This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gummesson, A. Articles by Carlsson, L. M. S. Search for Related Content PubMed PubMed Citation Articles by Gummesson, A. Articles by Carlsson, L. M. S. Related Collections Metabolism Obesity

Relations of Adipose Tissue CIDEA Gene Expression to Basal Metabolic Rate, Energy Restriction, and Obesity: Population-Based and Dietary Intervention Studies

Department of Molecular and Clinical Medicine (A.G., M.J., P.-A.S., C.A.M.G., E.S., L.G., K.S., T.C.L., L.S., B.C., L.M.S.C.), and Wallenberg Laboratory for Cardiovascular Research (A.G., B.F.), Institute of Medicine, the Sahlgrenska Academy, Göteborg University, SE-413 45 Göteborg, Sweden; Department of Body Composition and Metabolism (I.L.), Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden; and Department of Discovery Medicine (T.C.L., B.C.), AstraZeneca Research and Development, SE-431 83 Mölndal, Sweden

Address all correspondence and requests for reprints to: Anders Gummesson, Vita Stråket 15, SE-413 45 Göteborg, Sweden. E-mail: anders.gummesson{at}gu.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Cell death-inducing DNA fragmentation factor--like effector A (CIDEA) could be a potential target for the treatment of obesity via the modulation of metabolic rate, based on the findings that CIDEA inhibits the brown adipose tissue uncoupling process in rodents.

Objectives: Our objects were to investigate the putative link between CIDEA and basal metabolic rate in humans and to elucidate further the role of CIDEA in human obesity.

Design: We have explored CIDEA gene expression in adipose tissue in two different human studies: a cross-sectional and population-based study assessing body composition and metabolic rate (Mölndal Metabolic study, n = 92); and a longitudinal intervention study of obese subjects treated with a very low calorie diet (VLCD) (VLCD study, n = 24).

Results: The CIDEA gene was predominantly expressed in adipocytes as compared with other human tissues. CIDEA gene expression in adipose tissue was inversely associated with basal metabolic rate independently of body composition, age, and gender (P = 0.014). The VLCD induced an increase in adipose tissue CIDEA expression (P < 0.0001) with a subsequent decrease in response to refeeding (P < 0.0001). Reduced CIDEA gene expression was associated with a high body fat content (P < 0.0001) and high insulin levels (P < 0.01). No dysregulation of CIDEA expression was observed in individuals with the metabolic syndrome when compared with body mass index-matched controls. In a separate sample of VLCD-treated subjects (n = 10), uncoupling protein 1 expression was reduced during diet (P = 0.0026) and inversely associated with CIDEA expression (P = 0.0014).

Conclusion: The findings are consistent with the concept that CIDEA plays a role in adipose tissue energy expenditure.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE ADIPOSE TISSUE mass in a given individual is mainly determined by the balance between energy intake and energy expenditure, and obesity results when this balance is disrupted. Two types of adipose tissue exist in mammals: white adipose tissue and brown adipose tissue. Brown adipose tissue is present throughout the life in rodents but nearly disappears soon after birth in humans. In rodents, brown adipose tissue plays an important role in heat generation and in that capacity, also has substantial effects on energy balance. Uncoupling protein 1 (UCP1) is a key gene in brown adipose tissue that plays a critical role by uncoupling ATP production from the proton gradient in the mitochondria, thereby converting chemical energy to heat (1). UCP1 is expressed at much lower levels in white compared with brown adipose tissue, but its induction has had an effect on energy expenditure in both rodent and human white adipocytes (2, 3). Cell death-inducing DNA fragmentation factor--like effector A (CIDEA), initially identified as an apoptotic gene (4), was recently discovered to interfere with the uncoupling process. CIDEA-deficient mice are resistant to diet-induced obesity and diabetes. Their lean phenotype seems to be due to a loss of CIDEA inhibition of UCP1 in brown adipose tissue, thereby increasing energy expenditure through a higher metabolic rate (5). The possibility that CIDEA is involved also in human obesity was supported by the finding that the CIDEA gene V115F polymorphism was associated with body mass index (BMI) in a Swedish population (6). However, there are some striking discrepancies between human and rodent CIDEA expression patterns. Rodents display a high expression of CIDEA in brown adipose tissue, whereas CIDEA expression is undetectable in the white adipose tissue (7, 8). In contrast, CIDEA is highly expressed in human white adipose tissue (8, 9). Although the absence of CIDEA in mice protects against diet-induced obesity and diabetes, low CIDEA expression in humans is associated with the opposite phenotype: obesity and features of the metabolic syndrome (8).

