title: Tissue-specific insulin signaling in the regulation of metabolism and aging.
abstract: In mammals, insulin signaling regulates glucose homeostasis and plays an essential role in metabolism, organ growth, development, fertility, and lifespan. The defects in this signaling pathway contribute to various metabolic diseases such as type 2 diabetes, polycystic ovarian disease, hypertension, hyperlipidemia, and atherosclerosis. However, reducing the insulin signaling pathway has been found to increase longevity and delay the aging-associated diseases in various animals, ranging from nematodes to mice. These seemly paradoxical findings raise an interesting question as to how modulation of the insulin signaling pathway could be an effective approach to improve metabolism and aging. In this review, we summarize current understanding on tissue-specific functions of insulin signaling in the regulation of metabolism and lifespan. We also discuss the potential benefits and limitations in modulating tissue-specific insulin signaling pathway to improve metabolism and healthspan.
authors.affiliation: Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education; Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000375:Aging; D000818:Animals; D050260:Carbohydrate Metabolism; D004734:Energy Metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009928:Organ Specificity; D015398:Signal Transduction
chemical_list: D007328:Insulin
keywords: aging; insulin signaling; metabolism; tissue-specific
references.citation: Cell Metab. 2014 Jun 3;19(6):967-80
references.pmid: 24746805
references.citation: Mol Cell. 1998 Nov;2(5):559-69
references.pmid: 9844629
references.citation: Mol Cell Biol. 2011 Feb;31(3):430-41
references.pmid: 21135130
references.citation: Science. 2005 Nov 18;310(5751):1193-6
references.pmid: 16293764
references.citation: Curr Biol. 2004 May 25;14(10):885-90
references.pmid: 15186745
references.citation: FEBS Lett. 2002 Dec 4;532(1-2):1-6
references.pmid: 12459452
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Biochemistry (Mosc). 2013 Jan;78(1):8-18
references.pmid: 23379555
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42
references.pmid: 18316725
references.citation: Cell Metab. 2006 Apr;3(4):267-75
references.pmid: 16581004
references.citation: Diabetes. 1981 Dec;30(12):1000-7
references.pmid: 7030826
references.citation: Aging Cell. 2007 Dec;6(6):731-4
references.pmid: 17941970
references.citation: Diabetes. 2012 Oct;61(10):2414-23
references.pmid: 22596054
references.citation: Nature. 2012 Jan 11;481(7382):463-8
references.pmid: 22237023
references.citation: Am J Physiol Endocrinol Metab. 2000 Sep;279(3):E630-7
references.pmid: 10950832
references.citation: Physiology (Bethesda). 2006 Oct;21:362-9
references.pmid: 16990457
references.citation: Cell Metab. 2007 Apr;5(4):265-77
references.pmid: 17403371
references.citation: Cell Mol Life Sci. 2005 Feb;62(3):320-43
references.pmid: 15723168
references.citation: J Biol Chem. 2009 May 15;284(20):13296-13300
references.pmid: 19297333
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Am J Pathol. 2012 Oct;181(4):1142-6
references.pmid: 22841821
references.citation: Nature. 2012 Apr 19;484(7394):333-8
references.pmid: 22466288
references.citation: Nat Genet. 2006 May;38(5):583-8
references.pmid: 16642022
references.citation: Ann Med. 2005;37(5):347-56
references.pmid: 16179270
references.citation: Nat Genet. 2002 May;31(1):111-5
references.pmid: 11923875
references.citation: Nature. 1993 Dec 23-30;366(6457):740-2
references.pmid: 8264795
references.citation: Nature. 2009 Jul 16;460(7253):392-5
references.pmid: 19587680
references.citation: Diabetes Care. 1992 Mar;15(3):318-68
