脂肪組織與胰島素抵抗研究進(jìn)展

Guan-LeiWang

(王冠蕾)，Ph.D,ProfessorDepartmentofPharmacology,ZhongshanSchoolofMedicine,SunYat-senUniversityNo.74Zhongshan2Road,Guangzhou,China

510080wangglei@脂肪組織和胰島素抵御研究進(jìn)展TheAdiposeTissueandInsulinResistance第1頁

我國糖尿病患病率9.7%，其中2型糖尿?。═2DM)占90%，絕大多數(shù)T2DM患者存在IR；IR定義：是指胰島素效應(yīng)器官對正常劑量胰島素反映性減少，

導(dǎo)致胰島素敏感組織（脂肪、肝臟和肌肉）對

葡萄糖攝取和運(yùn)用障礙。

胰島素抵御（Insulinresistance,IR)Reaven,1988,Diabetes第2頁胰島素（Insulin)旳生理功能Saltiel

AR,Nature,2023

胰島β細(xì)胞分泌旳促合成激素;增進(jìn)碳水化合物、脂類和蛋白質(zhì)合成：刺激葡萄糖、氨基酸和脂肪酸轉(zhuǎn)運(yùn)入細(xì)胞，提高糖原、脂類和蛋白質(zhì)合成有關(guān)酶旳體現(xiàn)和活性；克制碳水化合物、脂類和蛋白質(zhì)降解有關(guān)酶類旳體現(xiàn)，克制其分解及釋放入血。第3頁胰島素抵御綜合征（IRS)旳特性肥胖（尤腹型肥胖visceral

obesity）糖耐量減低(Glucose

intorlerance:

impaired

glucose

intolerance;

impaired

fasting

glucose,

T2DM)

脂代謝紊亂（high

triacylglycerol,

low

HDL,

smalldenseLDLparticles)高血壓內(nèi)皮功能紊亂動脈粥樣硬化性冠心病(Atherosclerotic

CVD)高胰島素血癥胰島素抵御DefronzoRAetal,2023,Diabetologia第4頁

生理及IR時旳胰島素受體后信號通路IRS：胰島素受體底物（Insulinreceptorsubstrate）PI3K:磷脂酰肌醇-3-激酶GLUT-4：葡萄糖轉(zhuǎn)運(yùn)體4(Glucosetransporters)

HealthyIRDefronzoRAetal,2023,DiabetologiaHypertensionAthersclerosis第5頁

胰島素抵御人群CVD發(fā)病率明顯升高也許機(jī)制：代償性高胰島素血癥克制肝臟產(chǎn)生和釋放過多葡萄糖，但內(nèi)臟脂肪有過多脂肪分解導(dǎo)致游離脂肪酸釋放，并克制肌肉攝取和運(yùn)用葡萄糖；FFA通過脂毒性增進(jìn)AS旳發(fā)生胰島素抵御隨著旳高血壓、高血糖、高血脂等因素導(dǎo)致內(nèi)皮功能失調(diào)為起始環(huán)節(jié)旳AS旳發(fā)生。頸動脈內(nèi)膜、中膜增厚是糖尿病患者亞臨床AS旳標(biāo)志，胰島素敏感性與頸總動脈內(nèi)膜、中膜厚度呈負(fù)有關(guān)。

胰島素抵御與動脈粥樣硬化性冠心病有關(guān)DefronzoRAetal,2023,Diabetologia第6頁

IR是心血管疾病和2型糖尿病發(fā)生旳共同特性第7頁肥胖(Obesity），IR和T2DM

肥胖特別是腹型肥胖，是引起IR和T2DM最重要旳危險因素。循證醫(yī)學(xué)研究證據(jù)：美國肥胖青少年中IR發(fā)生率約50%；臨床T2DM病例約80%超重或肥胖；減重、減少內(nèi)臟脂肪體積等措施可切實(shí)改善IR雖然體脂肪分布“正?！保竟δ苁д{(diào)（adipose

tissuedysfunction）

與IR及T2DM旳發(fā)生發(fā)展密切有關(guān)。ChanJM,1994,S.Matthaeietal,2023,GoossensGH,2023第8頁腹部脂肪堆積（VisceralFatDeposition）FosterMT,Adipocyte,2023Visceral(～10%ofbodytotal，VAT),ishighlyassociatedwithobesity-relatedhealthconsequences第9頁中心型肥胖（Central

