.Proc Natl Acad Sci USA2003;100: 7265.

10.van Dielen FM,Buurman WA,Hadfoune M,Nijhuis J,

Greven JW.Macrophage inhibitory factor,plasminogen activator inhibitor-1,other acute phase proteins,and in?ammatory media-tors normalize as a result of weight loss in morbidly obese subjects treated with gastric restrictive surgery.J Clin Endocrinol Metab 2004;89:4062.

11.Cottam DR,Mattar SG,Barinas-Mitchell E,Eid G,Kuller L,

Kelley DE,Schauer PR.The chronic in?ammatory hypothesis for the morbidity associated with morbid obesity:implications and effects of weight loss.Obes Surg2004;14:589.

12.Esposito K,Pontillo A,Di Palo C,Giugliano G,Masella M,

Marfella R,Giugliano D.Effect of weight loss and lifestyle changes on vascular in?ammatory markers in obese women:a randomized trial.JAMA2003;289:1799.

13.Ryan AS,Nicklas BJ.Reductions in plasma cytokine levels with

weight loss improve insulin sensitivity in overweight and obese postmenopausal women.Diabetes Care2004;27:1699.

14.Rosen BS,Cook KS,Yaglom J,Groves DL,V olanakis JE,

Damm D,White T,Spiegelman BM.Adipsin and complement fac-tor D activity:an immune-related defect in obesity.Science1989;

244:1483.

15.Cousin B,Munoz O,Andre M,Fontanilles AM,Dani C,

Cousin JL,Laharrrague P,Casteilla L,Penicaud L.A role for preadipocytes as macrophage-like cells.F ASEB J1999;13:305.

16.Charriere G,Cousin B,Arnaud E,Andre M,Bacou F,Penicaud L,

Casteilla L.Preadipocyte conversion to macrophage.Evidence of plasticity.J Biol Chem2003;278:9850.

17.Totonoz P,Nagy L,Alvarez JG,Thomazy V A,Evans RM.PPAR-

gamma promotes monocyte/macrophage differentiation and up-take of oxidized LDL.Cell1998;93:241.

Obesity,in?ammation,and insulin resistance9

18.Nagy L,Totonoz P,Alvarez JG,Chen H,Evans RM.Oxidized

LDL regulates macrophage gene expression through ligand activa-tion of PPARgamma.Cell1998;93:229.

19.Makowski L,Boord JB,Maeda K,Babaev VR,Uysal KT,

Morgan MA,Parker RA,Suttles J,Fazio,Hotamisligil GS, Linton https://www.sodocs.net/doc/483076660.html,ck of macrophage fatty-acid-binding protein aP2 protects mice de?cient in apolipoprotein E against atherosclerosis.

Nat Med2001;7:699.

20.Ford ES.The metabolic syndrome and C-reactive protein,?brino-

gen,and leukocyte count:?ndings from the Third National Health and Nutrition Examination Survey.Atherosclerosis2003;168: 351.

21.Albert MA,Glynn RJ,Ridker PM.Plasma concentration of

C-reactive protein and the calculated Framingham Coronary Heart Disease Risk Score.Circulation2003;108:161.

22.Luc G,Bard JM,Juhan-Vague I,Ferrieres J,Evans A,Amouyel P,

Arveiler D,Fruchart JC,Ducimetiere P,PRIME Study Group.

C-reactive protein,interleukin-6,and?brinogen as predictors of coronary heart disease:the PRIME Study.Arterioscler Thromb Vasc Biol2003;23:1255.

23.Ridker PM,Cushman M,Stampfer MJ,Tracy RP,Hennekens CH.

In?ammation,aspirin,and the risk of cardiovascular disease in apparently healthy men.N Engl J Med1997;336:973.

24.Engstrom G,Hedblad B,Stavenow L,Lind P,Janzon L,

Lindgarde F.In?ammation-sensitive plasma proteins are associ-ated with future weight gain.Diabetes2003;52:2097.

25.Mosca L.C-reactive protein--to screen or not to screen?N Engl J

Med2002;347:1615.

26.Castell JV,Gomez-Lechon MJ,David M,Hirano T,Kishimoto T,

Heinrich PC.Recombinant human interleukin-6(IL-6/BSF-2/HSF)regulates the synthesis of acute phase proteins in human hepatocytes.FEBS Lett1988;232:347.

27.Barzilay JI,Abraham L,Heckbert SR,Cushman M,Kuller LH,

Resnick HE,Tracy RP.The relation of markers of in?ammation to the development of glucose disorders in the elderly:the Cardiovas-cular Health Study.Diabetes2001;50:2384.

28.Uysal KT,Wiesbrock SM,Marino MW,Hotamisligil GS.Protec-

tion from obesity-induced insulin resistance in mice lacking TNF-alpha function.Nature1997;389:610.