references.pmid: 1532777
references.citation: Annu Rev Nutr. 2008;28:233-51
references.pmid: 18481923
references.citation: Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S122-34
references.pmid: 11460564
references.citation: J Physiol. 1941 Sep 8;100(2):142-6
references.pmid: 16991514
references.citation: J Clin Endocrinol Metab. 2013 Dec;98(12):4899-907
references.pmid: 24057291
references.citation: J Clin Invest. 1999 Dec;104(12):R69-75
references.pmid: 10606633
references.citation: J Clin Invest. 2004 Oct;114(7):917-27
references.pmid: 15467830
references.citation: Genetics. 1996 Jul;143(3):1207-18
references.pmid: 8807294
references.citation: N Engl J Med. 1999 Jul 22;341(4):248-57
references.pmid: 10413738
references.citation: Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9
references.pmid: 21864752
references.citation: J Clin Invest. 1998 Jan 1;101(1):1-9
references.pmid: 9421459
references.citation: Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1064-71
references.pmid: 14534077
references.citation: Genetics. 2003 Jan;163(1):35-46
references.pmid: 12586694
references.citation: Prog Neurobiol. 2006 Jul;79(4):205-21
references.pmid: 16916571
references.citation: FASEB J. 2009 Oct;23(10):3315-24
references.pmid: 19487308
references.citation: Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E654-67
references.pmid: 18198355
references.citation: Cell Metab. 2008 Nov;8(5):399-410
references.pmid: 19046571
references.citation: Islets. 2009 Sep-Oct;1(2):95-101
references.pmid: 21099255
references.citation: Science. 2007 Jul 20;317(5836):369-72
references.pmid: 17641201
references.citation: Age (Dordr). 2013 Oct;35(5):1881-97
references.pmid: 23160735
references.citation: Nat Med. 2009 Aug;15(8):914-20
references.pmid: 19633658
references.citation: Phys Ther. 2008 Nov;88(11):1279-96
references.pmid: 18801860
references.citation: Am J Physiol. 1997 Mar;272(3 Pt 1):E371-8
references.pmid: 9124541
references.citation: J Clin Invest. 2012 Apr;122(4):1339-53
references.pmid: 22476196
references.citation: Cell Metab. 2007 Jun;5(6):438-49
references.pmid: 17550779
references.citation: Biochem J. 2012 Jan 1;441(1):1-21
references.pmid: 22168436
references.citation: J Physiol. 2009 Dec 1;587(Pt 23):5559-68
references.pmid: 19752112
references.citation: Diabetologia. 2012 Oct;55(10):2565-2582
references.pmid: 22869320
references.citation: Cell. 1999 Feb 5;96(3):329-39
references.pmid: 10025399
references.citation: Nat Rev Endocrinol. 2012 Apr 03;8(8):457-65
references.pmid: 22473333
references.citation: Nat Med. 2001 Oct;7(10):1133-7
references.pmid: 11590437
references.citation: Cell Rep. 2014 May 22;7(4):1227-38
references.pmid: 24813896
references.citation: Diabetes. 2012 May;61(5):1234-42
references.pmid: 22427376
references.citation: Int J Obes Relat Metab Disord. 2002 Jul;26(7):897-904
references.pmid: 12080441
references.citation: Nat Med. 2009 Nov;15(11):1307-11
references.pmid: 19838201
references.citation: Nature. 2003 Jan 9;421(6919):182-7
references.pmid: 12483226
references.citation: Diabetes. 2003 Aug;52(8):2129-36
references.pmid: 12882932
references.citation: J Biol Chem. 2012 May 25;287(22):18769-80
references.pmid: 22493495
references.citation: Nature. 2001 Feb 8;409(6821):729-33
references.pmid: 11217863
references.citation: Am J Physiol Endocrinol Metab. 2004 Jan;286(1):E41-9
references.pmid: 14519599
references.citation: Nature. 1993 Dec 2;366(6454):461-4
references.pmid: 8247153
references.citation: Sci STKE. 2005 Jan 25;2005(268):pe4
references.pmid: 15671481
references.citation: J Biol Chem. 2006 Jul 21;281(29):19881-91
references.pmid: 16670091
references.citation: Nature. 2003 Dec 11;426(6967):620
