دورية أكاديمية
أعرض في EDS

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue.

التفاصيل البيبلوغرافية
العنوان: Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue.
المؤلفون: Cederquist CT; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Lentucci C; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Martinez-Calejman C; Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St, Worcester, MA 01605, USA., Hayashi V; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Orofino J; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Guertin D; Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St, Worcester, MA 01605, USA., Fried SK; Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, 1 Gustav Levy Place, New York, NY 10029, USA., Lee MJ; Department of Medicine, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Cardamone MD; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA., Perissi V; Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA. Electronic address: vperissi@bu.edu.
المصدر: Molecular metabolism [Mol Metab] 2016 Oct 31; Vol. 6 (1), pp. 125-137. Date of Electronic Publication: 2016 Oct 31 (Print Publication: 2017).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: eCollection Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Adipose Tissue/*metabolism , Insulin/*metabolism , Intracellular Signaling Peptides and Proteins/*physiology, 3T3 Cells ; Adipocytes/metabolism ; Animals ; Diabetes Mellitus, Type 2/metabolism ; Inflammation/genetics ; Insulin/genetics ; Insulin/physiology ; Insulin Resistance/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Obesity/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Ubiquitin-Conjugating Enzymes/antagonists & inhibitors ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitination
مستخلص: Objective: Insulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT.
Methods: The molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice).
Results: Our results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling both in vitro and in vivo . As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved.
Conclusions: Our findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance.
References: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G1-4. (PMID: 17218471)
Nat Struct Mol Biol. 2011 Feb;18(2):177-84. (PMID: 21240272)
Biochim Biophys Acta. 2010 Mar;1801(3):338-49. (PMID: 20056169)
Methods Enzymol. 2014;537:93-122. (PMID: 24480343)
Cancer Res. 2000 Jul 15;60(14):3916-20. (PMID: 10919669)
Cell Cycle. 2010 Feb 1;9(3):487-97. (PMID: 20081374)
Cell Metab. 2011 Mar 2;13(3):249-59. (PMID: 21356515)
Mol Cell. 2009 May 14;34(4):510-8. (PMID: 19481530)
Nat Rev Cancer. 2011 Feb;11(2):85-95. (PMID: 21258394)
Nat Commun. 2015 Aug 05;6:7906. (PMID: 26243466)
Cell. 2009 Jul 23;138(2):389-403. (PMID: 19615732)
J Cell Biol. 2005 Aug 29;170(5):745-55. (PMID: 16129784)
Mol Cell. 2002 Mar;9(3):611-23. (PMID: 11931768)
Nature. 2010 Aug 19;466(7309):941-6. (PMID: 20725033)
J Biol Chem. 1993 Oct 25;268(30):22243-6. (PMID: 8226728)
Int J Obes Relat Metab Disord. 2000 Nov;24 Suppl 4:S67-70. (PMID: 11126246)
Biochim Biophys Acta. 2004 Nov 29;1695(1-3):55-72. (PMID: 15571809)
Stem Cells. 2014 Jul;32(7):1917-28. (PMID: 24504902)
Annu Rev Physiol. 2010;72:219-46. (PMID: 20148674)
J Clin Invest. 2003 Jul;112(1):91-100. (PMID: 12840063)
J Biol Chem. 2015 Feb 6;290(6):3666-79. (PMID: 25519902)
Br J Cancer. 2008 May 6;98(9):1533-5. (PMID: 18392055)
Cell Metab. 2013 Apr 2;17(4):575-85. (PMID: 23499424)
Mol Cell. 2012 Apr 13;46(1):91-104. (PMID: 22424771)
J Biol Chem. 2008 Mar 28;283(13):8580-90. (PMID: 18218630)
Nature. 2006 Dec 14;444(7121):860-7. (PMID: 17167474)
