高脂肪日粮引起肥胖和代谢综合征分子机制

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 leads to whitening of fat
What’s the underlying signaling mechanism?
Bartelt & Heeren, 2014
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
HFD further changes the color of fat
Three types of adipocytes：origin， function
Brown adipose tissue
White adipose tissue
Brown and Beige adipose: • Small lipid droplets • UCP1 expression • Dense mitochondria • Burn lipids into heat • More energy expenditure
Gene expression of Notch targets (left) and BAT-related genes (middle) and protein levels of N1ICD, Ucp1 and Pgc1-α (right) in cultured white adipocytes from MT mice treated with DAPT during induction and differentiation.
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
来自百度文库
How HFD induces obesity?
Systemic energy surplus leads to obesity
Patrick Seale et al., 2009
Gene expression of Notch 1flox/flox and Hes 1 (left) and Prdm 16 and Ppargc 1α (right) in Notch 1flox/flox preadipocytes after transfection with Cre or GFP (control) plasmids
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
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
Hibernating Organ
Energy storage Organ
Harms & Seale, 2013
Cannon & Nedergaard， 2012
White, beige and brown fat have distinct role in energy balance
Patrick Seale et al., 2009
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
Storage of nutrient-derived energy surplus
营养物质
消化系统
脑
胰腺
肝 葡萄糖 糖原
肌肉
葡萄糖 甘油三脂
脂肪因子
胰岛素
游离氨基酸 脂肪组织
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