Hence, CIDEA functions as an inhibitor of adipose tissue energy expenditure in rodents, but it is unclear whether these findings can be translated into human adipose tissue physiology. Modulation of basal metabolic rate (BMR) in adipose tissue could be an attractive strategy for the treatment of obesity. The present study aims to investigate the putative link between CIDEA and BMR in humans, and to elucidate further the role of CIDEA in human obesity.

For this purpose, we have compared CIDEA expression in human adipocytes with other human tissues, and explored CIDEA gene expression patterns in the cross-sectional and population-based Mölndal Metabolic study and in a longitudinal intervention study involving obese subjects treated with a very low calorie diet (VLCD) (VLCD study).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All study subjects received written and oral information before giving written informed consent. The studies were approved by the regional ethical review board at Göteborg University. All examinations took place at the Obesity Unit at the Sahlgrenska University Hospital.

The Mölndal Metabolic study

The Mölndal Metabolic study aims to elucidate the relation between body composition, energy expenditure, dietary intake, and risk factors for diabetes and cardiovascular disease in two age groups of 50 men and 50 women. Participants were recruited from a population-based sample of inhabitants in the city of Mölndal in Western Sweden, aged either 27–31 or 57–61 yr. Examinations included anthropometry, blood pressure recording, blood sampling, oral glucose tolerance test (OGTT), dual-energy x-ray absorptiometry (DEXA), abdominal sc adipose tissue biopsy, and measurement of BMR in a chamber of indirect calorimetry.

The VLCD study

The VLCD study aims to identify gene expression changes in adipose tissue of obese subjects undergoing weight loss from caloric restriction. As previously described (10, 11, 12), a total of 40 obese (BMI > 30) males and females 25–61 yr of age was included in the study: 21 subjects meeting the criteria for metabolic syndrome before study entry (MetS+ group), and 19 subjects that did not meet the criteria for metabolic syndrome (MetS– group). Diagnosis of metabolic syndrome was based on modified World Health Organization criteria (13): diabetes type 2 or impaired glucose tolerance as measured by OGTT, lipid disturbance [triglycerides (TGs) > 1.7 mmol/liter or high-density lipoprotein (HDL) < 0.9 mmol/liter in men and HDL < 1.0 mmol/liter in women], and hypertension (blood pressure > 140/90 mm Hg). All subjects in the MetS+ group had metabolic syndrome also according to International Diabetes Federation and National Cholesterol Education Program criteria. Smokers and those with pharmacological diabetes treatment or lipid lowering medication were excluded. The MetS+ and MetS– groups were matched according to age, gender, and BMI. All subjects were treated with a VLCD (450 kcal/d) for 16 wk, followed by a 2-wk period when regular food was gradually reintroduced. Study assessments were performed at the start of VLCD treatment (wk 0), twice during the VLCD phase (wk 8 and 16), and 2 wk after the end of VLCD treatment (wk 18). Anthropometrical measurements, blood pressure recording, blood sampling, OGTT, and abdominal sc adipose tissue biopsy were performed at each of the four time points.

Measurements

All measurements and samplings were performed after an overnight fast. Anthropometric measurements were performed with the subject dressed in underwear, using calibrated scales. Blood chemistry analyses of glucose, insulin, TGs, HDL, and highly sensitive C-reactive protein (hs-CRP) were performed at the Department of Clinical Chemistry, Sahlgrenska University Hospital (accredited according to the international standard International Organization for Standardization/International Electrotechnical Commission 17025). Glucose was measured in plasma in the VLCD study, and in blood in the Mölndal Metabolic study. The OGTT was performed by measuring blood/plasma glucose 120 min after oral intake of a solution containing 75 g sugar and 300 ml water. Body composition assessed by DEXA was performed with LUNAR DPX-L (Scanexport Medical, Helsingborg, Sweden) as previously described (14). The DEXA examination generates a three-compartment model consisting of body fat (BF), lean tissue mass (LTM), and bone mineral content (BMC). The fat-free mass (FFM) was calculated as LTM + BMC. BMR was assessed in standardized conditions in each subject after an overnight stay in a chamber of indirect calorimetry (15). The temperature in the chamber was 25 C, and humidity was 40%. The subject was awakened at 0730 h and instructed to lay still in complete silence in the bed, awake and relaxed with arms and legs stretched along the body during the next 60 min. Before analyzing the collected data of each subject, the first and last 15 min were withdrawn. The BMR from the remaining 30 min was extrapolated to 24-h values.