Diabetologia. 2013 May;56(5):949-64. (PMID: 23443243)
Biochem Soc Trans. 2010 Feb;38(Pt 1):21-8. (PMID: 20074029)
Cell Cycle. 2011 Sep 15;10 (18):3067-71. (PMID: 21926471)
EMBO Rep. 2001 Apr;2(4):282-6. (PMID: 11306547)
Nat Commun. 2016 Apr 21;7:11365. (PMID: 27098609)
Nat Rev Mol Cell Biol. 2010 Jan;11(1):9-22. (PMID: 20027184)
Cell. 2014 Oct 9;159(2):318-32. (PMID: 25303528)
Dev Cell. 2002 Jul;3(1):25-38. (PMID: 12110165)
Dis Model Mech. 2010 Sep-Oct;3(9-10):525-34. (PMID: 20713647)
Cell. 2014 Jan 16;156(1-2):20-44. (PMID: 24439368)
Biol Chem. 2010 Feb-Mar;391(2-3):163-9. (PMID: 20030582)
J Cell Biol. 2015 Mar 2;208(5):501-12. (PMID: 25733711)
Science. 2011 Oct 28;334(6055):474. (PMID: 21979934)
Nat Immunol. 2006 Sep;7(9):962-70. (PMID: 16862162)
Cell. 2012 May 25;149(5):1098-111. (PMID: 22632973)
Nature. 2012 Feb 22;483(7391):618-22. (PMID: 22367539)
J Virol. 2000 Jul;74(13):5872-9. (PMID: 10846067)
Cell Rep. 2014 Jul 10;8(1):163-76. (PMID: 24953653)
Annu Rev Nutr. 2007;27:79-101. (PMID: 17313320)
Cancer Res. 2013 Dec 1;73(23):6938-50. (PMID: 24154876)
Mol Metab. 2015 May 01;4(7):507-18. (PMID: 26137438)
Sci Signal. 2013 Jan 08;6(257):ra3. (PMID: 23300340)
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15665-70. (PMID: 17895379)
Science. 2009 Aug 28;325(5944):1134-8. (PMID: 19713527)
Carcinogenesis. 2007 Mar;28(3):584-94. (PMID: 17050554)
Biochem J. 2015 Jun 1;468(2):203-14. (PMID: 25997832)
J Clin Invest. 2007 Sep;117(9):2621-37. (PMID: 17717599)
J Biol Chem. 1996 Dec 6;271(49):31372-8. (PMID: 8940145)
Nat Med. 2016 Jul;22(7):780-91. (PMID: 27270589)
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7004-9. (PMID: 19372382)
J Biol Chem. 2007 Oct 12;282(41):29936-45. (PMID: 17709375)
J Biol Chem. 2009 Dec 25;284(52):36395-404. (PMID: 19858209)
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E635-46. (PMID: 19158325)
Clin Sci (Lond). 2006 Mar;110(3):267-78. (PMID: 16464169)
Diabetes. 2002 Nov;51(11):3189-95. (PMID: 12401709)
Cell Metab. 2016 May 10;23(5):770-84. (PMID: 27166942)
Obes Rev. 2005 Feb;6(1):13-21. (PMID: 15655035)
Nat Rev Immunol. 2011 Oct 10;11(11):738-49. (PMID: 21984069)
Methods Enzymol. 2014;537:47-73. (PMID: 24480341)
Mol Cell Biol. 1996 Dec;16(12):6698-706. (PMID: 8943324)
Nature. 2012 Apr 19;484(7394):333-8. (PMID: 22466288)
Nat Commun. 2012 Apr 10;3:771. (PMID: 22491319)
Genes Dev. 2010 Feb 15;24(4):381-95. (PMID: 20159957)
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7569-74. (PMID: 12808134)
DNA Repair (Amst). 2006 Jan 5;5(1):32-42. (PMID: 16122992)
Mol Cell Biol. 2010 Nov;30(21):5009-20. (PMID: 20733001)
Mol Cell Biol. 2001 Sep;21(17):5913-24. (PMID: 11486030)
Curr Opin Pharmacol. 2010 Dec;10 (6):684-91. (PMID: 20817607)
Cell. 2010 Nov 24;143(5):677-81. (PMID: 21111228)
J Clin Invest. 2013 Jan;123(1):362-79. (PMID: 23221346)
Nature. 2007 Jul 26;448(7152):439-44. (PMID: 17611497)
معلومات مُعتمدة: R01 DK094004 United States DK NIDDK NIH HHS; R01 DK100422 United States DK NIDDK NIH HHS; P30 DK046200 United States DK NIDDK NIH HHS; R01 CA196986 United States CA NCI NIH HHS; F31 DK108571 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: AKT; Adipose tissue; GPS2; Insulin; Obesity; Ubiquitin
المشرفين على المادة: 0 (GPS2 protein, mouse)
0 (Insulin)
0 (Intracellular Signaling Peptides and Proteins)
EC 2.3.2.23 (Ube2n protein, mouse)
EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
تواريخ الأحداث: Date Created: 20170127 Date Completed: 20181001 Latest Revision: 20190329
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5220281
DOI: 10.1016/j.molmet.2016.10.007
PMID: 28123943
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2016.10.007