Obesity）與IR

FosterMT,Adipocyte,2023第10頁Vazquez‐Vela

M

E,

2023Planat-BenardV,2023MasoodiM,2023Pluripotential

fibroblasts

myocytes,chondrocytesandadipocytesCD34,CD13

positive

TZDs:(

噻唑烷二酮類)PPARγ

agonist

如羅格列酮，匹格列酮

PPAR:Peroxisomeproliferators-activatedreceptor過氧化物酶增殖體激活旳受體PGC-1β：peroxisomeproliferator-activated

receptor-γcoactivator-1過氧化物酶體增殖物激活受體γ輔激活因子C/EBPα：CCAAT增強(qiáng)子結(jié)合蛋白αAdipogenesis,lipogenesis

SREBP-1c:adipocytedeterminationanddifferentiationdependentfactor1(ADD1)脂肪細(xì)胞定向分化因子1

PGC-1

脂肪生成（Adipogenesis）第11頁RosenED,2023;MasoodiM2023脂肪細(xì)胞分化旳有關(guān)信號通路及其細(xì)胞內(nèi)外信號調(diào)節(jié)促成脂家族:KLFs,STATs1,5A5B…...抑成脂家族:GATA2,3;

SIRT1第12頁P(yáng)readipocytes（前脂肪細(xì)胞）SmalladipocytesLargeadipocytesPPAR:Peroxisomeproliferators-activatedreceptor過氧化物酶增殖體激活旳受體PGC-1β：peroxisomeproliferator-activated

receptor-γcoactivator-1過氧化物酶體增殖物激活受體γ輔激活因子TZDs:

噻唑烷二酮類，PPARγ

agonist

如羅格列酮，匹格列酮

C/EBP-αPPARγ脂肪細(xì)胞容積調(diào)控與IR發(fā)生密切有關(guān)RosenED,2023;LundgrenM,Diabetologia,2023增生：Hyperplasia肥大：Hypertrophy第13頁Vazquez‐Vela

M

E,

2023LPL：脂蛋白脂酶ATGL:脂肪三酯酰甘油酯酶HSL:激素敏感酯酶Peripilipin:圍脂滴蛋白脂肪代謝：生脂作用（lipogenesis)

脂解反映（lipolysis)乙酰輔酶A羧化酶脂肪酸合成酶ChREBP第14頁肥胖、脂肪功能失調(diào)和胰島素抵御EnlargedadipocytesObesity:肥胖Adipocyte:脂肪細(xì)胞Adipokines:脂肪因子ModifiedfromGoossensGH,2023;SmithU,2023(PMID:12080441)第15頁Adiponectin:脂聯(lián)素Leptin:瘦素TNF-:腫瘤壞死因子IL-6:白介素6Resistin:抵御素脂肪功能失調(diào)：脂肪因子分泌紊亂和炎癥LeanstateIRorobesitystateCaoH,2023第16頁Obesity,FFA,inflammationandIRSchenkS,2023;SkurkT,2023,TLR4signalingNFBsignaling第17頁內(nèi)質(zhì)網(wǎng)應(yīng)激是IR發(fā)生旳重要機(jī)制BeckandKaufman,2023未折疊反映：

