title: 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.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Bi
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Tizhong
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Xin-Rong
authors.initials: XR
authors.lastname: Liang
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: 1] Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA. [2] Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: 1] Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA. [2] Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Shihuan
authors.identifier: 0000000191803180
authors.initials: S
authors.lastname: Kuang
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001786:Blood Glucose; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003984:Dibenzazepines / Q000494:pharmacology; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000378:metabolism / Q000628:therapy*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000096:biosynthesis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D000071256:Uncoupling Protein 1
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D003984:Dibenzazepines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007473:Ion Channels; D024101:Mitochondrial Proteins; C497762:Notch1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D012333:RNA, Messenger; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D053829:Amyloid Precursor Protein Secretases; D005947:Glucose; C527817:dibenzazepine