Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI.
OBJECTIVE
To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic, insulin-resistant individuals compared with insulin-sensitive individuals matched for BMI.


METHODS
A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity (31 insulin-resistant and 31 insulin-sensitive subjects; 40 were European American and 22 were African American) and matched for age and obesity measures. Global gene expression profiles were determined and compared between ethnic groups and between insulin-resistant and insulin-sensitive participants individually and using gene-set enrichment analysis.


RESULTS
African American and European American subjects differed in 58 muscle and 140 adipose genes, including many inflammatory and metabolically important genes. Peroxisome proliferator-activated receptor γ cofactor 1A (PPARGC1A) was 1.75-fold reduced with insulin resistance in muscle, and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated. Unexpected categories included ubiquitination, citrullination, and protein degradation. In adipose, highly represented categories included lipid and fatty acid metabolism, insulin action, and cell-cycle regulation. Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene-set enrichment analysis. FADS1, VEGFA, PTPN3, KLF15, PER3, STEAP4, and AGTR1 were among genes expressed differentially in both adipose and muscle.


CONCLUSIONS
Adipose tissue gene expression showed more differences between insulin-resistant versus insulin-sensitive groups than the expression of genes in muscle. We confirm the role of PPARGC1A in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues.
Section on Endocrinology and Metabolism, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Steven C
SC
Elbein
Philip A
PA
Kern
Neda
N
Rasouli
Aiwei
A
Yao-Borengasser
Neeraj K
NK
Sharma
Swapan K
SK
Das
D000328:Adult; D001823:Body Composition / Q000235:genetics; D015992:Body Mass Index; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism*
D000090943:Delta-5 Fatty Acid Desaturase; D007328:Insulin; D047495:PPAR gamma; C000716847:FADS1 protein, human; D005947:Glucose
Diabetes. 2009 Mar;58(3):600-8
19074983
Diabetes. 2008 Feb;57(2):432-9
18057090
Nature. 2008 Aug 21;454(7207):1000-4
18719589
Diabetes. 2009 Aug;58(8):1780-8
19509023
Diabetologia. 2008 Nov;51(11):2068-77
18719883
Biochem Biophys Res Commun. 2004 May 14;317(4):1045-51
15094374
J Lipid Res. 2008 Feb;49(2):308-23
17986714
Diabetes. 2007 Sep;56(9):2349-55
17563058
Obesity (Silver Spring). 2009 Feb;17(2):276-82
19039315
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
11309499
Nat Genet. 2009 Oct;41(10):1110-5
19734900
Nature. 2008 Mar 27;452(7186):423-8
18344981
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18745-50
19841271
Diabetologia. 2009 Oct;52(10):2169-81
19633828
Nat Genet. 2010 Feb;42(2):137-41
20037589
Am J Physiol Endocrinol Metab. 2009 Jun;296(6):E1300-10
19336660
Nat Protoc. 2009;4(1):44-57
19131956
PLoS One. 2009 Dec 09;4(12):e8183
20016837
Diabetes. 2008 Oct;57(10):2595-602
18633101
Nat Genet. 2008 May;40(5):638-45
18372903
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8466-71
12832613
J Biol Chem. 2007 May 25;282(21):15439-50
17416903
J Clin Endocrinol Metab. 2008 Jun;93(6):2249-54
18381574
PLoS One. 2009 Aug 11;4(8):e6575
19668377
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3545-50
18296638
J Clin Invest. 2005 Dec;115(12):3587-93
16284649
J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S64-73
18987272
Diabetes. 2009 Aug;58(8):1757-65
19478146
PLoS Med. 2007 May;4(5):e158
17472435
J Clin Endocrinol Metab. 1987 Jun;64(6):1169-73
3553221
Nat Genet. 2010 Feb;42(2):105-16
20081858
Appl Physiol Nutr Metab. 2007 Oct;32(5):874-83
18059612
J Clin Endocrinol Metab. 2010 Sep;95(9):4441-8
20591983
Obesity (Silver Spring). 2010 Sep;18(9):1781-7
20379148
Nat Genet. 2003 Jul;34(3):267-73
12808457
Neuroendocrinology. 2009;90(4):383-90
19672057
Mol Cell Biol. 2008 Jun;28(12):3967-78
18391014
Nature. 2006 Apr 13;440(7086):944-8
16612386
Curr Diab Rep. 2008 Jun;8(3):173-8
18625112
Diabetologia. 2008 Feb;51(2):328-35
18030445
Diabetes. 2006 Oct;55(10):2811-8
17003347
Obesity (Silver Spring). 2008 Jul;16(7):1493-500
18483477
Genome Biol. 2007;8(9):R183
17784955
J Clin Endocrinol Metab. 2008 Nov;93(11):4532-41
18728164
Cell Mol Life Sci. 2007 May;64(9):1145-57
17437057
Curr Opin Lipidol. 2008 Jun;19(3):248-56
18460915
Curr Opin Lipidol. 2010 Feb;21(1):38-43
19915462
Public Health Nutr. 2007 Oct;10(10A):1132-7
17903321
Nat Genet. 2007 Jun;39(6):770-5
17460697
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5
15100410
J Clin Endocrinol Metab. 2007 Dec;92(12):4656-63
17878257
BMC Bioinformatics. 2008 Dec 22;9:552
19099609
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W186-92
17526521
Nature. 2001 Jan 18;409(6818):307-12
11201732