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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online November 20, 2003 as doi:10.1096/fj.03-0591fje. |
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,2
* Metabolic Research Laboratory;
Laboratory of Biotechnology; Departments of
Surgery,
Biochemistry, and
Endocrinology, Clínica Universitaria de Navarra; and
Laboratory of Proteomics, Genomics and Bioinformatics, Applied Medical Research Center,University of Navarra, Pamplona, Spain
2Correspondence: Department of Endocrinology, Clínica Universitaria de Navarra, 31008 Pamplona, Spain. E-mail: gfruhbeck{at}unav.es
SPECIFIC AIMS
The aim was to gain insight into the pathophysiology of obesity by comparing the pattern of gene expression of omental adipose tissue of obese and lean volunteers. Omental adipose tissue is more closely involved in the comorbidities associated with obesity than fat from the subcutaneous depot.
PRINCIPAL FINDINGS
Omental adipose tissue biopsies were obtained by laparoscopic surgery from six male patients (44.2±6.3 years). RNA was extracted and pooled for the normoglycemic, normotensive obese (BMI 37.3±2.5 kg/m2), and lean (BMI 23.4±0.8 kg/m2) groups, then hybridized to the HO1 Express ChipTM DNA Microarray System (Mergen Ltd.). Of 1152 well-characterized genes analyzed, 41% were expressed at sufficient levels in human adipose tissue for detection in the microarray experiments in addition to the 10% embodying housekeeping genes, duplicates, and negative controls. From the 153 genes with a >2.0-fold variation, 89 (8% of the total number) were up-regulated and 64 were down-regulated (Table 1
).
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1. The set of genes with altered expression in omental adipose tissue of obese humans represents a broad spectrum of biological processes
The majority of genes with altered expression encode proteins involved in cell proliferation, immune response, angiogenesis, metabolism, and signal transduction which have not been described to be involved in obesity.
2. Omental adipose tissue of obese humans exhibits an up-regulation of lipolysis repressor genes and a down-regulation of genes involved in lipolysis activation
Relevant genes involved in inhibition of the lipolytic rate such as neuropeptide Y (NPY) receptors Y1 (NPY1R) and Y5 (NPY5R) and adrenergic ß receptor kinase 2 (ADRBK2) showed increased mRNA expression in obese patients (Fig. 1
). Genes participating in the activation of lipolysis, such as natriuretic peptide receptor C (NPR3) and adrenergic ß-2 receptor (ADRB2), showed decreased mRNA expression.
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3. Omental adipose tissue from obese patients presents a decreased expression of growth factors and an increased expression of MAPKs
Expression of genes involved in preadipocyte proliferation and differentiation such as IGF1, FGF2, 4, and 7 was decreased. Several members of the mitogen-activated protein kinase (MAPK) cascade such as MAPK3, MAP3K4, MAPK9, and MAP2K6 exhibited increased expression.
4. Obesity alters the expression in omental adipose tissue of genes involved in angiogenesis
Of special interest were the changes observed in angiogenic factors. While vascular endothelial growth factor B (VEGFB) and fibroblast growth factor (FGF) 1 (FGF1) were up-regulated, c-fos-induced growth factor (vascular endothelial growth factor D) (FIGF) was down-regulated.
5. JAK2 expression is reduced in omental adipose tissue of obese humans
The mRNA abundance level of Janus kinase 2 (JAK2) was reduced in adipose tissue samples from obese patients vs. lean subjects.
6. Obesity alters the expression in omental adipose tissue of genes involved in immune function
Our study shows the up-regulation of receptors for Fc fragment of IgG in adipose tissue of obese patients.
7. Distribution of differentially expressed genes according to the chromosome to which they are mapped reveals an unspecific pattern
Chromosomes 1, 11, and 19 showed the highest number of genes with changed expression in omental adipose tissue from obese patients; chromosomes 8, 13, 18, 21, and 22 were those to which fewer changed genes were mapped.
CONCLUSIONS AND SIGNIFICANCE
Given the epidemic proportions reached by obesity worldwide, there is a need for better understanding of dysregulated genes, which may be involved in its development. A key factor in energy balance is mobilization of lipids through lipolysis in fat cells; alterations in this process have been associated with obesity. Our study shows decreased expression of ADRB2 and increased expression of ADRBK2, a protein involved in the desensitization of ß-adrenergic receptors. NPY, a neurotransmitter involved in food intake and body weight regulation, has been shown to be a powerful anti-lipolytic agent. Transcripts of the main receptors for NPY in body weight regulation (i.e., NPY1R and NPY5R) were readily detectable in our experiments in accordance with earlier reports. The expression of both genes was increased in adipose tissue samples of obese patients, suggesting an increased capacity of lipolysis inhibition that may contribute to obesity. The NPR3 is a receptor for the C-type natriuretic peptide (CNP) expressed in adipose tissue. Natriuretic peptides have been identified as a lipolytic pathway, with binding of CNP to its receptor exerting a lipolytic effect. The reduced mRNA expression of NPR3 detected in the present study is concordant with an impaired lipolytic activity in human obesity. These findings provide evidence for impaired lipolytic function in the obese subjects enrolled in our study that could either contribute to the development of obesity or represent an underlying mechanism of action of this disease.
Members of the FGF family showed decreased expression in obese patients indicating an attempt to decrease preadipocyte proliferation and adipocyte differentiation. Some MAP kinases were shown to be up-regulated, further supporting an inhibition of adipogenesis. This hypothesis is supported by studies reporting a decrease in the expression of genes normally involved in adipogenesis.
VEGFB and FGF1 induce vascularization by acting as endothelial cell growth factors. Obese patients had an increased expression of VEGF-B and FGF1 mRNA in omental adipose tissue, in accordance with the need for increased vascularization to support adipose mass enlargement.
Leptin signaling occurs mainly through activation of JAK2 and STAT3. JAK2 expression in adipose tissue of obese patients was decreased, which may be an indicator of leptin resistance, at least at the peripheral level.
Obese subjects have an impaired lymphocyte response, with decreased B and T cell function and low NK cell activity. Fc receptors are known to mediate antibody dependent inflammatory responses and cytotoxicity. Our data show that obese patients have an increased expression of a variety of Fc
receptors and that adipocytes express a wide variety of genes involved in the immune response; this reinforces the link between adipose tissue and immunity.
To our knowledge this is the first study performed with humans in which obesity-induced gene expression changes were globally analyzed in omental adipose tissue by microarrays. Our data show that adipose tissue of obese patients exhibits a different expression profile from that of lean individuals. The high number and ample spectrum of genes changed in adipose tissue of obese patients substantiate a dramatically different obese adipocyte (Fig. 2
). The complex and complementary nature of the expression profile observed in obese adipose tissue reflects a pleiad of adaptive changes affecting crucial physiological functions that may underlie the difficulties encountered by obese patients to lose weight. Our findings may have implications in identifying adequate molecular therapeutic targets.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0591fje 
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