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Downregulation of Electron Transport Chain Genes in Visceral Adipose Tissue in Type 2 Diabetes Independent of Obesity and Possibly Involving Tumor Necrosis Factor-

¹ Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
² Biovitrum, Stockholm, Sweden
³ Karolinska Institutet Danderyds Hospital, Stockholm, Sweden

Address correspondence and reprint requests to Prof. Peter Arner, MD, Department of Medicine, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}ki.se

Abbreviations: GABPA, GA-binding transcription factor -subunit; GABPB, GA-binding transcription factor ß-subunit; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSEA, gene set enrichment analysis; ESRRA, estrogen-related receptor-; HOMA_IR, homeostasis model assessment of insulin resistance; LRP10, LDL receptor–related protein 10; NRF1, nuclear respiratory factor 1; PGC1, peroxisome proliferator–activated receptor- coactivator 1; PPAR, peroxisome proliferator–activated receptor; SAM, significance analysis of microarrays; TNF, tumor necrosis factor

Impaired oxidative phosphorylation is suggested as a factor behind insulin resistance of skeletal muscle in type 2 diabetes. The role of oxidative phosphorylation in adipose tissue was elucidated from results of Affymetrix gene profiling in subcutaneous and visceral adipose tissue of eight nonobese healthy, eight obese healthy, and eight obese type 2 diabetic women. Downregulation of several genes in the electron transport chain was the most prominent finding in visceral fat of type 2 diabetic women independent of obesity, but the gene pattern was distinct from that previously reported in skeletal muscle in type 2 diabetes. A similar but much weaker effect was observed in subcutaneous fat. Tumor necrosis factor- (TNF-) is a major factor behind inflammation and insulin resistance in adipose tissue. TNF- treatment decreased mRNA expression of electron transport chain genes and also inhibited fatty acid oxidation when differentiated human preadipocytes were treated with the cytokine for 48 h. Thus, type 2 diabetes is associated with a tissue- and region-specific downregulation of oxidative phosphorylation genes that is independent of obesity and at least in part mediated by TNF-, suggesting that impaired oxidative phosphorylation of visceral adipose tissue has pathogenic importance for development of type 2 diabetes.

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