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 C. Chua, Jr., Liang Zhu

Research output: Contribution to journalArticle

10 Citations (Scopus)

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

Fingerprint

High Fat Diet
Nutrition
Hypothalamus
Neurons
Obesity
Fats
Pro-Opiomelanocortin
Arcuate Nucleus of Hypothalamus
Phosphorylation
AMP-Activated Protein Kinases
Genes
Hyperphagia
Reentry
Medical problems
Energy balance
Tumors
Cell Cycle
Chemical activation
Cells
Pharmacology

Keywords

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

ASJC Scopus subject areas

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

Cite this

PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location. / Lu, Zhonglei; Marcelin, Genevieve; Bauzon, Frederick; Wang, Hongbo; Fu, Hao; Dun, Siok Le; Zhao, Hongling; Li, Xiaosong; Jo, Young-Hwan; Wardlaw, Sharon; Dun, Nae; Chua, Jr., Streamson C.; Zhu, Liang.

In: EMBO Journal, Vol. 32, No. 6, 20.03.2013, p. 844-857.

Research output: Contribution to journalArticle

Lu, Z, Marcelin, G, Bauzon, F, Wang, H, Fu, H, Dun, SL, Zhao, H, Li, X, Jo, Y-H, Wardlaw, S, Dun, N, Chua, Jr., SC & Zhu, L 2013, 'PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location', EMBO Journal, vol. 32, no. 6, pp. 844-857. https://doi.org/10.1038/emboj.2013.25
Lu, Zhonglei ; Marcelin, Genevieve ; Bauzon, Frederick ; Wang, Hongbo ; Fu, Hao ; Dun, Siok Le ; Zhao, Hongling ; Li, Xiaosong ; Jo, Young-Hwan ; Wardlaw, Sharon ; Dun, Nae ; Chua, Jr., Streamson C. ; Zhu, Liang. / PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location. In: EMBO Journal. 2013 ; Vol. 32, No. 6. pp. 844-857.
@article{c19f66ea346941e790af1855cfa23406,
title = "PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location",
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.",
keywords = "E2F1, high-fat diet, obesity, POMC neurons, pRb phosphorylation",
author = "Zhonglei Lu and Genevieve Marcelin and Frederick Bauzon and Hongbo Wang and Hao Fu and Dun, {Siok Le} and Hongling Zhao and Xiaosong Li and Young-Hwan Jo and Sharon Wardlaw and Nae Dun and {Chua, Jr.}, {Streamson C.} and Liang Zhu",
year = "2013",
month = "3",
day = "20",
doi = "10.1038/emboj.2013.25",
language = "English (US)",
volume = "32",
pages = "844--857",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - PRb is an obesity suppressor in hypothalamus and high-fat diet inhibits pRb in this location

AU - Lu, Zhonglei

AU - Marcelin, Genevieve

AU - Bauzon, Frederick

AU - Wang, Hongbo

AU - Fu, Hao

AU - Dun, Siok Le

AU - Zhao, Hongling

AU - Li, Xiaosong

AU - Jo, Young-Hwan

AU - Wardlaw, Sharon

AU - Dun, Nae

AU - Chua, Jr., Streamson C.

AU - Zhu, Liang

PY - 2013/3/20

Y1 - 2013/3/20

N2 - 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.

AB - 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.

KW - E2F1

KW - high-fat diet

KW - obesity

KW - POMC neurons

KW - pRb phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=84875450168&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875450168&partnerID=8YFLogxK

U2 - 10.1038/emboj.2013.25

DO - 10.1038/emboj.2013.25

M3 - Article

C2 - 23403926

AN - SCOPUS:84875450168

VL - 32

SP - 844

EP - 857

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 6

ER -