29.Fernandes G,Handwerger BS,Yunis EJ,Brown DM.Immune re-

sponse in the mutant diabetic C57BL/Ks-dt+mouse.Discrepan-cies between in vitro and in vivo immunological assays.J Clin Invest1978;61:243.

30.Farooqi IS,Materese G,Lord GM,Keogh JM,Lawrence E,

Agwu C,Sanna V,Jebb SA,Perna F,Fontana S,Lechler RI, DePaoli AM,O’Rahilly SA.Bene?cial effects of leptin on obesity, T cell hyporesponsiveness,and neuroendocrine/metabolic dys-function of human congenital leptin de?ciency.J Clin Invest2002;

110:1093.

31.Chandra RK.Cell-mediated immunity in genetically obese

C57BL/6J ob/ob)mice.Am J Clin Nutr1980;331:13.

32.Lord GM,Materese G,Howard JK,Baker RJ,Bloom SR,

Lechler RI.Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.Nature1998;

394:897.

33.Soukas A,Cohen P,Socci ND,Friedman JM.Leptin-speci?c pat-

terns of gene expression in white adipose tissue.Genes Dev2000;

14:963.

34.Weisberg SP,McCann D,Desai M,Rosenbaum M,Leibel RL,

Ferrante Jr.AW.Obesity is associated with macrophage accumu-lation in adipose tissue.J Clin Invest2003;112:1796.

35.Xu H,Barnes HT,Yang Q,Tan G,Yang D,Chou CJ,Sole J,

Nichols A,Ross JS,Tartaglia LA,Chen H.Chronic in?ammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest2003;112:1821.36.Cinti S,Mitchell G,Barbatelli G,Murano I,Ceresi E,Faloia E,

Wang S,Fortier M,Greenberg AS,Obin MS.Adipocyte death de-?nes macrophage localization and function in adipose tissue of obese mice and humans.J Lipid Res2005;46:2347.

37.Clement K,Viguerie N,Poitou C,Carette C,Pelloux V,Curat CA,

Sicard A,Rome S,Benis A,Zucker JD,Vidal H,Laville M, Barsh GS,Basdevant A,Stich V,Cancello R,Langin D.Weight loss regulates in?ammation-related genes in white adipose tissue of obese subjects.F ASEB J2004;18:1657.

38.Cancello R,Henegar C,Viguerie N,Taleb S,Poitou C,Rouault C,

Coupaye M,Pelloux V,Hugol D,Bouillot JL,Bouloumie A, Barbatelli G,Cinti S,Svensson PA,Barsh GS,Zucker JD, Basdevant A,Langin D,Clement K.Reduction of macrophage in?ltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss.Diabetes2005;54:2277.

39.Curat CA,Miranville A,Sengenes C,Diehl M,Tonus C,Busse R,

Bouloumie A.From blood monocytes to adipose tissue-resident macrophages:induction of diapedesis by human mature adipo-cytes.Diabetes2004;53:1285.

40.Tchoukaloya YD,Sarr MG,Jensen MD.Measuring committed

preadipocytes in human adipose tissue from severely obese pa-tients by using adipocyte fatty acid binding protein.Am J Physiol Regul Integr Comp Physiol2004;287:R1132.

41.Wellen KE,Hotamisligil GS.Obesity-induced in?ammatory

changes in adipose tissue.J Clin Invest2003;112:1785.

42.Wellen KE,Hotamisligil GS.In?ammation,stress,and diabetes.

J Clin Invest2005;115:1111.

43.Cousin B,Andre M,Villena P,Casteilla L,Penicaud L.Human

adipose cells as candidates in defense and tissue remodeling phe-nomena.Biochem Biophys Res Commun2003;309:502.

44.Christiansen T,Richelsen B,Bruun JM.Monocyte chemoattrac-

tant protein-1is produced in isolated adipocytes,associated with adiposity and reduced after weight loss in morbid obese subjects.

Int J Obes2005;29:146.

45.Avogaro A,de Kreutzenberg SV.Mechanisms of endothelial dys-

function in obesity.Clin Chim Acta2005;360:9.

46.Trayhurn P,Wood IS.Adipokines:in?ammation and the pleiotro-

pic role of white adipose tissue.Br J Nutr2004;92:347.

47.Zhang Y,Proenca R,Maffei M,Barone M,Leopold L,

Friedman JM.Positional cloning of the mouse obese gene and its human homologue.Nature1994;372:425.

48.Ahima RS,Flier JS.Leptin.Annu Rev Physiol2000;62:413.

49.Considine RV,Sinha MK,Heiman ML,Kriauciunas A,

Stephens TW,Nyce MR,Ohannesian JP,Marco CC,McKee LJ, Bauer TL,Caro JF.Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N Engl J Med1996;334: 292.

