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Originally published In Press as doi:10.1194/jlr.M700199-JLR200 on November 6, 2007

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Journal of Lipid Research, Vol. 49, 308-323, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissueboxs

R. MacLaren*,{dagger}, W. Cui*,{dagger}, S. Simard{dagger} and K. Cianflone1,*,{dagger}

* Experimental Medicine, McGill University Health Centre, Montreal, Canada
{dagger} Centre de Recherche Hôpital Laval, Laval University, Quebec, Canada

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables.

Published, JLR Papers in Press, November 6, 2007.

1 To whom correspondence should be addressed. e-mail: katherine.cianflone{at}crhl.ulaval.ca

Obesity and insulin resistance are independent risk factors for metabolic syndrome, diabetes, and cardiovascular disease. Adipose tissue samples from nonobese (NO), insulin-sensitive obese (ISO), and insulin-resistant obese (IRO) subjects from subcutaneous (SC) and omental (OM) adipose tissue (n = 28) were analyzed by microarray and confirmed by real-time PCR. Insulin signaling gene expression changes were greater in OM than in SC tissue and were related to insulin resistance rather than to obesity; few genes correlated with body mass index. Insulin receptor and insulin receptor substrate 1 (IRS-1) increased in the IRO versus pooled insulin-sensitive (NO+ISO) subjects. In glucose transport, PI3K{alpha} and PDK2 decreased in IRO subjects, whereas PI3K{gamma}, Akt2, GLUT4, and GLUT1 increased. IRS-1 regulators Jnk and IKK increased in IRO (P < 0.01 and P < 0.001 respectively). In protein synthesis, most genes examined were downregulated in IRO subjects, including mTor, Rheb, and 4EBP and eIF members (all P < 0.05). In proliferation, SHC, SOS, and Raf1 (P < 0.05) were increased, whereas Ras and MEK1/2 kinase 1 (P < 0.05) were decreased, in IRO subjects. Finally, in differentiation, PPAR{gamma}, CEBP{alpha}, and CEBPβ decreased, whereas PPAR{delta}, CEBP{gamma}, and CEBP{epsilon} increased, in IRO subjects (P < 0.05). Together, microarray and real-time PCR data demonstrate that insulin resistance rather than obesity is associated with altered gene expression of insulin signaling genes, especially in OM adipose tissue.

Supplementary key words differentiation • glucose • proliferation • protein synthesis • insulin-sensitive obese • insulin-resistant obese

Abbreviations: BMI, body mass index; cRNA, complimentary RNA; FDR, false discovery rate; HOMA-IR, homeostasis model assessment insulin resistance; InsR, insulin receptor; IRO, insulin-resistant obese; IRS-1, insulin receptor substrate 1; ISO, insulin-sensitive obese; NIDDM, non-insulin-dependent diabetes mellitus; NO, nonobese; OM, omental; SAM, Significant Analysis of Microarrays; SC, subcutaneous


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