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Activated Receptor Gamma and Retinoic Acid Receptor Alpha Gene Expression in Obese Human Adipose Tissue

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Activated Receptor Gamma and Retinoic Acid Receptor Alpha Gene Expression in Obese Human Adipose Tissue International Journal of Obesity (2002) 26, 920–927 ß 2002 Nature Publishing Group All rights reserved 0307–0565/02 $25.00 www.nature.com/ijo PAPER Relationship between peroxisome proliferator- activated receptor gamma and retinoic acid receptor alpha gene expression in obese human adipose tissue A Redonnet1, S Bonilla1, C Noe¨l-Suberville1, V Pallet1, H Dabadie2, H Gin2 and P Higueret1* 1Laboratoire de Nutrition et Signalisation Cellulaire (USC-INRA), ISTAB, Universite´ Bordeaux I, Talence, France; and 2Service de Nutrition-Diabe´tologie, Hoˆpital du Haut Le´veˆque, Pessac, France OBJECTIVE: To investigate in human adipose tissue a possible relationship between per oxisome proliferator-activated receptor gamma (PPARg) and retinoic acid receptor alpha (RARa) gene expression, two genes involved in the control of adipocyte differentiation. SUBJECTS: Ten lean control women (age 31 – 60 y, body mass index (BMI) 18 – 24.7 kg=m2) and an obese group of 15 women (age 27 – 62 y, BMI 30 – 57.5 kg=m2), of whom 10 subjects were in weight-gain phase and five were in weight-loss phase. MEASUREMENTS: We assessed the relative PPARg and RARa mRNA levels in subcutaneous abdominal adipose tissue using a real- time PCR method. RESULTS: PPARg mRNA level were significantly increased ( þ 91%; P < 0.01) in obese women compared to lean control women. In the obese group, we observed a PPARg mRNA level 42% lower in weight-loss obese than in weight-gain obese subjects. We obtained a positive correlation (r ¼ 0.56; P < 0.01) between PPARg mRNA level and the BMI of all subjects. Relative mRNA abundance level of RARa in subcutaneous adipose tissue of obese subjects is significantly lower than in control subjects ( 7 56%, P < 0.01), and a negative correlation was found between PPARg and RARa mRNA levels in subcutaneous adipose tissue of subjects study (r ¼ 7 0.75; P < 0.01). CONCLUSION: Our findings suggest that obesity is associated with an inverse relationship between PPARg and RARa expressions in human subcutaneous adipose tissue. Modulations of nuclear receptor profile could be an important event in the body’s early adaptive mechanisms promoting adipose tissue plasticity and leading to the onset of obesity. International Journal of Obesity (2002) 26, 920 – 927. doi:10.1038/sj.ijo.0802025 Keywords: obesity; human adipose tissue; PPARg; RAR; gene expression Introduction Among these factors, peroxisome proliferator-activated In humans, adipose tissue is dynamic with the lifelong receptor gamma (PPARg), a nuclear receptor which is highly potential for hyperplasia through preadipocyte replication expressed in adipose tissue, is known to be a dominant and differentiation, leading to the development of obesity. activator of fat cell differentiation. Furthermore, its expres- This process requires the continuous differentiation of new sion is induced very early in the adipocyte differentiation.4 adipocytes1 and involves a complex regulatory pathway con- Activated PPARg forms a heterodimer with retinoid X recep- trolled by the sequential and coordinate expression of spe- tors (RXRs) and binds to PPAR response elements occurring in cific regulatory genes and several transcription factors.2,3 the promoter region of adipose specific genes involved in adipose differentiation, lipid storage and metabolism.4 White adipose tissue (WAT) plays a key role in the storage *Correspondence: P Higueret, Laboratoire de Nutrition et Signalisation and metabolism of lipids and is known as a potential target Cellulaire, ISTAB, Universite´ Bordeaux I, avenue des Faculte´s, 33405 organ for retinoic acid (RA) action. Indeed, recent studies have Talence cedex, France. indicated that adipose tissue may play an important action in E-mail: [email protected] 5 Received 11 September 2001; revised 11 February 2002; retinoid uptake, storage, mobilization and transport. More- accepted 14 February 2002 over, RA receptors, RAR and RXR, which are known to mediate PPARg and RARa expression in human adipose tissue A Redonnet et al 921 the RA action, are expressed in adipose tissue.6 It has been was washed in cold saline and frozen in liquid nitrogen established that activation of RA receptors, and in particular and stored at 7 80C until analysis. the RARa isoform, is required for the inhibition of adipocyte differentiation.7,8 Furthermore, recent reports have suggested that convergence of the RA and PPAR signaling pathways Total RNA preparation regulates the fate of the cultured preadipocytes in acquisition About 60 mg (wet weight) of frozen tissue samples were of the adipocyte phenotype.8,9 directly homogenized in 1 ml TRIzol reagent (Invitrogen, Given the key