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

Abstract	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.
Authors	Pengpeng Bi, Tizhong Shan, Weiyi Liu, Feng Yue, Xin Yang, Xin-Rong Liang, Jinghua Wang, Jie Li, Nadia Carlesso, Xiaoqi Liu, Shihuan Kuang
Journal	Nature medicine (Nat Med) Vol. 20 Issue 8 Pg. 911-8 (Aug 2014) ISSN: 1546-170X [Electronic] United States
PMID	25038826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Blood Glucose DNA-Binding Proteins Dibenzazepines Immunoglobulin J Recombination Signal Sequence-Binding Protein Ion Channels Mitochondrial Proteins Notch1 protein, mouse Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Prdm16 protein, mouse RNA, Messenger Rbpj protein, mouse Receptor, Notch1 Transcription Factors Ucp1 protein, mouse Uncoupling Protein 1 Amyloid Precursor Protein Secretases Glucose dibenzazepine
Topics	Adipocytes, Brown (metabolism) Adipose Tissue, Brown (drug effects, metabolism) Adipose Tissue, White (drug effects, metabolism) Amyloid Precursor Protein Secretases (antagonists & inhibitors) Animals Blood Glucose Cells, Cultured DNA-Binding Proteins (antagonists & inhibitors, biosynthesis, genetics) Dibenzazepines (pharmacology) Diet, High-Fat Energy Metabolism Female Glucose (metabolism) Immunoglobulin J Recombination Signal Sequence-Binding Protein (antagonists & inhibitors, genetics) Ion Channels (biosynthesis, genetics) Male Mice Mice, Inbred C57BL Mitochondrial Proteins (biosynthesis, genetics) Obesity (metabolism, therapy) Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha RNA, Messenger (biosynthesis) Receptor, Notch1 (antagonists & inhibitors, genetics) Signal Transduction Transcription Factors (antagonists & inhibitors, biosynthesis, genetics) Transcription, Genetic Uncoupling Protein 1

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