50.Vidal H,Auboeuf D,De V os P,Staels B,Riou JP,Auwerx J,

Laville M.The expression of ob gene is not acutely regulated by insulin and fasting in human abdominal subcutaneous adipose tissue.J Clin Invest1996;98:251.

51.Lefebvre AM,Laville M,Vega N,Riou JP,van Gaal L,Auwerx J,

Vidal H.Depot-speci?c differences in adipose tissue gene expres-sion in lean and obese subjects.Diabetes1998;47:98.

52.Loffreda S,Yang SQ,Lin HZ,Karp CL,Brengman ML,Wang DJ,

Klein AS,Bulkley GB,Bao C,Noble PW,Lane MD,Diehl AM.

Leptin regulates proin?ammatory immune responses.F ASEB J 1998;12:57.

53.van Dielen FM,van’t Veer C,Schols AM,Soeters PB,

Buurman WA,Greve JW.Increased leptin concentrations correlate with increased concentrations of in?ammatory markers in mor-bidly obese individuals.Int J Obes2001;25:1759.

10J.-P.Bastard,et al.

54.Dusserre E,Moulin P,Vidal H.Differences in mRNA expression

of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues.Biochim Biophys Acta2000;1500:

88.

55.Montague CT,Prins JB,Sanders L,Zhang J,Sewter CP,Digby J,

Byrne CD,O’Rahilly S.Depot-related gene expression in human subcutaneous and omental adipocytes.Diabetes1998;47:1384.

56.Koistinen HA,Bastard JP,Dusserre E,Ebeling P,Zegari N,

Andreelli F,Jardel C,Donner M,Meyer L,Moulin P,Hainque B, Riou JP,Laville M,Koivisto V A,Vidal H.Subcutaneous adipose tissue expression of tumour necrosis factor-alpha is not associated with whole body insulin resistance in obese nondiabetic or in type-2diabetic subjects.Eur J Clin Invest2000;30:302.

57.Mohamed-Ali V,Goodrick S,Rawesh A,Katz DR,Miles JM,

Yudkin JS,Klein S,Coppack SW.Subcutaneous adipose tissue releases interleukin-6,but not tumor necrosis factor-alpha,in vivo.

J Clin Endocrinol Metab1997;82:4196.

58.Fain JN,Madan AK,Hiler ML,Cheema P,Bahouth https://www.sodocs.net/doc/483076660.html,-

parison of the release of adipokines by adipose tissue,adipose tissue matrix,and adipocytes from visceral and subcutaneous ab-dominal adipose tissues of obese humans.Endocrinology2004;

145:2273.

59.Ridker PM.Clinical application of C-reactive protein for cardio-

vascular disease detection and prevention.Circulation2003;107: 363.

60.Maachi M,Piéroni L,Bruckert E,Jardel C,Fellahi S,Hainque B,

Capeau J,Bastard JP.Systemic low grade inflammation is related to both circulating and adipose tissue TNF a,leptin and IL-6levels in obese women.Int J Obes2004;28:993.

61.Yudkin JS,Kumari M,Humphries SE,Mohamed-Ali V.In?am-

mation,obesity,stress and coronary heart disease:is interleukin-6 the link?Atherosclerosis2000;148:209.

62.Nonogaki K,Fuller GM,Fuentes NL,Moser AH,Staprans I,

Grunfeld C,Feingold CR.Interleukin-6stimulates hepatic triglyc-eride secretion in rats.Endocrinology1995;136:2143.

63.Bastard JP,Jardel C,Bruckert E,Blondy P,Capeau J,Laville M,

Vidal H,Hainque B.Elevated levels of interleukin6are reduced in serum and subcutaneous adipose tissue of obese women after weight loss.J Clin Endocrinol Metab2000;8:3338.

64.Ihle JN,Witthuhn BA,Quelle FW,Yamamoto K,Silvennoinen O.

Signaling through the hematopoietic cytokine receptors.Annu Rev Immunol1995;13:369.

65.Kroder G,Bossenmaier B,Kellerer M,Capp E,Stoyanov B,

Mühlh?fer A,Berti L,Horikoshi H,Ullrich A,H?ring H.Tumor necrosis factor-alpha-and hyperglycemia-induced insulin resis-tance.Evidence for different mechanisms and different effects on insulin signalling.J Clin Invest1996;97:1471.

66.Mooney RA,Senn J,Cameron S,Inamdar N,Boivin LM,

Shang Y,Furlanetto RW.Suppressors of cytokine signaling-1and -6associate with and inhibit the insulin receptor.A potential mechanism for cytokine-mediated insulin resistance.J Biol Chem 2001;276:25889.

https://www.sodocs.net/doc/483076660.html,gathu C,Bastard JP,Auclair M,Maachi M,Capeau J,Caron M.

Chronic Interleukin-6(IL-6)treatment increased IL-6secretion and induced insulin resistance in adipocyte:Prevention by Rosigli-tazone.Biochem Biophys Res Com2003;311:372.

