Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue.
In adipose tissue, insulin controls glucose and lipid metabolism through the intracellular mediators phosphatidylinositol 3-kinase and serine-threonine kinase AKT. Phosphatase and a tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, is hypothesized to inhibit the metabolic effects of insulin. Here we report the generation of mice lacking PTEN in adipose tissue. Loss of Pten results in improved systemic glucose tolerance and insulin sensitivity, associated with decreased fasting insulin levels, increased recruitment of the glucose transporter isoform 4 to the cell surface in adipose tissue, and decreased serum resistin levels. Mutant animals also exhibit increased insulin signaling and AMP kinase activity in the liver. Pten mutant mice are resistant to developing streptozotocin-induced diabetes. Adipose-specific Pten deletion, however, does not alter adiposity or plasma fatty acids. Our results demonstrate that in vivo PTEN is a potent negative regulator of insulin signaling and insulin sensitivity in adipose tissue. Furthermore, PTEN may be a promising target for nutritional and/or pharmacological interventions aimed at reversing insulin resistance.
Kurlawalla-Martinez
Christine
C
Department of Pediatrics, Division of Neonatology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Stiles
Bangyan
B
Wang
Ying
Y
Devaskar
Sherin U
SU
Kahn
Barbara B
BB
Wu
Hong
H
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000097:blood; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic / Q000097:blood / Q000378:metabolism*; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D009124:Muscle Proteins / Q000032:analysis / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010179:Pancreas / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D052243:Resistin; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D006729:Hormones, Ectopic; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D052243:Resistin; D025521:Tumor Suppressor Proteins; C499623:Retn protein, mouse; C495693:Slc2a4 protein, mouse
FEBS Lett. 2004 Jan 16;557(1-3):64-8
14741342
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2082-7
14769918
Science. 2004 Feb 20;303(5661):1195-8
14976316
Physiol Rev. 2004 Apr;84(2):623-47
15044684
Curr Pharm Des. 2004;10(10):1161-81
15078147
Science. 2004 May 28;304(5675):1325-8
15166380
J Clin Invest. 2004 Jul;114(2):224-31
15254589
Science. 1976 Jul 30;193(4251):415-7
180605
Nature. 1994 Nov 10;372(6502):182-6
7969452
Science. 1995 Jul 28;269(5223):540-3
7624776
Science. 1995 Jul 28;269(5223):543-6
7624777
J Clin Invest. 2000 Jan;105(2):199-205
10642598
J Biol Chem. 2000 Apr 28;275(17):12889-95
10777587
Int J Obes Relat Metab Disord. 2000 Jun;24(6):719-24
10878678
Anticancer Res. 2000 May-Jun;20(3B):1901-4
10928124
J Clin Invest. 2000 Aug;106(4):473-81
10953022
Hepatology. 2000 Oct;32(4 Pt 1):796-802
11003625
Nature. 2001 Jan 18;409(6818):307-12
11201732
Nature. 2001 Feb 8;409(6821):729-33
11217863
Nature. 2001 Jan 4;409(6816):92-7
11343120
Am J Physiol Endocrinol Metab. 2001 Jun;280(6):E827-47
11350765
Science. 2001 Jun 1;292(5522):1728-31
11387480
Cancer Res. 2001 Jun 1;61(11):4569-75
11389092
FEBS Lett. 2001 Jun 29;500(1-2):60-3
11434927
J Biol Chem. 2001 Jul 13;276(28):25651-3
11373275
Mol Endocrinol. 2001 Aug;15(8):1411-22
11463863
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5
11504907
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
11504908
Nat Genet. 1996 Jan;12(1):106-9
8528241
EMBO J. 1996 Apr 1;15(7):1542-7
8612577
J Pathol. 1996 Feb;178(2):176-81
8683386
Endocrinology. 1997 Apr;138(4):1604-11
9075721
FEBS Lett. 1997 Apr 7;406(1-2):211-5
9109420
Cancer Res. 1997 Jun 1;57(11):2124-9
9187108
Nat Med. 1997 Oct;3(10):1096-101
9334720
Nature. 1998 Feb 26;391(6670):900-4
9495343
J Biol Chem. 1998 May 29;273(22):13375-8
9593664
Science. 1999 Mar 5;283(5407):1544-8
10066179
N Engl J Med. 1999 Jul 22;341(4):248-57
10413738
Nat Med. 2004 Nov;10(11):1208-15
15489860
Horm Metab Res. 2004 Oct;36(10):662-6
15523589
Nature. 2001 Sep 13;413(6852):131-8
11557972
FEBS Lett. 2001 Oct 19;507(1):105-8
11682067
Biochem Biophys Res Commun. 2001 Nov 9;288(4):1011-7
11689011
Biochem Biophys Res Commun. 2001 Nov 9;288(4):1027-31
11689013
Trends Biochem Sci. 2001 Nov;26(11):657-64
11701324
Nat Genet. 2001 Dec;29(4):404-11
11726927
Science. 2001 Dec 7;294(5549):2186-9
11691952
Lancet. 2002 Jan 5;359(9300):46-7
11809189
Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E703-13
11832376
Genesis. 2002 Feb;32(2):148-9
11857804
Front Biosci. 2002 Apr 1;7:d903-7
11897556
Diabetes. 2002 Apr;51(4):1028-34
11916922
EMBO Rep. 2002 Apr;3(4):323-8
11943762
Mol Cell Biol. 2002 Jun;22(11):3842-51
11997518
Diabetes. 2002 Jun;51(6):1737-44
12031960
Science. 2002 May 31;296(5573):1655-7
12040186
J Clin Endocrinol Metab. 2002 Jun;87(6):2520-4
12050208
Dev Cell. 2002 Jul;3(1):25-38
12110165
J Clin Endocrinol Metab. 2002 Sep;87(9):4403-6
12213907
J Clin Endocrinol Metab. 2002 Sep;87(9):4407-10
12213908
Nat Med. 2002 Nov;8(11):1288-95
12368907
Biochem Biophys Res Commun. 2002 Nov 29;299(2):291-8
12437985
Diabetes. 2003 Jan;52(1):21-8
12502489
Cancer Res. 2003 Feb 1;63(3):674-81
12566313
J Clin Endocrinol Metab. 2003 Mar;88(3):1258-63
12629116
Am J Physiol Endocrinol Metab. 2003 May;284(5):E901-14
12540375
Nature. 2003 May 29;423(6939):550-5
12754525
Adv Enzyme Regul. 2003;43:15-28
12791379
Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E106-15
12618360
Diabetes. 2003 Jul;52(7):1611-8
12829623
J Clin Invest. 2003 Jul;112(2):197-208
12843127
J Biol Chem. 2003 Sep 5;278(36):33609-12
12788932
Cancer Cell. 2003 Sep;4(3):209-21
14522255
J Biol Chem. 2003 Nov 14;278(46):45209-15
12944409