references.pmid: 14668850
references.citation: Biochem Biophys Res Commun. 2011 Aug 26;412(2):197-202
references.pmid: 21806970
references.citation: Endocr Rev. 1981 Fall;2(4):471-94
references.pmid: 6118266
references.citation: Nature. 2008 Feb 28;451(7182):1069-75
references.pmid: 18305538
references.citation: Science. 2003 Jan 24;299(5606):572-4
references.pmid: 12543978
references.citation: Science. 2001 Apr 6;292(5514):107-10
references.pmid: 11292875
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3100-5
references.pmid: 14981233
references.citation: Eur J Pharmacol. 2004 Apr 19;490(1-3):71-81
references.pmid: 15094074
references.citation: Nature. 1998 Feb 26;391(6670):900-4
references.pmid: 9495343
references.citation: Diabetologia. 1996 Oct;39(10):1180-9
references.pmid: 8897005
references.citation: J Pathol. 2011 Sep;225(1):54-62
references.pmid: 21598254
references.citation: Biochem J. 2005 Jun 1;388(Pt 2):393-406
references.pmid: 15901248
references.citation: Biochem J. 2004 Sep 1;382(Pt 2):619-29
references.pmid: 15193147
references.citation: Arch Intern Med. 1969 Mar;123(3):252-60
references.pmid: 4974823
references.citation: Annu Rev Biochem. 1999;68:913-63
references.pmid: 10872469
references.citation: Mol Cell. 2010 Jul 30;39(2):171-83
references.pmid: 20670887
references.citation: Cell Metab. 2009 Nov;10(5):405-18
references.pmid: 19883618
references.citation: Diabetes. 2004 Jul;53(7):1824-30
references.pmid: 15220207
references.citation: Science. 2006 Sep 15;313(5793):1604-10
references.pmid: 16902091
references.citation: J Biol Chem. 2006 Feb 3;281(5):2649-53
references.pmid: 16326700
references.citation: Science. 2000 Sep 22;289(5487):2122-5
references.pmid: 11000114
references.citation: J Biol Chem. 2007 Nov 23;282(47):34213-8
references.pmid: 17884815
references.citation: J Endocrinol. 2014 Jan 08;220(2):T1-T23
references.pmid: 24281010
references.citation: J Clin Endocrinol Metab. 2006 Mar;91(3):1112-8
references.pmid: 16384854
references.citation: Aging (Albany NY). 2009 Apr 20;1(4):357-62
references.pmid: 20157523
references.citation: J Clin Invest. 2000 Jun;105(12):1791-7
references.pmid: 10862794
references.citation: Nature. 1979 Nov 29;282(5738):503-5
references.pmid: 116135
references.citation: Mol Cells. 2014 Jan;37(1):51-7
references.pmid: 24552710
references.citation: Endocr Pract. 2008 Apr;14(3):373-80
references.pmid: 18463047
references.citation: Genesis. 2010 Nov;48(11):628-34
references.pmid: 20824628
references.citation: Science. 2000 Oct 6;290(5489):147-50
references.pmid: 11021802
references.citation: Diabetes. 2012 Jun;61(6):1455-62
references.pmid: 22522614
references.citation: J Clin Invest. 1985 Jul;76(1):149-55
references.pmid: 3894418
references.citation: Front Biosci. 2004 Jan 01;9:387-403
references.pmid: 14766376
references.citation: Dev Cell. 2002 Jul;3(1):25-38
references.pmid: 12110165
references.citation: Proc Natl Acad Sci U S A. 1984 Mar;81(6):1835-8
references.pmid: 6608731
references.citation: J Clin Invest. 2000 Aug;106(4):459-65
references.pmid: 10953020
references.citation: FEBS J. 2013 Jan;280(2):445-58
references.pmid: 22404968
references.citation: Aging Cell. 2011 Apr;10(2):185-90
references.pmid: 21176090
references.citation: Diabetologia. 2007 Jun;50(6):1248-56
references.pmid: 17393136
references.citation: Science. 2001 Apr 6;292(5514):104-6
references.pmid: 11292874
references.citation: Diabetes. 2005 May;54(5):1264-76
references.pmid: 15855309
references.citation: Cell Mol Neurobiol. 2003 Feb;23(1):1-25
references.pmid: 12701881
references.citation: Nat Med. 2009 Sep;15(9):1082-7
references.pmid: 19718037