68.Rieusset J,Bouzakri K,Chevillotte E,Ricard N,Jacquet D,

Bastard JP,Laville M,Vidal H.SOCS(Suppressor Of Cytokine Signaling)-3Expression and Insulin Resistance in Skeletal Muscle of Obese and Type2Diabetic Patients.Diabetes2004;53:2232.

69.Hotamisligil GS,Peraldi P,Budavari A,Ellis R,White MF,

Spiegelman BM.IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance.Science1996;271:665.

70.Grimble RF.In?ammatory status and insulin resistance.Curr Opin

Clin Nutr Metab Care2002;5:551.71.Kadowaki T,Yamauchi T.Adiponectin and Adiponectin Recep-

tors.Endocr Rev2005;26:439.

72.Lihn AS,Bruun JM,He G,Pedersen SB,Jensen PF,Richelsen B.

Lower expression of adiponectin mRNA in visceral adipose tissue in lean and obese subjects.Mol Cell Endocrinol2004;219:9. 73.Yamauchi T,Kamon J,Minokoshi Y,Ito Y,Waki H,Uchida S,

Yamashita S,Noda M,Kita S,Ueki K,Eto K,Akanuma Y, Froguel P,Foufelle F,Ferre P,Carling D,Kimura S,Nagai R, Kahn BB,Kadowaki T.Adiponectin stimulates glucose utilization and fatty-acid oxidaion by activating AMP-activated protein ki-nase.Nat Med2002;8:1288.

74.Ouchi N,Kihara S,Arita Y,Maeda K,Kuriyama H,Okamoto Y,

Hotta K,Nishida M,Takahashi M,Nakamura T,Yamashita S, Funahashi T,Matsuzawa Y.Novel modulator for endothelial adhe-sion molecules:adipocyte-derived plasma protein Adiponectin.

Circulation1999;100:2473.

75.Ouchi N,Kihara S,Arita Y,Nishida M,Matsuyama A,

Okamoto Y,Ishigami M,Kuriyama H,Kishida K,Nishizawa H, Hotta K,Muraguchi M,Ohmoto Y,Yamashita S,Funahashi T, Matsuzawa Y.Adipocyte-derived plasma protein,adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages.Circulation 2001;103:1057.

76.Arita Y,Kihara S,Ouchi N,Maeda K,Kuriyama H,Okamoto Y,

Kumada M,Hotta K,Nishida M,Takahashi M,Nakamura T, Shimomura I,Muraguchi M,Ohmoto Y,Funahashi T, Matsuzawa Y.Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regu-lates growth factor-induced common postreceptor signal in vascu-lar smooth muscle cell.Circulation2002;105:2893.

77.Ouchi N,Kihara S,Arita Y,Okamoto Y,Maeda K,Kuriyama H,

Hotta K,Nishida M,Takahashi M,Muraguchi M,Ohmoto Y, Nakamura T,Yamashita S,Funahashi T,Matsuzawa Y.Adiponec-tin,an adipocyte-derived plasma protein,inhibits endothelial NF-kappaB signalling through a camp-dependent pathway.Circula-tion2000;102:1296.

78.Bruun JM,Lihn AS,Verdich C,Pedersen SB,Toubro S,Astrup A,

Richelsen B.Regulation of adiponectin by adipose tissue-derived cytokines:in vivo and in vitro investigations in humans.Am J Physiol Endocrinol Metab2003;285:E527.

79.Yamauchi T,Kamon J,Ito Y,Tsuchida A,Yokomizo T,Kita S,

Sugiyama T,Miyagishi M,Hara K,Tsunoda M,Murakami K, Ohteki T,Uchida S,Takekawa S,Waki H,Tsuno NH,Shibata Y, Terauchi Y,Froguel P,Tobe K,Koyasu S,Taira K,Kitamura T, Shimizu T,Nagai R,Kadowaki T.Cloning of adiponectin recep-tors that mediate antidiabetic metabolic effects.Nature2003;423: 762.

80.Steppan CM,Bailey ST,Bhat S,Brown EJ,Banerjee R,

Wright CM,Patel HR,Ahima RS,Lazar MA.The hormone resis-tin links obesity to diabetes.Nature2001;409:307.

81.Kim KH,Lee K,Moon YS,Sul HK.A cysteine-rich adipose

tissue-speci?c secretory factor inhibits adipocyte differentiation.J Biol Chem2001;276:11252.

82.Jackson MB,Osei SY,Ahima RS.The endocrine role of adipose

tissue:focus on adiponectin and resistin.Cur Opin Endocrinol Diab2005;12:163.

83.Ebstein W.Zur therapie des diabetes mellitus,insbesondereüber

die Answendung des salicylsauren natron bei demselben.Berlin Klin Wochenschrift1876;13:337.