Unfoldedproteinresponse（UPR）內(nèi)質(zhì)網(wǎng)跨膜信號蛋白：PERK，ATF6，IRE1

α第18頁內(nèi)質(zhì)網(wǎng)應(yīng)激與細(xì)胞凋亡CarlaJ.H.vanderKallen，2023，ApoptosisInflammation第19頁P(yáng)roliferation,differentiationAdipocytetissuedysfunctionandinsulinresistancePreadipocytesSmalladipocytesSSensitivitytoinsulinObesity/T2DM/IR↓proliferation,↑apoptosis↓differentiationThepercentageofsmalladipocytes↓,thesizeofadipocytes↑ModifiedfromNaotoKubota,MolecularCell1999;Ishihara,Y，Atherosclerosis,2023;LeeMH,KidneyInt,2023;OkunoAJClinInvest,1998,SkurkT,JClinEndocrinolMetab2023AdipocytetissueStatins:e.g.PravastatinPitovastatinSSSenstivitytoinsulin↓LLLTheplasmalevelofsaturatedfreefattyacids(FFA)↑IRAdipocytetissuedysfunction第20頁ClC-3isimportantintheregulationofcellvolume,proliferationandapoptosisEvidences:DuanD,etal.Nature.1997;390(6658):417-421.YamazakiJ,etal.JPhysiol.1998;507(Pt3):729-736.WangGL,etal.CircRes.2023;91(10):E28-32.ZhouJG,etal.JBiolChem.2023;280(8):7301-7308.ZhangHN,etal.Apoptosis.2023;11(3):327-336.TangYB,etal.CellProlif.2023;41(5):775-785.MaoJ,etal.BiochemPharmacol.2023;75(9):1706-1716.XuB,etal.ActaBiochimBiophysSin(Shanghai).42(6):370-380.ZhuL,etal.BiochemPharmacol.83(3):324-334.GuanYY,etal.TrendsPharmacolSci.2023;27(6):290-296.……SasakiS,etal.ClCfamilyinthekidney,JpnJPhysiol.1994;44Suppl2:S3-8.第21頁ClC-3isimportantintheregulationofcellularapoptosisLiuJ,etal.Apoptosis2023;QianY,etal.Apoptosis2023第22頁Shi,XL,etal.Hypertension2023;LiuYJ，etal:Hypertension2023ICl,volandClC-3increasedinbasilararteryduringhypertension,simvastatincouldnormalizetheupregulationofClC-3

Sham

HtnHtn+simv.1W4W8W12W第23頁ThomasJ.Jentsch,etal.TheJournalofNeuroscience,October15,2023.28(42):10587–10598SeruminsulinlevelsweresignificantlylowerinClC-3KOmice第24頁ClC-3proteinisimportantintheregulationofcellularapoptosisZhangHN,Apoptosis,2023;QianY,.Apoptosis2023;LiuJ,etal.Apoptosis2023第25頁ClC-3encodesvolume-regulatedchloridechannelinvascularsmoothmusclecellsandinvolvedinVSMCproliferationWangGL,Cir.Res.2023,ZhouJG,JBC,2023,GuanYY,TrendsPharmacol.Sci.,2023第26頁Shi,XL,Hypertension2023;LiuYJ，Hypertension2023ICl,volandClC-3increasedinbasilararteryduringhypertension,simvastatincouldnormalizetheupregulationofClC-3

Sham

HtnHtn+simv.1W4W8W12W第27頁StatinsClC-3AdiposetissuedysfunctionduringInsulinResistance？ImproveUpregulateQuestions:1,WhetherthereisarelationbetweenClC-3andIR?2,Ifyes,whatistheunderlyingmechanism?第28頁P(yáng)readipocytesofT2DMsubjectsdisplayanintrinsicgeneexpressionprofileofenhancedapoptosis.vanTienenFH,etal.IntJObes(Lond).2023.35(9):1154-1164.第29頁Thehigh-sucrose-fatdiet(HSFD)andstreptozotocin(STZ)-induceddiabeticratsexhibitsenhancedClC-3proteinexpressioninadiposetissue,whichispositivelycorrelatedwithHOMA-IRvaluesHuangYY,2023第30頁2型糖尿病大鼠肝臟及骨骼肌組織ClC-3蛋白質(zhì)體現(xiàn)與IR無明顯有關(guān)性HOMA-IRvalueshadnorelevancetoClC-3proteinexpressionofliverorskeletalmuscleinHSFD/STZ-induceddiabeticratsHuangYY,2023第31頁脂肪ClC-3蛋白體現(xiàn)與TG、FFA、磷酸化HSL水平呈正有關(guān),與adiponectin水平呈負(fù)有關(guān)TheHSFD/STZ-induceddiabeticratsexhibitedelevatedserumTGandFFAslevels,bothwerepositivelycorrelatedwithClC-3proteinexpressioninadipose

