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.
authors: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Zhonglei
authors: Z
authors: Lu
authors: Genevieve
authors: G
authors: Marcelin
authors: Frederick
authors: F
authors: Bauzon
authors: Hongbo
authors: H
authors: Wang
authors: Hao
authors: H
authors: Fu
authors: Siok Le
authors: SL
authors: Dun
authors: Hongling
authors: H
authors: Zhao
authors: Xiaosong
authors: X
authors: Li
authors: Young-Hwan
authors: YH
authors: Jo
authors: Sharon
authors: S
authors: Wardlaw
authors: Nae
authors: N
authors: Dun
authors: Streamson
authors: S
authors: Chua
authors: Liang
authors: L
authors: Zhu
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism / Q000502:physiology; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056865:Ideal Body Weight / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D016160:Retinoblastoma Protein; D011333:Pro-Opiomelanocortin; D000263:Adenylate Kinase
references: Cell. 2005 Dec 16;123(6):1093-106
references: 16360038
references: Cell Metab. 2008 Feb;7(2):179-85
references: 18249177
references: Nat Genet. 1998 Apr;18(4):360-4
references: 9537419
references: Endocrinology. 2004 Nov;145(11):4880-9
references: 15271881
references: Nature. 2004 Apr 1;428(6982):569-74
references: 15058305
references: Nature. 2000 Apr 6;404(6778):661-71
references: 10766253
references: Science. 2005 Oct 28;310(5748):679-83
references: 16254185
references: J Clin Invest. 2012 Jan;122(1):142-52
references: 22201680
references: Nat Med. 2010 Apr;16(4):403-5
references: 20348924
references: Dev Cell. 2009 Feb;16(2):256-70
references: 19217427
references: Dev Cell. 2007 Jul;13(1):87-102
references: 17609112
references: J Biol Chem. 2004 Mar 26;279(13):12005-8
references: 14742438
references: Nature. 2003 Jul 10;424(6945):223-8
references: 12853964
references: J Biol Chem. 2005 May 20;280(20):19746-56
references: 15767262
references: Dev Cell. 2002 Jul;3(1):39-49
references: 12110166
references: Nature. 2001 Sep 20;413(6853):323-7
references: 11565035
references: Endocrinology. 2006 Aug;147(8):3906-14
references: 16675525
references: J Clin Invest. 2012 Jan;122(1):153-62
references: 22201683
references: Nat Neurosci. 2008 Sep;11(9):998-1000
references: 19160495
references: Nat Neurosci. 2005 May;8(5):566-70
references: 15856064
references: Neuron. 2004 Jun 24;42(6):983-91
references: 15207242
references: J Biol Chem. 2004 May 7;279(19):19970-6
references: 15028725
references: Curr Biol. 1996 Oct 1;6(10):1307-16
references: 8939573
references: Nat Cell Biol. 2012 Oct;14(10):999-1012
references: 22940906
references: Nat Genet. 2010 Jan;42(1):83-8
references: 19966802
references: J Biol Chem. 2005 Apr 22;280(16):16088-95
references: 15701640
references: Nat Protoc. 2008;3(1):59-69
references: 18193022
references: EMBO J. 2000 May 2;19(9):2069-81
references: 10790373
references: PLoS One. 2009;4(4):e5045
references: 19340313
references: J Clin Endocrinol Metab. 1993 Mar;76(3):620-4
references: 8383142
references: BMC Dev Biol. 2001;1:4
references: 11299042
references: J Biol Chem. 2005 Dec 2;280(48):39681-3
references: 16219771
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10848-53
references: 12954980
references: Brain Res. 2010 Sep 2;1350:139-50
references: 20380814
references: Mol Cell. 2003 Sep;12(3):639-49
references: 14527410
references: Peptides. 2002 Feb;23(2):377-82
references: 11825652
references: Nat Neurosci. 2012 Mar 25;15(5):700-2
references: 22446882
references: Endocrinology. 1986 Jul;119(1):19-24
references: 3013585
references: Science. 1996 Dec 6;274(5293):1672-7
references: 8939849
references: Cell Metab. 2008 May;7(5):377-88
references: 18460329
references: Nat Rev Mol Cell Biol. 2002 Jan;3(1):11-20
references: 11823794
references: J Biol Chem. 2006 Jul 14;281(28):18933-41
references: 16687413
references: Cancer Cell. 2008 Jan;13(1):11-22
references: 18167336