单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2017/5/10,#,Molecular Mechanisms of High Fat Diet-Induced Obesity and Metabolic Syndromes,高脂肪日粮引起肥胖和代谢综合症的分子机制,Shihuan Kuang,Ph.D.,Associate Professor,Purdue University,USA,Modern high fat diet(HFD)and overfeeding,HFD lead to obesity,Gesta et al.,2007,How HFD induces obesity?,Systemic energy surplus leads to obesity,Patrick Seale et al.,2021,Storage 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“fat,HFD leads to adipocyte hypertrophy,TISSUE TURNS BAD,Cell overloaded with lipid rapidly outgrow oxygen supply,leading to cell death and inflammation.,HFD also leads to adipocyte hyperplasia,HFD further changes the color of fat,Three types of adipocytes,：,origin,，,function,Brown adipose tissue,White adipose tissue,Hibernating Organ,Energy storage Organ,Brown and Beige adipose:,Small lipid droplets,UCP1,expression,Dense mitochondria,Burn lipids into heat,More energy expenditure,Harms&Seale,2021,Cannon&Nedergaard，2021,White,beige and brown fat have distinct role in energy balance,Patrick Seale et al.,2021,HFD leads to whitening of fat,Whats the underlying signaling mechanism?,Bartelt&Heeren,2021,抑制,Notch,信号通路促进白色脂肪组织的棕色化并减轻肥胖,Notch Signaling Transduction,Grabher et al.,2006,HFD activates Notch signaling in adipose,Receptors,Ligands,SD-standard diet,N1ICD-activated Notch 1,Notch is inversely correlated to brown fat gene expression,Adipose-specific ablation of Notch 1 in mice,脂肪结合蛋白,4,的表达量标志着白色和棕色脂肪组织中原始脂肪细胞的数量,Notch 1 cKO leads to browning and reduce adiposity,Notch 1 cKO increases brown/beige gene expression,Rbpjk cKO in adipose also lead to browning,Notch1 cKO boosts cold induced browning,4,Notch cKO improves glucose metabolism,GTT,glucose tolerance test,；,ITT,insulin,tolerance test,Notch1 cKO increases metabolic rate,Notch1,cKO protects mice against HFD-induced obesity,Summary-1,HDF activates Notch signaling in white adipose tissues,Notch is inversely correlated with brown fat gene expression,Genetic mutation of Notch induced browning and prevented HFD-induced obesity,Ablation of Notch1 improves glucose tolerance and insulin sensitivity,How does it happen,？,Notch inhibition upregulates BAT genes in,cultured white adipocytes,Gene expression of Notch 1,flox/flox,and Hes 1(left)and Prdm 16 and Ppargc 1,(right)in Notch 1,flox/flox,preadipocytes after transfection with Cre or GFP(control)plasmids,Gene 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-autonomously,Gene expression in,Rosa,N1ICD,preadipocytes,after,transfection with Cre or GFP(control),plasmids,Gene expression of WT preadipocytes after,transfection with,Hey1(d)or Hes1(e),plasmids,Hes1 inhibits Pgc1,and Prdm16 gene transcription,Summary-2,Inhibition of Notch increases BAT gene expression,Activation of Notch decrease BAT gene expression,Notch cell-autonomously inhibits transcription of Beige-specific PGC1a and Prdm16,Pharmaceutical application？药物应用,Can Notch inhibitor ameliorate obesity in Ob/Ob mice-a model of HFD-induced obesity,？,Notch inhibitor blocks body weight gain of Ob mice,aBody weight ratio normalized to day 0.,Arrows mark the doses of DMSO or DBZ injection.,bEnergy intake assay.,Notch inhibitor reduces adiposity in Ob mice,Notch inhibitor ameliorates glucose metabolism in Ob mice,Summary-3,Pharmacological inhibition of Notch protects mice from obesity and ameliorates glucose metabolism and insulin sensitivity,.,Thank you for your attention!,