Samples and RNA preparation

Abdominal sc adipose tissue biopsies were obtained in local anesthesia with needle aspirations and stored at –80 C until analysis. In the Mölndal Metabolic study, a sufficient amount of adipose tissue was available from 92 subjects. In the VLCD study, complete series of adipose tissue biopsies large enough for microarray analysis were available from 24 subjects: nine males and three females in each of the two groups (MetS+ and MetS–). Subcutaneous adipose tissue samples were also obtained from 10 additional VLCD-treated subjects: five males and five females (age 27–57 yr). Large sc adipocytes were isolated as previously described (16). For the microarray-based tissue distribution profiling, we used adipose tissue and isolated adipocytes from three subjects: two males and one female (age 37–50 yr, with BMI 23.9–28.2). Adipose tissue and isolated adipocytes from an additional five healthy volunteers (females, age 30–60 yr, with BMI 23.0–27.6), together with RNA from the Human Total RNA Master Panel II (Clontech, Palo Alto, CA), were used for verification of tissue distribution with real-time PCR. Total RNA was prepared with the RNeasy lipid tissue kit (QIAGEN, Chatsworth, CA), or using the phenol-chloroform extraction method of Chomczynski and Sacchi (17) with further purification with RNeasy clean-up columns. The RNA concentration was measured spectrophotometrically, and the A260/A280 ratio was 1.8–2.0. The quality of the RNA was verified by agarose gel electrophoresis before RT into cDNA.

Microarray analysis

RNA from the adipose tissue biopsies in the VLCD study and from isolated adipocytes was used for gene expression analysis with the Human Genome U133A DNA microarray (Affymetrix, Santa Clara, CA). Preparation of cRNA and hybridization to DNA microarrays was performed according to standard Affymetrix protocols, as previously described (16, 18). The hybridization and analysis were performed according to the Minimum Information about a Microarray Experiment guideline (19). Expression profiles of isolated large adipocytes were compared with the U133A expression profiles of 67 human tissues and cell types obtained from the SymAtlas data set [http://symatlas.gnf.org/SymAtlas/ (20)]. Using the same algorithms as previously described (10, 21), expression profiles from the adipocyte samples were analyzed using the MAS5 software (Affymetrix), and an adipocyte expression profile was calculated as average signal values of the three samples. To allow comparison between tissues, each tissue-specific profile was normalized by dividing with its average value.

Real-time PCR analysis

Based on our previous reports (16, 22), human low-density lipoprotein receptor-related protein 10 (LRP10) was used as reference to normalize the expression levels between adipose tissue samples, and peptidyl-prolyl isomerase A (PPIA) was used as reference in the tissue distribution panel. RNA samples were reverse transcribed using the High Capacity cDNA Reverse Transcription kit (Applied Biosystems, Foster City, CA). Reagents for real-time PCR analysis of CIDEA, UCP1, LRP10, and PPIA were supplied by Applied Biosystems. cDNA corresponding to 10 ng RNA per reaction was used for real-time PCR amplification, except for UCP1 reactions in which we used cDNA corresponding to 400 ng RNA. Specific products were amplified and detected with the ABI Prism 7900HT Sequence Detection System (Applied Biosystems) using default cycle parameters. All standards and samples were analyzed in triplicate.