84.Yuan M,Konstantopoulos N,Lee J,Hansen L,Li ZW,Karin M,

Shoelson SE.Reversal of obesity-and diet-induced insulin resis-tance with salicylates or targeted disruption of Ikkbeta.Science 2001;293:1673.

85.Kim JK,Kim YJ,Fillmore JJ,Chen Y,Moore I,Lee J,Yuan M,

Li ZW,Karin M,Perret P,Shoelson SE,Shulman GI.Prevention of fat-induced insulin resistance by salicylate.J Clin Invest2001;

108:437.

Obesity,in?ammation,and insulin resistance11

86.Cai D,Yuan M,Frantz DF,Melendez PA,Hansen L,Lee J,

Shoelson SE.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med2005;11: 183.

87.Hirosumi J,Tuncman G,Chang L,G?rgün CZ,Uysal KT,

Maeda K,Karin M,Hotamisligil GS.A central role for JNK in obesity and insulin resistance.Nature2002;420:333.

88.Nakatani Y,Kaneto H,Kawamori D,Hatazaki M,Miyatsuka T,

Matsuoka TA,Kajimoto Y,Matsuhisa M,Yamasaki Y,Hori M.

Modulation of the JNK pathway in liver affects insulin resistance status.J Biol Chem2004;279:45803.

89.Yin MJ,Yamamoto Y,Gaynor RB.The anti-in?ammatory agents

aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.

Nature1998;396:77.

90.Gao Z,Zuberi A,Quon MJ,Dong Z,Ze J.Aspirin inhibits serine

phosphorylation of insulin receptor substrate1in tumor necrosis factor-treated cells through targeting multiple serine kinases.J Biol Chem2003;278:24944.91.Shi X,Ding M,Dong Z,Chen F,Ye J,Wang S,Leonard SS,

Castranova V,Vallyathan V.Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation,DNA damage,NF-kappaB activation,and TNF-alpha production.Mol Cell Biochem1999;199:93.

92.Hundal RS,Petersen KF,Mayerson AB,Randhawa PS,

Inzucchi S,Shoelson SE,Shulman GI.Mechanism by which high-dose aspirin improves glucose metabolism in type2diabetes.

J Clin Invest2002;109:1321.

93.Moller DE,Berger JP.Role of PPARs in the regulation of obesity-

related insulin sensitivity and in?ammation.Int J Obes2003(Suppl

3):S17.

94.Weitz-Schmidt G.Statins as anti-in?ammatory agents.Trends

Pharmacol Sci2002;23:482.

12J.-P.Bastard,et al.

The way常见用法

The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法）举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法：在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because

The way的用法及其含义(二)

The way的用法及其含义（二）二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中

(完整版)the的用法

定冠词the的用法：定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...

“the way+从句”结构的意义及用法

“tｈｅwａｙ+从句”结构的意义及用法首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法

不对。Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.

way 用法

表示“方式”、“方法”，注意以下用法： 1.表示用某种方法或按某种方式，通常用介词in(此介词有时可省略)。如： Do it (in) your own way. 按你自己的方法做吧。 Please do not talk (in) that way. 请不要那样说。 2.表示做某事的方式或方法，其后可接不定式或of doing sth。如： It’s the best way of studying [to study] English. 这是学习英语的最好方法。 There are different ways to do [of doing] it. 做这事有不同的办法。 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句，但是其后的从句不能由how 来引导。如：我不喜欢他说话的态度。正：I don’t like the way he spoke. 正：I don’t like the way that he spoke. 正：I don’t like the way in which he spoke. 误：I don’t like the way how he spoke. 4.注意以下各句the way 的用法： That’s the way (=how) he spoke. 那就是他说话的方式。 Nobody else loves you the way(=as) I do. 没有人像我这样爱你。 The way (=According as) you are studying now, you won’tmake much progress. 根据你现在学习情况来看，你不会有多大的进步。 2007年陕西省高考英语中有这样一道单项填空题： ——I think he is taking an active part insocial work. ——I agree with you_____. A、in a way B、on the way C、by the way D、in the way 此题答案选A。要想弄清为什么选A，而不选其他几项，则要弄清选项中含way的四个短语的不同意义和用法，下面我们就对此作一归纳和小结。一、in a way的用法表示：在一定程度上，从某方面说。如： In a way he was right.在某种程度上他是对的。注：in a way也可说成in one way。二、on the way的用法 1、表示：即将来(去)，就要来(去)。如： Spring is on the way.春天快到了。 I'd better be on my way soon.我最好还是快点儿走。 Radio forecasts said a sixth-grade wind was on the way.无线电预报说将有六级大风。 2、表示：在路上，在行进中。如： He stopped for breakfast on the way.他中途停下吃早点。 We had some good laughs on the way.我们在路上好好笑了一阵子。 3、表示：(婴儿)尚未出生。如： She has two children with another one on the way.她有两个孩子，现在还怀着一个。 She's got five children，and another one is on the way.她已经有5个孩子了，另一个又快生了。三、by the way的用法

