title: Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex.
abstract: Inflammation has a critical role in the development of insulin resistance. Recent evidence points to a contribution by the central nervous system in the modulation of peripheral inflammation through the anti-inflammatory reflex. However, the importance of this phenomenon remains elusive in type 2 diabetes pathogenesis. Here we show that rat insulin-2 promoter (Rip)-mediated deletion of Pten, a gene encoding a negative regulator of PI3K signaling, led to activation of the cholinergic anti-inflammatory pathway that is mediated by M2 activated macrophages in peripheral tissues. As such, Rip-cre(+) Pten(flox/flox) mice showed lower systemic inflammation and greater insulin sensitivity under basal conditions compared to littermate controls, which were abolished when the mice were treated with an acetylcholine receptor antagonist or when macrophages were depleted. After feeding with a high-fat diet, the Pten-deleted mice remained markedly insulin sensitive, which correlated with massive subcutaneous fat expansion. They also exhibited more adipogenesis with M2 macrophage infiltration, both of which were abolished after disruption of the anti-inflammatory efferent pathway by left vagotomy. In summary, we show that Pten expression in Rip(+) neurons has a critical role in diabetes pathogenesis through mediating the anti-inflammatory reflex.
authors.affiliation: 1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Linyuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Opland
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.affiliation: 1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [3] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.affiliation: Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Allison
authors.affiliation: 1] The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada. [2] Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Caren
authors.initials: C
authors.lastname: Furlonger
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [2] Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [3] Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [2] The Campbell Family Institute for Breast Cancer Research, Toronto, Ontario, Canada. [3] Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [4] Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: 1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Department of Immunology, University of Toronto, Toronto, Ontario, Canada. [3] Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. [4] Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.affiliation: Department of Molecular and Integrative Physiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: 1] Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [4] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. [5] Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002490:Central Nervous System / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D059305:Diet, High-Fat; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011976:Receptors, Muscarinic / Q000008:administration & dosage; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; D007328:Insulin; D011976:Receptors, Muscarinic; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
references.citation: Nat Med. 2011 May;17(5):610-7
references.pmid: 21499269
references.citation: Nat Rev Immunol. 2006 Apr;6(4):318-28
references.pmid: 16557263
references.citation: Nat Rev Immunol. 2005 Aug;5(8):641-54
references.pmid: 16056256
references.citation: PLoS Genet. 2010 May 06;6(5):e1000938
references.pmid: 20463885
references.citation: J Intern Med. 2005 Feb;257(2):139-55
references.pmid: 15656873
references.citation: J Clin Invest. 2003 Dec;112(12):1821-30
references.pmid: 14679177
references.citation: J Clin Endocrinol Metab. 2005 Jul;90(7):4145-50
references.pmid: 15855252
references.citation: Int J Obes (Lond). 2011 Jul;35(7):971-81
references.pmid: 20975726
references.citation: Br J Pharmacol. 2011 Jul;163(5):1007-16
references.pmid: 21371006
