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Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: distinct expression of cell-cycle- and differentiation-related genes.

ABSTRACT: BACKGROUND: Obesity results from an imbalance between food intake and energy expenditure, which leads to an excess of adipose tissue. The excess of adipose tissue and adipocyte dysfunction associated with obesity are linked to the abnormal regulation of adipogenesis. The objective of this study was to analyze the expression profile of cell-cycle- and lipid-metabolism-related genes of adipose tissue in morbid obesity. METHODS: We used a custom-made focused cDNA microarray to determine the adipose tissue mRNA expression profile. Gene expression of subcutaneous abdominal fat samples from 15 morbidly obese women was compared with subcutaneous fat samples from 10 nonobese control patients. The findings were validated in an independent population of 31 obese women and 9 obese men and in an animal model of obesity (Lepob/ob mice) by real-time RT-PCR. RESULTS: Microarray analysis revealed that transcription factors that regulate the first stages of adipocyte differentiation, such as CCAAT/enhancer binding protein beta (C/EBP?) and JUN, were upregulated in the adipose tissues of morbidly obese patients. The expression of peroxisome proliferator-activated receptor gamma (PPAR?), a transcription factor which controls lipid metabolism and the final steps of preadipocyte conversion into mature adipocytes, was downregulated. The expression of three cyclin-dependent kinase inhibitors that regulate clonal expansion and postmitotic growth arrest during adipocyte differentiation was also altered in obese subjects: p18 and p27 were downregulated, and p21 was upregulated. Angiopoietin-like 4 (ANGPTL4), which regulates angiogenesis, lipid and glucose metabolism and it is know to increase dramatically in the early stages of adipocyte differentiation, was upregulated. The expression of C/EBP?, p18, p21, JUN, and ANGPTL4 presented similar alterations in subcutaneous adipose tissue of Lepob/ob mice. CONCLUSIONS: Our microarray gene profiling study revealed that the expression of genes involved in adipogenesis is profoundly altered in the subcutaneous adipose tissue of morbidly obese subjects. This expression pattern is consistent with an immature adipocyte phenotype that could reflect the expansion of the adipose tissue during obesity.

SUBMITTER: Rodriguez-Acebes S

PROVIDER: S-EPMC3022546 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: distinct expression of cell-cycle- and differentiation-related genes.

Rodríguez-Acebes Sara S Palacios Nuria N Botella-Carretero José I JI Olea Nuria N Crespo Lorena L Peromingo Roberto R Gómez-Coronado Diego D Lasunción Miguel A MA Vázquez Clotilde C Martínez-Botas Javier J

BMC medical genomics 20101223

<h4>Background</h4>Obesity results from an imbalance between food intake and energy expenditure, which leads to an excess of adipose tissue. The excess of adipose tissue and adipocyte dysfunction associated with obesity are linked to the abnormal regulation of adipogenesis. The objective of this study was to analyze the expression profile of cell-cycle- and lipid-metabolism-related genes of adipose tissue in morbid obesity.<h4>Methods</h4>We used a custom-made focused cDNA microarray to determin ...[more]

PMID: 21182758

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Project description:BackgroundMicroRNAs are emerging as new mediators in the regulation of adipocyte physiology and have been approved to play a role in obesity. Despite several studies have focused on microRNA expression profiles and functions in different metabolic tissues, little is known about their response to nutritional interventions in white adipose tissue during obesity stages, and whether they differ in this response to weight-reduction strategy is poorly understood. Our objectives were to study the dysregulation of some miRNAs in subcutaneous inguinal white adipose tissue during weight change, expansion/reduction; in response to both a high-fat diet and switching to a normal diet feeding, and to evaluate them as potential biomarkers and therapeutic targets for early obesity management METHOD: A hundred 6-week-old male Wister rats were randomly divided into a normal diet group (N.D), a high-fat diet group (H.F.D), and a switched to a normal diet group (H.F.D/N.D). At the beginning and at intervals 2 weeks, serum lipid, hormone levels, total body fat mass, and inguinal subcutaneous white adipose tissue mass (WAT) measurements were recorded using dual-energy X-ray absorptiometry (DEXA). The expression levels of microRNAs were evaluated using real-time PCR.ResultsSignificant alterations were observed in serum glucose, lipid profile, and adipokine hormones during the early stages of obesity development. Alteration in rno-mir 30a-5p, rno-mir 133a-5p, and rno-mir 107-5p expression levels were observed at more than one time point. While rno-let-7a-5p, rno-mir 193a-5p, and rno-mir125a-5p were downregulated and rno-mir130a-5p was upregulated at all time points within 2 to 4 weeks in response to H.F.D feeding for 10 weeks. The impact of switching to normal diet has a reversed effect on lipid profile, adipokine hormone levels, and some miRNAs. The bioinformatics results have identified a novel and important pathway related to inflammatory signalling.ConclusionOur research demonstrated significant alterations in some adipocyte-expressed miRNAs after a short time of high caloric diet consumption. This provides further evidence of the significant role of nutrition as an epigenetic factor in regulation of lipid and glucose metabolism genes by modulating of related key miRNAs. Therefore, we suggest that miRNAs could be used as biomarkers for adiposity during diet-induced obesity. Perhaps limitation in calories intake is a way to manipulate obesity and associated metabolic disorders. Further studies are needed to fully elucidate the role of microRNAs in the development of obesity.

Project description:Two types of adipose tissues, white (WAT) and brown (BAT) are found in mammals. Increasingly novel strategies are being proposed for the treatment of obesity and its associated complications by altering amount and/or activity of BAT using mouse models.The present study was designed to: (a) investigate the differential expression of genes in LACA mice subcutaneous WAT (sWAT) and BAT using mouse DNA microarray, (b) to compare mouse differential gene expression with previously published human data; to understand any inter- species differences between the two and (c) to make a comparative assessment with C57BL/6 mouse strain. In mouse microarray studies, over 7003, 1176 and 401 probe sets showed more than two-fold, five-fold and ten-fold change respectively in differential expression between murine BAT and WAT. Microarray data was validated using quantitative RT-PCR of key genes showing high expression in BAT (Fabp3, Ucp1, Slc27a1) and sWAT (Ms4a1, H2-Ob, Bank1) or showing relatively low expression in BAT (Pgk1, Cox6b1) and sWAT (Slc20a1, Cd74). Multi-omic pathway analysis was employed to understand possible links between the organisms. When murine two fold data was compared with published human BAT and sWAT data, 90 genes showed parallel differential expression in both mouse and human. Out of these 90 genes, 46 showed same pattern of differential expression whereas the pattern was opposite for the remaining 44 genes. Based on our microarray results and its comparison with human data, we were able to identify genes (targets) (a) which can be studied in mouse model systems to extrapolate results to human (b) where caution should be exercised before extrapolation of murine data to human.Our study provides evidence for inter species (mouse vs human) differences in differential gene expression between sWAT and BAT. Critical understanding of this data may help in development of novel ways to engineer one form of adipose tissue to another using murine model with focus on human.

Dataset Information

Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: distinct expression of cell-cycle- and differentiation-related genes.

Publications

Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: distinct expression of cell-cycle- and differentiation-related genes.

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