The way的用法及其含义(一)

The way的用法及其含义（一）有这样一个句子：In 1770 the room was completed the way she wanted. 1770年，这间琥珀屋按照她的要求完成了。 the way在句中的语法作用是什么？其意义如何？在阅读时，学生经常会碰到一些含有the way 的句子，如：No one knows the way he invented the machine. He did not do the experiment the way his teacher told him.等等。他们对the way 的用法和含义比较模糊。在这几个句子中，the way之后的部分都是定语从句。第一句的意思是，“没人知道他是怎样发明这台机器的。”the way的意思相当于how；第二句的意思是，“他没有按照老师说的那样做实验。”the way 的意思相当于as。在In 1770 the room was completed the way she wanted.这句话中，the way也是as的含义。随着现代英语的发展，the way的用法已越来越普遍了。下面，我们从the way的语法作用和意义等方面做一考查和分析：一、the way作先行词，后接定语从句以下3种表达都是正确的。例如：“我喜欢她笑的样子。” 1. the way+ in which +从句 I like the way in which she smiles. 2. the way+ that +从句 I like the way that she smiles. 3. the way + 从句(省略了in which或that) I like the way she smiles. 又如：“火灾如何发生的，有好几种说法。” 1. There were several theories about the way in which the fire started. 2. There were several theories about the way that the fire started.

way 的用法

way 的用法【语境展示】 1. Now I’ll show you how to do the experiment in a different way. 下面我来演示如何用一种不同的方法做这个实验。 2. The teacher had a strange way to make his classes lively and interesting. 这位老师有种奇怪的办法让他的课生动有趣。 3. Can you tell me the best way of working out this problem? 你能告诉我算出这道题的最好方法吗？ 4. I don’t know the way (that / in which) he helped her out. 我不知道他用什么方法帮助她摆脱困境的。 5. The way (that / which) he talked about to solve the problem was difficult to understand. 他所谈到的解决这个问题的方法难以理解。 6. I don’t like the way that / which is being widely used for saving water. 我不喜欢这种正在被广泛使用的节水方法。 7. They did not do it the way we do now. 他们以前的做法和我们现在不一样。【归纳总结】 ●way作“方法，方式”讲时，如表示“以……方式”，前面常加介词in。如例1； ●way作“方法，方式”讲时，其后可接不定式to do sth.，也可接of doing sth. 作定语，表示做某事的方法。如例2，例3；

the-way-的用法讲解学习

t h e-w a y-的用法

The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.

way的用法总结大全

way的用法总结大全 way的用法你知道多少，今天给大家带来way的用法，希望能够帮助到大家，下面就和大家分享，来欣赏一下吧。 way的用法总结大全 way的意思 n. 道路,方法,方向,某方面 adv. 远远地，大大地 way用法 way可以用作名词 way的基本意思是“路,道,街,径”,一般用来指具体的“路,道路”,也可指通向某地的“方向”“路线”或做某事所采用的手段,即“方式,方法”。way还可指“习俗,作风”“距离”“附近,周围”“某方面”等。 way作“方法,方式,手段”解时,前面常加介词in。如果way前有this, that等限定词,介词可省略,但如果放在句首,介词则不可省略。

way作“方式,方法”解时,其后可接of v -ing或to- v 作定语,也可接定语从句,引导从句的关系代词或关系副词常可省略。 way用作名词的用法例句 I am on my way to the grocery store.我正在去杂货店的路上。 We lost the way in the dark.我们在黑夜中迷路了。 He asked me the way to London.他问我去伦敦的路。 way可以用作副词 way用作副词时意思是“远远地,大大地”,通常指在程度或距离上有一定的差距。 way back表示“很久以前”。 way用作副词的用法例句 It seems like Im always way too busy with work.我工作总是太忙了。 His ideas were way ahead of his time.他的思想远远超越了他那个时代。 She finished the race way ahead of the other runners.她第一个跑到终点,远远领先于其他选手。 way用法例句

the_way的用法大全教案资料

t h e_w a y的用法大全

The way 在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或 in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的

the way 的用法

The way 的用法 "the way+从句"结构在英语教科书中出现的频率较高, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 一.在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮.

the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms. 从那天起,其他同学是夹着书本来上课,而他们却带着"失败"的思想负担来上课.