references.citation: Mol Cell Biol. 1999 May;19(5):3760-8
references.pmid: 10207099
references.citation: Diabetes. 2010 Dec;59(12):3090-8
references.pmid: 20802254
references.citation: J Aging Res. 2012;2012:384017
references.pmid: 22500228
references.citation: Cancer Res. 1997 Nov 1;57(21):4667-72
references.pmid: 9354418
references.citation: Nat Med. 2012 Feb 19;18(3):388-95
references.pmid: 22344295
references.citation: Diabetes. 1998 Aug;47(8):1243-52
references.pmid: 9703324
references.citation: Nat Med. 2009 Feb;15(2):159-68
references.pmid: 19136964
references.citation: Mol Cell Biol. 2009 Sep;29(18):5070-83
references.pmid: 19596788
references.citation: Mol Cell. 2006 Apr 21;22(2):159-68
references.pmid: 16603397
references.citation: Trends Endocrinol Metab. 2005 Mar;16(2):59-65
references.pmid: 15734146
references.citation: Scientifica (Cairo). 2013;2013:849186
references.pmid: 24379984
references.citation: Biochem J. 2009 Dec 10;424(3):399-410
references.pmid: 19747167
references.citation: Nature. 1994 Oct 27;371(6500):762-7
references.pmid: 7935836
references.citation: Am J Physiol. 1996 Jan;270(1 Pt 1):E197-201
references.pmid: 8772493
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13705-9
references.pmid: 21808028
references.citation: Diabetes. 1997 Feb;46(2):187-96
references.pmid: 9000693
references.citation: Mol Cell Biol. 2010 Nov;30(21):5009-20
references.pmid: 20733001
references.citation: Science. 1997 Aug 15;277(5328):942-6
references.pmid: 9252323
references.citation: Nature. 2004 Jun 3;429(6991):562-6
references.pmid: 15175753
references.citation: Diabetes. 2000 Feb;49(2):284-92
references.pmid: 10868945
references.citation: Diabetologia. 2002 Sep;45(9):1201-10
references.pmid: 12242452
references.citation: Nature. 1999 May 13;399(6732):162-6
references.pmid: 10335847
references.citation: Best Pract Res Clin Endocrinol Metab. 2005 Sep;19(3):391-403
references.pmid: 16150382
references.citation: Cell Metab. 2011 Mar 2;13(3):249-59
references.pmid: 21356515
references.citation: J Clin Invest. 1996 Aug 1;98(3):741-9
references.pmid: 8698866
references.citation: Mol Cell. 2000 Jul;6(1):87-97
references.pmid: 10949030
references.citation: J Clin Invest. 2000 Nov;106(10):1221-8
references.pmid: 11086023
references.citation: Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S202-14
references.pmid: 11460571
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13656-61
references.pmid: 10570128
references.citation: J Clin Invest. 1977 Feb;59(2):369-74
references.pmid: 833282
references.citation: Cell Metab. 2011 Apr 6;13(4):376-388
references.pmid: 21459323
references.citation: J Clin Invest. 2001 Oct;108(8):1205-13
references.pmid: 11602628
references.citation: J Biol Chem. 2008 Sep 12;283(37):25428-25436
references.pmid: 18614531
references.citation: Biochim Biophys Acta. 2010 Apr;1802(4):396-405
references.pmid: 20079433
references.citation: Toxicol Sci. 1999 Dec;52(2 Suppl):35-40
references.pmid: 10630588
references.citation: Am J Clin Nutr. 2003 Sep;78(3):361-9
references.pmid: 12936916
references.citation: Nature. 2000 Apr 6;404(6778):635-43
references.pmid: 10766250
references.citation: Am J Physiol. 1990 May;258(5 Pt 1):E841-9
references.pmid: 2185665
references.citation: Science. 2002 Aug 2;297(5582):811
references.pmid: 12161648
references.citation: Cell Metab. 2008 Jul;8(1):49-64
references.pmid: 18590692
references.citation: Aging Cell. 2008 Jan;7(1):13-22
references.pmid: 17996009
references.citation: Cell. 2014 Jan 16;156(1-2):20-44
references.pmid: 24439368
references.citation: Diabetologia. 2013 May;56(5):949-64
references.pmid: 23443243
references.citation: Diabetes. 2013 Jul;62(7):2157-63
references.pmid: 23801714