Human adipose tissue. Genes predominantly expressed in the visceral depot and in hypertrophic adipocytes

Abstract

The obesity prevalence is increasing worldwide and obesity is closely linked to type 2 diabetes and cardiovascular disease. Both visceral fat accumulation and enlarged adipocyte size are risk factors for obesity related metabolic disorders. The aim of this thesis was therefore to detect genes, with higher expression in visceral versus subcutaneous adipose tissue, and in large versus small adipocytes, that potentially may contribute to metabolic disease related to obesity.DNA microarray was used to identify genes differentially expressed in human adipose tissue depots of obese subjects, and real-time PCR was used for verification and further investigation of selected genes. Complement (C2, C3, C4, C7, factor B) and immunoglobulin (Ig) (IGHG3, IGK@, IGL@) genes were higher expressed in omental compared to subcutaneous adipose tissue. Serum C3 and C4 levels correlated to measures of adiposity and analysis of tissue distribution showed that, in comparison with the omentum, only liver had higher expression of the classical complement components C2, C3 and C4. These results suggest that the complement system may be involved in metabolic complications associated with increased visceral fat mass. The density of Ig producing plasma cells was twice as high in omental compared to subcutaneous adipose tissue analyzed by immunohistochemistry. Fc receptors (FcgammaRII) were present on adipocyte membranes and the Fc moiety of IgG reduced adipocyte interleukin expression and stimulated lipogenesis in vitro, indicating that Ig have anti-inflammatory and lipid accumulating effects in human adipose tissue.Serum amyloid A (SAA) and NAD(P)H:quinone oxidoreductase 1 (NQO1) were identified as predominantly expressed in omental adipocytes when compared to expression profiles from 32 other human tissues and cell types. Adipose tissue expression and serum levels of the acute-phase protein SAA were down regulated in obese subjects during diet induced weight loss, and serum levels of SAA correlated to measures of adiposity and insulin levels during the diet. Liver displayed the second highest SAA expression indicating that adipose tissue is a major expression site for SAA during nonacute-phase. The NQO1 expression also decreased during weight loss and correlated to measures of adiposity, insulin, AST and ALT.A technique to separate human adipocytes from an adipose tissue sample into populations of small and large cells was developed and the expression profiles of the populations were compared. Fourteen genes, of which five immune-related (E-selectin, IL-8, SAA, C1q receptor 1, MIP-2), were markedly higher expressed in large versus small cells. SAA was 19-fold higher expressed in large adipocytes and the expression correlated to adipocyte size.Many immune-related genes (complement, Ig, SAA) and NQO1, implicated in oxidative stress, are highly expressed in human visceral adipose tissue and large subcutaneous adipocytes. These genes may link visceral and hypertrophic obesity to metabolic disorders. The results support the suggested connection between obesity and inflammation.