Gene expression in human adipose tissue. Studies of leptin and genes selected by expression profiling

Doctoral thesis, 2002

Obesity, and in particular the amount of visceral adipose tissue, is correlated to development of type 2diabetes and cardiovascular disease. The aim of this thesis was to study genes expressed in humanadipose tissue that could be involved in regional adipose tissue homeostasis and/or obesity-associateddisease.Leptin gene mutations with subsequent dysregulation of body energy homeostasis have been described inrodent models. To investigate whether similar defects occur in human obesity, the coding region of theleptin gene was analyzed by DNA sequencing in 94 obese human subjects. No mutations were detected,implying that leptin gene defects are rare in human obesity.To identify novel genes that could be involved in obesity and related diseases, a non-biased approach wasimplemented by analyzing gene expression profiles of human adipose tissue using DNA array andHU95A microarrays. This led to the identification of genes and gene families with high expression inhuman fat or differential expression in omental and subcutaneous adipose tissue. In this thesis I havefocused on three of them sulfonylurea receptor 2 (SUR2), the fibroblast growth factor (FGF) family andgenes of the complement system.Sulfonylureas, which are used in the management of type 2 diabetes, act by closing a receptor-channelcomplex, composed of sulfonylurea receptor (SUR) and inward rectifying potassium channel (Kir6.x)subunits, causing depolarization of the cell. Expression of SUR2B, Kir6.1 and a-endosulfine, but not ofSUR1, SUR2A or Kir6.2, was detected in human subcutaneous adipocytes. The expression of SUR2Bwas higher in subcutaneous compared to omental adipose tissue in obese men. There was no change inSUR2B expression during diet-induced weight loss in obese men.FGFs constitute a family of 22 polypeptide growth factors that are expressed in a variety of cell typesduring embryonic development and in adult tissues. The expression of FGF2, FGF7 and FGF10 wassimilar in paired biopsies of subcutaneous and omental adipose tissue from obese men. FGF1 and FGF9were expressed at higher levels in omental fat and immunohistochemistry showed staining for FGF1 andFGF9 in mesothelial cells in omental fat. The depot-differences in expression suggests that locallyexpressed FGFs could play a role in the regulation of regional adipose tissue mass.Comparison of the expression profiles of 12,000 genes in paired subcutaneous and omental adipose tissuebiopsies from six obese men revealed that three genes of the complement system, Factor B (7-fold), C4(17-fold) and C7 (10-fold), were expressed at higher levels in the omental depot. Other classical pathwaycomponents, C1QB, C1R, C1S, C2 and C3, were detected in both depots. Additionally, C2 and C3expression was higher in omental compared to subcutaneous fat.In summary, expression of novel genes in human adipose tissue was detected. Some of these genesare expressed at high levels in omental adipose tissue and may contribute to the metaboliccomplications observed in visceral obesity.