The way的用法及其含义(三)

The way的用法及其含义（三）三、the way的语义 1. the way=as（像） Please do it the way I’ve told you.请按照我告诉你的那样做。 I'm talking to you just the way I'd talk to a boy of my own.我和你说话就像和自己孩子说话一样。 Plant need water the way they need sun light. 植物需要水就像它们需要阳光一样。 2. the way=how（怎样，多么） No one can imagine the way he misses her.没人能够想象出他是多么想念她！ I want to find out the way a volcano has formed.我想弄清楚火山是怎样形成的。 He was filled with anger at the way he had been treated.他因遭受如此待遇而怒火满腔。That’s the way she speaks.她就是那样讲话的。 3. the way=according as （根据） The way you answer the questions, you must be an excellent student.从你回答问题来看，你一定是名优秀的学生。 The way most people look at you, you'd think a trash man was a monster.从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物。 The way I look at it, it’s not what you do that matters so much.依我看，重要的并不是你做什么。 I might have been his son the way he talked.根据他说话的样子，好像我是他的儿子一样。One would think these men owned the earth the way they behave.他们这样行动，人家竟会以为他们是地球的主人。

way的用法

一．Way：“方式”、“方法” 1.表示用某种方法或按某种方式 Do it (in) your own way. Please do not talk (in) that way. 2.表示做某事的方式或方法 It’s the best way of studying [to study] English.。 There are different ways to do [of doing] it. 3.其后通常可直接跟一个定语从句(不用任何引导词)，也可跟由that 或in which 引导的定语从句正：I don’t like the way he spoke. I don’t like the way that he spoke. I don’t like the way in which he spoke.误：I don’t like the way how he spoke. 4. the way 的从句 That’s the way (=how) he spoke. I know where you are from by the way you pronounce my name. That was the way minority nationalities were treated in old China. Nobody else loves you the way(=as) I do. He did not do it the way his friend did. 二．固定搭配 1. In a/one way：In a way he was right. 2. In the way /get in one’s way I'm afraid your car is in the way， If you are not going to help，at least don't get in the way. You'll have to move－you're in my way. 3. in no way Theory can in no way be separated from practice. 4. On the way (to……) Let’s wait a few moments. He is on the way Spring is on the way. Radio forecasts said a sixth-grade wind was on the way. She has two children with another one on the way. 5. By the way By the way，do you know where Mary lives? 6. By way of Learn English by way of watching US TV series. 8. under way 1. Elbow one’s way He elbowed his way to the front of the queue. 2. shoulder one’s way 3. feel one‘s way 摸索着向前走；We couldn’t see anything in the cave, so we had to feel our way out 4. fight/force one’s way 突破。。。而前进The surrounded soldiers fought their way out. 5.. push/thrust one‘s way（在人群中）挤出一条路He pushed his way through the crowd. 6. wind one’s way 蜿蜒前进 7. lead the way 带路，领路；示范 8. lose one‘s way 迷失方向 9. clear the way 排除障碍，开路迷路 10. make one’s way 前进，行进The team slowly made their way through the jungle.

the way的用法大全

在the way+从句中, the way 是先行词, 其后是定语从句.它有三种表达形式:1) the way+that 2)the way+ in which 3)the way + 从句(省略了that或in which),在通常情况下, 用in which 引导的定语从句最为正式,用that的次之,而省略了关系代词that 或in which 的, 反而显得更自然,最为常用.如下面三句话所示,其意义相同. I like the way in which he talks. I like the way that he talks. I like the way he talks. 如果怕弄混淆，下面的可以不看了另外，在当代美国英语中,the way用作为副词的对格,"the way+从句"实际上相当于一个状语从句来修饰全句. the way=as 1)I'm talking to you just the way I'd talk to a boy of my own. 我和你说话就象和自己孩子说话一样. 2)He did not do it the way his friend did. 他没有象他朋友那样去做此事. 3)Most fruits are naturally sweet and we can eat them just the way they are ----all we have to do is clean or peel them . 大部分水果天然甜润,可以直接食用,我们只需要把他们清洗一下或去皮. the way=according to the way/judging from the way 4)The way you answer the qquestions, you must be an excellent student. 从你回答就知道,你是一个优秀的学生. 5)The way most people look at you, you'd think a trashman was a monster. 从大多数人看你的目光中,你就知道垃圾工在他们眼里是怪物. the way=how/how much 6)I know where you are from by the way you pronounce my name. 从你叫我名字的音调中,我知道你哪里人. 7)No one can imaine the way he misses her. 人们很想想象他是多么想念她. the way=because 8) No wonder that girls looks down upon me, the way you encourage her. 难怪那姑娘看不起我, 原来是你怂恿的 the way =while/when(表示对比) 9)From that day on, they walked into the classroom carrying defeat on their shoulders the way other students carried textbooks under their arms.