references.citation: Nat Med. 2012 Mar 06;18(3):363-74
references.pmid: 22395709
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Nature. 2000 May 25;405(6785):458-62
references.pmid: 10839541
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Circulation. 2008 Feb 12;117(6):806-15
references.pmid: 18227385
references.citation: Nat Med. 2009 Aug;15(8):930-9
references.pmid: 19633656
references.citation: J Exp Med. 2010 Dec 20;207(13):2831-42
references.pmid: 21149549
references.citation: Immunobiology. 2006;211(6-8):487-501
references.pmid: 16920488
references.citation: Mol Cell Biol. 2006 Jun;26(12):4511-8
references.pmid: 16738317
references.citation: Cell Metab. 2007 Aug;6(2):137-43
references.pmid: 17681149
references.citation: J Clin Invest. 2007 Jan;117(1):175-84
references.pmid: 17200717
references.citation: J Clin Invest. 2004 Oct;114(7):917-27
references.pmid: 15467830
references.citation: J Biol Chem. 1999 Jan 1;274(1):305-15
references.pmid: 9867845
references.citation: Genesis. 2000 Feb;26(2):139-42
references.pmid: 10686610
references.citation: J Exp Med. 2006 Jul 10;203(7):1623-8
references.pmid: 16785311
references.citation: Nat Immunol. 2005 Aug;6(8):844-51
references.pmid: 16025117
references.citation: Nat Neurosci. 2005 May;8(5):566-70
references.pmid: 15856064
references.citation: J Exp Med. 2002 Mar 18;195(6):781-8
references.pmid: 11901203
references.citation: Trends Immunol. 2004 Dec;25(12):677-86
references.pmid: 15530839
references.citation: Br J Pharmacol. 1995 Aug;115(7):1155-62
references.pmid: 7582538
references.citation: J Exp Med. 2005 Apr 4;201(7):1113-23
references.pmid: 15809354
references.citation: Cancer Cell. 2005 Sep;8(3):185-95
references.pmid: 16169464
references.citation: J Physiol Pharmacol. 2006 Nov;57 Suppl 10:43-51
references.pmid: 17242490
references.citation: J Clin Invest. 2002 Nov;110(9):1243-50
references.pmid: 12417562
references.citation: J Clin Invest. 2007 Sep;117(9):2621-37
references.pmid: 17717599
references.citation: Nat Genet. 2001 Dec;29(4):396-403
references.pmid: 11726926
references.citation: Genesis. 2010 Nov;48(11):628-34
references.pmid: 20824628
references.citation: Neurosci Biobehav Rev. 2005 May;29(3):493-500
references.pmid: 15820552
references.citation: J Clin Invest. 2006 Jul;116(7):1793-801
references.pmid: 16823477
references.citation: Diabetologia. 2007 Jun;50(6):1248-56
references.pmid: 17393136
references.citation: Diabetes. 2010 Dec;59(12):3090-8
references.pmid: 20802254
references.citation: J Clin Invest. 2005 Apr;115(4):940-50
references.pmid: 15841180
references.citation: J Clin Invest. 2006 Jul;116(7):1886-901
references.pmid: 16794735
references.citation: Annu Rev Immunol. 2012;30:313-35
references.pmid: 22224768
references.citation: Mol Cell Biol. 2005 Feb;25(3):1135-45
references.pmid: 15657439
references.citation: Nature. 2007 Jun 28;447(7148):1116-20
references.pmid: 17515919
references.citation: J Clin Invest. 2006 Jun;116(6):1494-505
references.pmid: 16691291
references.citation: J Appl Physiol (1985). 2005 Apr;98(4):1154-62
references.pmid: 15772055
references.citation: Nat Med. 2009 Aug;15(8):921-9
references.pmid: 19633657
references.citation: Science. 2002 May 10;296(5570):1118-20
references.pmid: 12004130
references.citation: Cell Metab. 2007 Dec;6(6):431-45
references.pmid: 18054313
references.citation: Mol Med. 2012 May 09;18:539-43
references.pmid: 22183893
references.citation: Ann N Y Acad Sci. 1998 May 1;840:289-300
references.pmid: 9629257
references.citation: Diabetes. 2010 Dec;59(12):3117-26
references.pmid: 20852026
references.citation: J Neurosci. 2007 Jan 3;27(1):69-74
references.pmid: 17202473
references.citation: J Clin Invest. 2003 Dec;112(12):1796-808
references.pmid: 14679176
references.citation: J Clin Invest. 2006 Jan;116(1):115-24
references.pmid: 16341265
references.citation: Genes Dev. 2006 Nov 1;20(21):2955-60
references.pmid: 17079685
references.citation: Nat Rev Immunol. 2009 Jun;9(6):418-28
references.pmid: 19461672
references.citation: Cell Metab. 2008 Jun;7(6):496-507
references.pmid: 18522831