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Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity

Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation o... Full description

Journal Title: Nature medicine 2014-08, Vol.20 (8), p.911-918
Main Author: Bi, Pengpeng
Other Authors: Shan, Tizhong , Liu, Weiyi , Yue, Feng , Yang, Xin , Liang, Xin-Rong , Wang, Jinghua , Li, Jie , Carlesso, Nadia , Liu, Xiaoqi , Kuang, Shihuan
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/25038826
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title: Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
format: Article
creator:
  • Bi, Pengpeng
  • Shan, Tizhong
  • Liu, Weiyi
  • Yue, Feng
  • Yang, Xin
  • Liang, Xin-Rong
  • Wang, Jinghua
  • Li, Jie
  • Carlesso, Nadia
  • Liu, Xiaoqi
  • Kuang, Shihuan
subjects:
  • Adipocytes, Brown - metabolism
  • Adipose Tissue, Brown - drug effects
  • Adipose Tissue, Brown - metabolism
  • Adipose Tissue, White - drug effects
  • Adipose Tissue, White - metabolism
  • Adipose tissues
  • Amyloid Precursor Protein Secretases - antagonists & inhibitors
  • Animals
  • Blood Glucose
  • Blood sugar
  • Cells, Cultured
  • Diabetes
  • Dibenzazepines - pharmacology
  • Diet, High-Fat
  • DNA-Binding Proteins - antagonists & inhibitors
  • DNA-Binding Proteins - biosynthesis
  • DNA-Binding Proteins - genetics
  • Energy Metabolism
  • Female
  • Glucose
  • Glucose - metabolism
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein - antagonists & inhibitors
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
  • Ion Channels - biosynthesis
  • Ion Channels - genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins - biosynthesis
  • Mitochondrial Proteins - genetics
  • Obesity
  • Obesity - metabolism
  • Obesity - therapy
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Physiological aspects
  • Receptor, Notch1 - antagonists & inhibitors
  • Receptor, Notch1 - genetics
  • Risk factors
  • RNA, Messenger - biosynthesis
  • Rodents
  • Signal Transduction
  • Tissues
  • Transcription Factors - antagonists & inhibitors
  • Transcription Factors - biosynthesis
  • Transcription Factors - genetics
  • Transcription, Genetic
  • Uncoupling Protein 1
ispartof: Nature medicine, 2014-08, Vol.20 (8), p.911-918
description: Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleInhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
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descriptionBeige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
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subjectAdipocytes, Brown - metabolism ; Adipose Tissue, Brown - drug effects ; Adipose Tissue, Brown - metabolism ; Adipose Tissue, White - drug effects ; Adipose Tissue, White - metabolism ; Adipose tissues ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Animals ; Blood Glucose ; Blood sugar ; Cells, Cultured ; Diabetes ; Dibenzazepines - pharmacology ; Diet, High-Fat ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - genetics ; Energy Metabolism ; Female ; Glucose ; Glucose - metabolism ; Immunoglobulin J Recombination Signal Sequence-Binding Protein - antagonists & inhibitors ; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics ; Ion Channels - biosynthesis ; Ion Channels - genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial Proteins - biosynthesis ; Mitochondrial Proteins - genetics ; Obesity ; Obesity - metabolism ; Obesity - therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Physiological aspects ; Receptor, Notch1 - antagonists & inhibitors ; Receptor, Notch1 - genetics ; Risk factors ; RNA, Messenger - biosynthesis ; Rodents ; Signal Transduction ; Tissues ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - biosynthesis ; Transcription Factors - genetics ; Transcription, Genetic ; Uncoupling Protein 1
ispartofNature medicine, 2014-08, Vol.20 (8), p.911-918
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7Li, Jie
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9Liu, Xiaoqi
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descriptionBeige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
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0Adipocytes, Brown - metabolism
1Adipose Tissue, Brown - drug effects
2Adipose Tissue, Brown - metabolism
3Adipose Tissue, White - drug effects
4Adipose Tissue, White - metabolism
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6Amyloid Precursor Protein Secretases - antagonists & inhibitors
7Animals
8Blood Glucose
9Blood sugar
10Cells, Cultured
11Diabetes
12Dibenzazepines - pharmacology
13Diet, High-Fat
14DNA-Binding Proteins - antagonists & inhibitors
15DNA-Binding Proteins - biosynthesis
16DNA-Binding Proteins - genetics
17Energy Metabolism
18Female
19Glucose
20Glucose - metabolism
21Immunoglobulin J Recombination Signal Sequence-Binding Protein - antagonists & inhibitors
22Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
23Ion Channels - biosynthesis
24Ion Channels - genetics
25Male
26Mice
27Mice, Inbred C57BL
28Mitochondrial Proteins - biosynthesis
29Mitochondrial Proteins - genetics
30Obesity
31Obesity - metabolism
32Obesity - therapy
33Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
34Physiological aspects
35Receptor, Notch1 - antagonists & inhibitors
36Receptor, Notch1 - genetics
37Risk factors
38RNA, Messenger - biosynthesis
39Rodents
40Signal Transduction
41Tissues
42Transcription Factors - antagonists & inhibitors
43Transcription Factors - biosynthesis
44Transcription Factors - genetics
45Transcription, Genetic
46Uncoupling Protein 1
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titleInhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
authorBi, Pengpeng ; Shan, Tizhong ; Liu, Weiyi ; Yue, Feng ; Yang, Xin ; Liang, Xin-Rong ; Wang, Jinghua ; Li, Jie ; Carlesso, Nadia ; Liu, Xiaoqi ; Kuang, Shihuan
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14DNA-Binding Proteins - antagonists & inhibitors
15DNA-Binding Proteins - biosynthesis
16DNA-Binding Proteins - genetics
17Energy Metabolism
18Female
19Glucose
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21Immunoglobulin J Recombination Signal Sequence-Binding Protein - antagonists & inhibitors
22Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
23Ion Channels - biosynthesis
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26Mice
27Mice, Inbred C57BL
28Mitochondrial Proteins - biosynthesis
29Mitochondrial Proteins - genetics
30Obesity
31Obesity - metabolism
32Obesity - therapy
33Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
34Physiological aspects
35Receptor, Notch1 - antagonists & inhibitors
36Receptor, Notch1 - genetics
37Risk factors
38RNA, Messenger - biosynthesis
39Rodents
40Signal Transduction
41Tissues
42Transcription Factors - antagonists & inhibitors
43Transcription Factors - biosynthesis
44Transcription Factors - genetics
45Transcription, Genetic
46Uncoupling Protein 1
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abstractBeige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation of Notch1 or its signaling mediator Rbpj in mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet-induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces, Ppargc1a and Prdm16 transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
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