“the-way+从句”结构的意义及用法知识讲解

“the way+从句”结构的意义及用法首先让我们来看下面这个句子： Read the following passage and talk about it with your classmates. Try to tell what you think of Tom and of the way the children treated him. 在这个句子中，the way是先行词，后面是省略了关系副词that 或in which的定语从句。下面我们将叙述“the way+从句”结构的用法。 1．the way之后，引导定语从句的关系词是that而不是how,因此，<<现代英语惯用法词典>>中所给出的下面两个句子是错误的：This is the way how it happened. This is the way how he always treats me. 2. 在正式语体中，that可被in which所代替；在非正式语体中，that则往往省略。由此我们得到the way后接定语从句时的三种模式：1) the way +that-从句2) the way +in which-从句3) the way +从句例如：The way(in which ,that) these comrades look at problems is wrong.这些同志看问题的方法不对。

The way(that ,in which)you’re doing it is completely crazy.你这么个干法，简直发疯。 We admired him for the way in which he faces difficulties. Wallace and Darwin greed on the way in which different forms of life had begun.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 This is the way (that) he did it. I liked the way (that) she organized the meeting. 3.the way(that)有时可以与how(作“如何”解)通用。例如： That’s the way (that) she spoke. = That’s how she spoke. I should like to know the way/how you learned to master the fundamental technique within so short a time. 4．the way的其它用法：以上我们讲的都是用作先行词的the way，下面我们将叙述它的一些用法。

定冠词the的12种用法

定冠词the的12种用法定冠词the 的12 种用法，全知道?快来一起学习吧。下面就和大家分享，来欣赏一下吧。定冠词the 的12 种用法，全知道? 定冠词the用在各种名词前面，目的是对这个名词做个记号，表示它的特指属性。所以在词汇表中，定冠词the 的词义是“这个，那个，这些，那些”，可见，the 即可以放在可数名词前，也可以修饰不可数名词，the 后面的名词可以是单数，也可以是复数。定冠词的基本用法： (1) 表示对某人、某物进行特指，所谓的特指就是“不是别的，就是那个!”如： The girl with a red cap is Susan. 戴了个红帽子的女孩是苏珊。 (2) 一旦用到the，表示谈话的俩人都知道说的谁、说的啥。如：

The dog is sick. 狗狗病了。(双方都知道是哪一只狗) (3) 前面提到过的，后文又提到。如： There is a cat in the tree.Thecat is black. 树上有一只猫，猫是黑色的。 (4) 表示世界上唯一的事物。如： The Great Wall is a wonder.万里长城是个奇迹。(5) 方位名词前。如： thenorth of the Yangtze River 长江以北地区 (6) 在序数词和形容词最高级的前面。如： Who is the first?谁第一个? Sam is the tallest.山姆最高。但是不能认为，最高级前必须加the，如： My best friend. 我最好的朋友。 (7) 在乐器前。如： play the flute 吹笛子

Way的用法

Way用法 A:I think you should phone Jenny and say sorry to her. B:_______. It was her fault. A. No way B. Not possible C. No chance D. Not at all 说明：正确答案是A. No way，意思是“别想！没门！决不！” 我认为你应该打电话给珍妮并向她道歉。没门！这是她的错。再看两个关于no way的例句：（1）Give up our tea break? NO way! 让我们放弃喝茶的休息时间？没门儿！（2）No way will I go on working for that boss. 我决不再给那个老板干了。 way一词含义丰富，由它构成的短语用法也很灵活。为了便于同学们掌握和用好它，现结合实例将其用法归纳如下：一、way的含义 1. 路线

He asked me the way to London. 他问我去伦敦的路。 We had to pick our way along the muddy track. 我们不得不在泥泞的小道上择路而行。 2. （沿某）方向 Look this way, please. 请往这边看。 Kindly step this way, ladies and gentlemen. 女士们、先生们，请这边走。 Look both ways before crossing the road. 过马路前向两边看一看。 Make sure that the sign is right way up. 一定要把符号的上下弄对。 3. 道、路、街，常用以构成复合词 a highway（公路），a waterway（水路），a railway（铁路），wayside（路边）

way与time的特殊用法

way/time的特殊用法 1、当先行词是way意思为”方式.方法”的时候,引导定语从句的关系词有下列3种形式： Way在从句中做宾语 The way that / which he explained to us is quite simple. Way在从句中做状语 The way t hat /in which he explained the sentence to us is quite simple. 2、当先行词是time时,若time表示次数时,应用关系代词that引导定语从句,that可以省略; 若time表示”一段时间”讲时,应用关系副词when或介词at/during + which引导定语从句 1.Is this factory _______ we visited last year? 2.Is this the factory-------we visited last year? A. where B in which C the one D which 3. This is the last time _________ I shall give you a lesson. A. when B that C which D in which 4.I don’t like the way ________ you laugh at her. A . that B on which C which D as 5.He didn’t understand the wa y ________ I worked out the problem. A which B in which C where D what 6.I could hardly remember how many times----I’ve failed. A that B which C in which D when 7.This is the second time--------the president has visited the country. A which B where C that D in which 8.This was at a time------there were no televisions, no computers or radios. A what B when C which D that