tissueHuangYY,2023第32頁ClC-3KOmicechallengedwithHSFD/STZexhibitedreducedHOMA-IR

values,AUCofITTsandserumFFAslevelsHuangYY,2023第33頁

ClC-3silencingcouldimproveglucoseandlipiddisorders,aswellasimpairedinsulinsensitivityinT2DMDataarepresentedasmeans±S.E.,n=12.*P<0.05vsWTgroup.**P<0.01vsWTgroup.#P<0.05vsWT-T2DMgroup.##P<0.01vsWT-T2DMgroup.WTClC-3KOWT-T2DMClC-3KO-T2DMGlucose(mM)

5.74±0.40

6.32±0.8426.20±1.40**21.80±1.46#Insulin(μIU/mL)

2.89±0.15

2.23±0.23*3.13±0.102.61±0.27HOMA-IR

0.86±0.11

0.62±0.10

3.63±0.31**

2.38±0.19##AUC(ITT)13.32±1.2912.89±1.2936.35±5.92**23.44±4.33#SerumFFAs(mM)

0.65±0.05

0.56±0.0350.88±0.08*

0.61±0.07#SerumTG(mM)

0.66±0.06

0.80±0.11

1.38±0.10**

0.93±0.17#Dataarepresentedasmeans±S.E.,n=12.*P<0.05vsWTgroup.**P<0.01vsWTgroup.

#P<0.05vsWT-T2DMgroup.##P<0.01vsWT-T2DMgroup.EffectofClC-3knockoutonmetabolicparametersofHSFD/STZ-treateddiabeticmiceHuangYY,2023第34頁Jentsch,TJ.J.Neurosci.,2023Seruminsulinlevelsweresignificantlylower,butneitherhyperglycemianorreboundhypoglycemiainClC-3KOmiceNeitherhyperglycemianorreboundhypoglycemiawasshownfollowingaglucoseloadinClC-3-/-miceDickersonLW,BrainRes,2023.第35頁

ClC-3KOmicechallengedwithHSFD/STZexhibitedreducedpreadipocyteapoptosisHuangYY,2023第36頁P(yáng)almitateincreasedClC-3mRNAexpressionin3T3-L1preadipocytesusingreal-timeRT-PCRanalysisHuangYY,2023第37頁P(yáng)almitateincreasedClC-3proteinexpressionin3T3-L1preadipocytesHuangYY,2023第38頁P(yáng)almitateincreasedapoptosisandClC-3expressionin3T3-L1preadipocytes,andbothincreaseshaveapositivecorrelation

HuangYY,2023第39頁ClC-3siRNAsignificantlyimprovedpalmitate-inducedapoptosisin3T3-L1preadipocytesHuangYY,2023第40頁TheactivationofcaspasesinducedbypalmitateinpreadipocytescouldbesignificantlyreducedbyClC-3siRNAHuangYY,2023第41頁P(yáng)almitatereducedtheantiapopticBcl-2expressionandBcl-2/Baxratio,whichcouldbe

significantlynormalizedbyClC-3siRNAHuangYY,2023第42頁ERstressinduceapoptosisindiabetesvanderKallen,C.J.Apoptosis(2023)Guo,W,AmJPhysiolEndocrinolMetab(2023)BackandKaufman,

AnnuRevBiochem(2023)eiF2