PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location

Zhonglei Lu, Genevieve Marcelin, Frederick Bauzon, Hongbo Wang, Hao Fu, Siok Le Dun, Hongling Zhao, Xiaosong Li, Young Hwan Jo, Sharon Wardlaw, Nae Dun, Streamson Chua, Liang Zhu

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11 Scopus citations

Abstract

pRb is frequently inactivated in tumours by mutations or phosphorylation. Here, we investigated whether pRb plays a role in obesity. The Arcuate nucleus (ARC) in hypothalamus contains antagonizing POMC and AGRP/NPY neurons for negative and positive energy balance, respectively. Various aspects of ARC neurons are affected in high-fat diet (HFD)-induced obesity mouse model. Using this model, we show that HFD, as well as pharmacological activation of AMPK, induces pRb phosphorylation and E2F target gene de-repression in ARC neurons. Some affected neurons express POMC; and deleting Rb1 in POMC neurons induces E2F target gene de-repression, cell-cycle re-entry, apoptosis, and a hyperphagia-obesity-diabetes syndrome. These defects can be corrected by combined deletion of E2f1. In contrast, deleting Rb1 in the antagonizing AGRP/NPY neurons shows no effects. Thus, pRb-E2F1 is an obesity suppression mechanism in ARC POMC neurons and HFD-AMPK inhibits this mechanism by phosphorylating pRb in this location.

Original languageEnglish (US)
Pages (from-to)844-857
Number of pages14
JournalEMBO Journal
Volume32
Issue number6
DOIs
StatePublished - Mar 20 2013

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Keywords

  • E2F1
  • POMC neurons
  • high-fat diet
  • obesity
  • pRb phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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