role that RAR and PPAR play as master France) and total RNA was extracted following the manufac- regulator genes for differentiation and pro- or antiprolifera- turer’s suggested protocol for small quantities of tissue. tion in many tissues, increased understanding of these cri- Purified RNA was quantitated and assessed for purity by UV tical factors and how they are regulated will provide insights spectrophotometry. Average yield of total RNA was into adipose tissue development. To illustrate this purpose, it 7.2Æ 0.7 mg=100 mg of adipose tissue and was not signifi- is suggested that modulation of adipose tissue cellularity by cantly different in tissue from control and obese subjects. food intake involves a potential dysregulation of the genetic development program. We obtained evidence in a previous study in which we examined the effect of exposure to an Reverse transcription obesity-inducing diet on the pattern of expression of the cDNA was synthesized with Superscript II reverse transcrip- RAR, RXR, TR (triiodothyronine receptor) and PPAR nuclear tase (Invitrogen, France) according to the protocol recom- receptors in rat WAT. Thus, data obtained for WAT of rats fed mended by the manufacturer with minor modifications. on a fat-rich high-energy diet showed that a significantly Briefly, 1 mg of total RNA was incubated at 70C for 5 min decreased expression of RARa and TR was concomitant with and then placed on ice before addition of RT reaction an increased expression of PPARg.10 Since few human studies reagents with a specific reverse primer (120 ng) in a final have been performed, the present work was undertaken to volume of 20 ml. The RT reaction was performed at 42C for obtain an insight into possible modulation of the expression 60 min. Parallel reactions for each RNA samples were run in of these different nuclear receptors in adipose tissue of obese the absence of RT to assess the degree of any contaminating subjects. genomic DNA. Methods Analysis of gene expression using real-time PCR Subjects and tissues PCR was carried out using a LightCycler2 system (Roche This study included 25 unrelated white female subjects. We Diagnostics, Mannheim, Germany), which combines the studied 10 lean women (mean age 41.8Æ 3.4 y, body mass processes of amplification and detection (by fluorescence) index (BMI) 23.3Æ 2.8 kg=m2) and a group of 15 obese of a PCR product, enabling on-line and real-time detection. women (mean age 47.6Æ 2.3 y, BMI 40.9Æ 1.9 kg=m2). The For detection of target gene amplification products, Light- obese group was composed of 10 subjects in the weight-gain Cycler DNA Master SYBR Green I was used as described by phase (defined as weight gain 4% or more in body weight the manufacturer. PCR reactions were performed in micro- over the previous 6 months) and five subjects in the weight- capillary tubes in a final volume of 20 ml containing 1X LC- loss phase (defined as weight loss 4% or more in body DNA Master SYBR Green I mix, 4 mM of MgCl2, 0.5 mMof weight over the previous 6 months). These latter subjects each primer and 2 ml of cDNA. The amplification conditions received nutritional advice in a medical context and were were 95C for 8 min to activate the polymerase, followed by regularly followed. Dietary intake was assessed by food 45 cycles of denaturation at 95C for 6 s, annealing at 64C frequency. Among the 10 weight-gain obese patients, six for 6 s, and elongation at 72C for 10 s. After each elongation were impaired fasting glucose tolerant (IFGT). None of phase the fluorescence of SYBR Green I (a double-stranded them received insulin, thiazolidinedione or other hypogly- DNA binding dye) was measured and increasing amounts of cemic drugs. Moreover, no subject in the entire study was on PCR products can be monitored from cycle to cycle. The medications known to affect adipose tissue mass or lipopro- forward and reverse primer sequences are shown in Table 1. tein metabolism. All participants gave their written consent For each primer pair used, melting curve analysis showed a after being informed of the nature of the study. The experi- single melting peak after amplification, indicating specific mental protocol was approved by the Ethics Committee of product. the Bordeaux University Hospital and performed according Quantification data were analyzed using the LightCycler to French legislation (Huriet law). analysis software version 3.5 (Roche Diagnostics, Mannheim, After an overnight fast, blood was drawn and fasting Germany). In this analysis, the background fluorescence is serum insulin, glucose, triglycerides, cholesterol were mea- removed by setting a noise band. The log – linear portion of sured in blood samples. the standard amplification curve is identified and the cross- Abdominal subcutaneous adipose biopsies were taken ing point (Cp) is the intersection of the best-fit line through under local anesthesia by needle liposuction.
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