1、Molecular Mechanisms of High Molecular Mechanisms of High Fat Diet-Induced Obesity and Fat Diet-Induced Obesity and Metabolic SyndromesMetabolic Syndromes高脂肪日粮引起肥胖和代谢综合症的高脂肪日粮引起肥胖和代谢综合症的分子机制分子机制ShihuanShihuan KuangKuang,Ph.D.,Ph.D.Associate ProfessorAssociate ProfessorPurdue University,USAPurdue Uni
2、versity,USAModern high fat diet(HFD)and overfeedingModern high fat diet(HFD)and overfeedingHFD lead to obesityHFD lead to obesityGesta et al.,2007How HFD induces obesity?How HFD induces obesity?Systemic energy surplus leads to obesitySystemic energy surplus leads to obesityPatrick Seale et al.,2009S
3、torage of nutrient-derived energy surplusStorage of nutrient-derived energy surplus营养物质消化系统脑肝胰腺葡萄糖糖原肌肉甘油三脂胰岛素脂肪组织脂肪因子游离氨基酸葡萄糖Adipocytes store HFD-derived Adipocytes store HFD-derived“fat”fat”HFD leads to adipocyte hypertrophyHFD leads to adipocyte hypertrophyTISSUE TURNS BADTISSUE TURNS BADCell over
4、loaded with lipid rapidly outgrow oxygen supply,leading to cell death and inflammation.HFD also leads to adipocyte hyperplasiaHFD also leads to adipocyte hyperplasiaHFD further changes the color of fatThree types of adipocytes：origin，functionBrown adipose tissueWhite adipose tissueHibernating OrganE
5、nergy storage OrganBrown and Beige adipose:Small lipid droplets UCP1UCP1 expression Dense mitochondria Burn lipids into heat More energy expenditureHarms&Seale,2013Cannon&Nedergaard，2012White,beige and brown fat have distinct White,beige and brown fat have distinct role in energy balancerole in ener
6、gy balancePatrick Seale et al.,2009HFD leads to whitening of fat HFD leads to whitening of fat Whats the underlying signaling mechanism?Bartelt&Heeren,2014抑制抑制Notch信号通路促进白色脂肪组织的棕色化并减轻肥胖信号通路促进白色脂肪组织的棕色化并减轻肥胖Notch Signaling TransductionGrabher et al.,2006HFD activates Notch signaling in adiposeHFD act
7、ivates Notch signaling in adiposeReceptorsReceptorsLigandsLigandsSD-standard dietN1ICD-activated Notch 1Notch is inversely correlated to Notch is inversely correlated to brown fat gene expressionbrown fat gene expressionAdipose-specific ablation of Notch 1 in mice脂肪结合蛋白脂肪结合蛋白4 4的表达量标志着白色和棕色脂肪组的表达量标志
8、着白色和棕色脂肪组织中原始脂肪细胞的数量织中原始脂肪细胞的数量Notch 1 Notch 1 cKOcKO leads to browning and reduce leads to browning and reduce adiposityadiposityNotch 1 Notch 1 cKOcKO increases brown/beige increases brown/beige gene expressiongene expressionRbpjkRbpjk cKOcKO in adipose also lead to in adipose also lead to brownin
9、gbrowningNotch1 cKO boosts cold induced browning4Notch Notch cKOcKO improves glucose improves glucose metabolismmetabolismGTT,glucose tolerance test；ITT,insulin tolerance test Notch1 Notch1 cKOcKO increases metabolic rate increases metabolic rateNotch1 Notch1 cKOcKO protects mice against protects mi
10、ce against HFD-induced obesityHFD-induced obesitySummary-1Summary-1 HDF activates Notch signaling in white adipose tissuesHDF activates Notch signaling in white adipose tissues Notch is inversely correlated with brown fat gene expressionNotch is inversely correlated with brown fat gene expression Ge
11、netic mutation of Notch induced browning and prevented Genetic mutation of Notch induced browning and prevented HFD-induced obesityHFD-induced obesity Ablation of Notch1 improves glucose tolerance and insulin Ablation of Notch1 improves glucose tolerance and insulin sensitivitysensitivity How does i
12、t happenHow does it happen？Notch inhibition Notch inhibition upregulatesupregulates BAT genes in BAT genes in cultured white adipocytescultured white adipocytesGene expression of Notch 1flox/flox and Hes 1(left)and Prdm 16 and Ppargc 1(right)in Notch 1flox/flox preadipocytes after transfection with
13、Cre or GFP(control)plasmidsGene expression of Notch targets(left)and BAT-related genes(middle)and protein levels of N1ICD,Ucp1 and Pgc1-(right)in cultured white adipocytes from MT mice treated with DAPT during induction and differentiation.Notch inhibits BAT genes cell-autonomouslyGene expression in
14、 Gene expression in RosaRosaN1ICDN1ICD preadipocytespreadipocytes after after transfection with transfection with CreCre or GFP(control)or GFP(control)plasmidsplasmidsGene expression of WT Gene expression of WT preadipocytespreadipocytes after after transfection transfection with with Hey1(d)or Hes1
15、(e)Hey1(d)or Hes1(e)plasmidsplasmidsHes1 inhibits Pgc1 and Prdm16 gene transcriptionSummary-2Summary-2 Inhibition ofInhibition of Notch increases BAT gene expressionNotch increases BAT gene expression Activation of Notch decrease BAT gene expressionActivation of Notch decrease BAT gene expression No
16、tch cell-autonomously inhibits transcription of Notch cell-autonomously inhibits transcription of Beige-specific PGC1a and Prdm16Beige-specific PGC1a and Prdm16 Pharmaceutical applicationPharmaceutical application？（药物应用）？（药物应用）Can Notch inhibitor ameliorate obesity in Ob/Ob Can Notch inhibitor ameli
17、orate obesity in Ob/Ob mice-a model of HFD-induced obesitymice-a model of HFD-induced obesity？Notch inhibitor blocks body weight Notch inhibitor blocks body weight gain of Ob micegain of Ob mice（a）Body weight ratio normalized to day 0.Arrows mark the doses of DMSO or DBZ injection.（b）Energy intake a
18、ssay.Notch inhibitor reduces adiposity in Ob miceNotch inhibitor reduces adiposity in Ob miceNotch inhibitor ameliorates glucose metabolism in Ob miceSummary-3Summary-3 Pharmacological inhibition of Notch protects Pharmacological inhibition of Notch protects mice from obesity and ameliorates glucose mice from obesity and ameliorates glucose metabolism and insulin sensitivitymetabolism and insulin sensitivity.Thank you for your attention!
