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

Pengpeng Bi, Tizhong Shan, Weiyi Liu, Feng Yue, Xin Yang, Xin Rong Liang, Jinghua Wang, Jie Li, Nadia Carlesso, Xiaoqi Liu, Shihuan Kuang

Research output: Contribution to journalArticle

128 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)911-918
Number of pages8
JournalNature Medicine
Volume20
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Bi, P., Shan, T., Liu, W., Yue, F., Yang, X., Liang, X. R., Wang, J., Li, J., Carlesso, N., Liu, X., & Kuang, S. (2014). Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nature Medicine, 20(8), 911-918. https://doi.org/10.1038/nm.3615