Statistics

Values are given as mean ± SD unless otherwise indicated. Skewed variables were log transformed before statistical analyses. In the Mölndal Metabolic study, Pearson correlations were calculated, and multivariate linear regression analysis was performed. In the VLCD study, relationships between CIDEA gene expression and clinical measurements for individual time points were analyzed as Spearman correlations. The within-person dependence of observations over time during VLCD treatment invalidates the use of standard Pearson or Spearman correlations. Instead, correlation of within-person longitudinal measurements was addressed with the use of generalized estimating equations (23). Tests of parameters within these models were performed with generalized Wald tests (24), which yielded standard Z statistics. The Wilcoxon signed ranks test was used to test differences in CIDEA expression between time points, and the Mann-Whitney U test was used to test differences in CIDEA expression between genders and between the MetS+ and MetS– groups. In the 10 additional VLCD-treated subjects, an exact binomial test was used to assess regulation of CIDEA and UCP1 expression from baseline. A P value less than 0.05 (two-sided) was considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CIDEA is predominantly expressed in human adipocytes

The expression of CIDEA was compared between human adipocytes and 67 other human cell types and tissues using microarray expression levels. This showed that the expression of CIDEA was at least 12-fold higher in isolated adipocytes compared with all the other tissues and cell types. Figure 1A illustrates the tissue panel obtained from microarray data, presenting a selection of the other human tissues, including the ones with the highest CIDEA expression. CIDEA expression was also analyzed in additional subjects using real-time PCR in isolated adipocytes (n = 3) and adipose tissue (n = 3), and was compared with CIDEA expression in 16 other human tissues. The resulting tissue distribution showed that CIDEA mRNA levels were 15- to 2500-fold higher in adipocytes compared with the other human tissues (Fig. 1B).

View larger version (10K): [in this window] [in a new window]   FIG. 1. CIDEA mRNA tissue distribution. A, Results from DNA microarrays presenting a selection of the 67 tissues that were used for the analysis, including the ones with the highest CIDEA expression. B, Results from validation of CIDEA gene expression with real-time PCR of isolated adipocytes (n = 3), adipose tissue (n = 3) (mean ± SEM), and a human tissue panel.

The characteristics of the subjects participating in the Mölndal Metabolic and VLCD studies are presented in Table 1. Correlations between clinical measurements and CIDEA expression in adipose tissue are shown in Table 2. BF was the body composition variable that showed the strongest association with CIDEA adipose tissue mRNA levels (r = –0.65; P < 0.0001), and neither LTM nor BMC was associated with CIDEA expression. A higher level of CIDEA expression was observed in the young subjects compared with the old (1.4-fold difference between age groups; P = 0.003), but this difference did not remain significant (P = 0.13) after adjustment for DEXA body composition measurements. In the obese subjects in the VLCD study, there was a negative association between CIDEA adipose tissue expression and all measurements of adiposity: BMI, waist, and waist-to-hip ratio (WHR) (Table 2). No differences in CIDEA expression levels were observed between men and women in either of the two study populations.

Of the 92 subjects in the Mölndal Metabolic study that had been analyzed for CIDEA gene expression, BMR measurements had been performed in 88. Among these subjects, the mean value of the BMR measurement was 1411 ± 278 kcal/24 h. As expected, the FFM was strongly associated with BMR (r = 0.72; P < 0.0001), whereas the association between BF and BMR was weaker (r = 0.22; P = 0.038). CIDEA gene expression showed a significant negative correlation with the BMR measurement (r = –0.22; P = 0.042). Due to the strong influence of FFM on the BMR measurement, and of BF on CIDEA expression, the analysis was performed with adjustment for these body composition variables. In a linear regression model, CIDEA expression and BMR remained significantly associated after adjustment for BF and FFM (estimated slope for BMR = –0.20; P = 0.032), and after additional adjustment for age and gender (estimated slope for BMR = –0.23; P = 0.014).

CIDEA and UCP1 gene expression during caloric restriction and weight loss

In the VLCD study, there was a strong induction of the CIDEA gene after 8 wk (1.9-fold increase from wk 0; P < 0.0001) and 16 wk (2.4-fold increase from wk 0; P < 0.0001) of diet (Fig. 2). Between wk 16 and 18 when regular food was gradually reintroduced, the average body weight was unchanged, whereas CIDEA expression decreased (P < 0.0001) to a level that was still higher than baseline (1.4-fold increase from wk 0; P = 0.028). In all 24 subjects, the average CIDEA expression was higher during the VLCD phase (mean of wk 8 and 16), compared with time points of regular food intake (mean of wk 0 and 18). In the VLCD study, UCP1 was not detected by the microarray, and there was not enough RNA to perform real-time PCR analysis of UCP1 expression. Instead, we used adipose tissue samples from 10 additional subjects, receiving the same treatment as in the main VLCD study, for analysis of UCP1 and CIDEA mRNA with real-time PCR. The 10 subjects had an initial BMI of 38.8 ± 5.1 kg/m², with an average weight loss of 28.4 ± 6.7 kg after 18 wk. Adipose tissue biopsies were available at baseline, and wk 8 and 18. As seen in Fig. 3, the expression pattern of CIDEA was the same as in the main VLCD study, with increase during diet (P = 0.020). In contrast, UCP1 was significantly down-regulated from baseline (P = 0.0026), and its expression level was inversely correlated to that of CIDEA (estimated slope for UCP1 = –0.14; P = 0.0014).

View larger version (14K): [in this window] [in a new window]   FIG. 2. CIDEA gene expression in adipose tissue from 12 obese subjects with metabolic syndrome (MetS+) and 12 obese subjects without metabolic syndrome (MetS–), treated with VLCD for 16 wk, followed by a 2-wk gradual reintroduction of regular food. *, P < 0.05; , P < 0.001 with Wilcoxon signed-ranks test using all subjects.

View larger version (10K): [in this window] [in a new window]   FIG. 3. Adipose tissue gene expression (mean ± SEM of normalized ratios with LRP10) of UCP1 and CIDEA in 10 subjects treated with VLCD for 16 wk, followed by a gradual reintroduction of regular food, with adipose tissue biopsies obtained at wk 0, 8, and 18. Both CIDEA and UCP1 were regulated by diet (P = 0.020 and P = 0.0026, respectively, using an exact binomial test to assess expressional regulation from wk 0), and there was a negative association between CIDEA and UCP1 gene expression (P = 0.0014, using a generalized Wald test of all time points).

Of the 24 VLCD study subjects with adipose tissue biopsies, 12 met the criteria for metabolic syndrome (MetS+ group), and 12 did not meet the criteria for metabolic syndrome (MetS– group). There were no differences in CIDEA expression levels between the MetS+ and MetS– groups at any of the study assessment time points. As seen in Table 2, fasting insulin was the only feature of the metabolic syndrome that was associated with CIDEA expression in the VLCD study, showing a negative correlation (P = 0.0042). In the Mölndal Metabolic study, there were negative correlations between CIDEA expression and fasting glucose, fasting insulin, total cholesterol, TGs, and blood pressure. Because these variables are all well-known covariates to body adiposity, the correlations in the Mölndal Metabolic study were reanalyzed with adjustment for BF content. Only fasting insulin levels remained significantly associated with CIDEA after this procedure (P = 0.0010; Table 2).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CIDEA was found to be highly expressed in adipocytes compared with other human tissues according to gene expression data from two independent experiments. The implication of this finding for human physiology is that CIDEA is likely to have its main function in adipose tissue.

CIDEA-null mice are lean and resistant to diet-induced obesity and diabetes, due to a significantly higher metabolic rate compared with wild-type mice. We decided to investigate the possibility of a link between metabolic rate and CIDEA expression in human white adipose tissue. The data from the Mölndal Metabolic study showed a negative correlation between CIDEA gene expression in adipose tissue and the BMR measurement, which is consistent with the hypothesis that CIDEA might function as a negative regulator of energy expenditure. This association remained significant after adjustment for body composition, age, and gender. The present findings are observational and single-handedly do not provide evidence for causality, but when interpreted together with results from CIDEA-deficient mice, there is reason to believe that CIDEA plays an active role in the regulation of energy expenditure in humans.

It has been reported that CIDEA adipose mRNA expression is increased by weight reduction from an energy-restricted diet (9), and from bariatric surgery (8). However, CIDEA was not regulated by a moderately calorie-restricted diet in another study (25). Previous reports have not discriminated between the effects of caloric restriction on one hand and weight loss on the other. Our results show a rapid reversal of CIDEA expression when calories are reintroduced while body weight is stable. This shows that during a diet-induced weight loss, it is the caloric restriction per se that has the major impact on CIDEA expression, rather than the actual weight change. The CIDEA response to drastic caloric restriction almost seemed inevitable, considering that it was observed in all VLCD-treated subjects.

Studies of human white adipose tissue and rodent brown adipose tissue have demonstrated that CIDEA inhibits lipolysis (5, 8). The VLCD represents a profound calorie deficit and, consequently, a state of rapid lipolysis in adipose tissue to meet the energy demands of other tissues. Therefore, an increase in CIDEA expression in this situation seems like a paradox. On the other hand, studies of CIDEA-null mice showed that although the abolition of CIDEA resulted in an increase in brown adipose tissue lipolysis and glycerol release, there was a decrease in the release of free fatty acids (5). Thus, the enhanced lipolysis in brown adipose tissue of CIDEA-null mice seems to be due to an increased fatty acid oxidation within the same tissue. The findings in the present report that CIDEA is suppressed during the well-fed state and induced by caloric restriction raise the possibility that CIDEA might have a similar function in humans, i.e. to restrain fatty acid expenditure within the adipose tissue.

The mechanism for increased energy expenditure in CIDEA-deficient mice appears to be an elevation of adaptive thermogenesis in brown adipose tissue due to enhanced uncoupling activity through UCP1 (5). We investigated the adipose tissue expression pattern of UCP1 and CIDEA in 10 VLCD-treated subjects from which we had sufficient amounts of RNA for UCP1 real-time PCR analysis. Although CIDEA increased during VLCD, UCP1 was at its peak level at baseline and was down-regulated by the diet. To our knowledge, no previous study has investigated the effect of energy restriction on UCP1 expression in humans. The complementary relationship between UCP1 and CIDEA during different states of energy balance is consistent with their putative role in the regulation of energy expenditure.

A previous study has shown that CIDEA expression in adipose tissue is associated with BMI (8), and here we provide additional evidence that the BF content, as measured with DEXA, has a strong and inverse correlation with CIDEA expression. There was no difference in adipose tissue CIDEA expression between obese subjects with and without the metabolic syndrome, and the observed associations with metabolic syndrome variables among the Mölndal Metabolic study subjects did not remain after adjustment for BF content. This indicates that the previously described link between CIDEA and metabolic syndrome (8) might be explained by differences in adiposity. Insulin was inversely associated with CIDEA expression, even after adjustment for the DEXA BF measurement, a finding that might reflect the suppression of CIDEA during the well-fed state.

Conclusions

In this report we show that the human CIDEA gene is predominantly expressed in adipocytes, and its expression is inversely associated with the BMR of the human study subjects. CIDEA expression in adipose tissue is under strong influence by energy intake and not only BF, but also hyperinsulinemia is associated with a reduced CIDEA expression. UCP1 expression in adipose tissue is down-regulated by energy restriction and inversely associated with CIDEA expression, which indicates a role of mitochondrial uncoupling in human energy balance. Our findings are consistent with data obtained in rodents, and support the concept that CIDEA could be an important regulator of adipose tissue energy expenditure.

	Acknowledgments

 
We thank Lauren Lissner and Jarl S:son Torgerson for their contribution to the Mölndal Metabolic and Very Low Calorie Diet studies, respectively. We also thank the staff at the Obesity Unit at Sahlgrenska University Hospital for their committed work to perform these two studies.

	Footnotes

 
This work was supported by grants from The Swedish Research Council (11285, 529-2002-6671, 521-2005-6736), Hoffmann-La Roche, the National Board of Health and Welfare, the Swedish Diabetes Foundation, the Sahlgrenska University Hospital Foundation, the IngaBritt and Arne Lundberg Research Foundation, the Fredrik and Ingrid Thuring Foundation, the Royal Physiographic Society in Lund, the Tore Nilson Foundation for Medical Research, Dr. P. Håkanssons Foundation, the Göteborg Medical Society, the Swedish Foundation for Strategic Research, and the Swedish federal government under the LUA/ALF agreement.

Disclosure Statement: A.G., M.J., P.-A.S., I.L., C.A.M.G., E.S., L.G., B.F., and L.M.S.C. have nothing to declare. T.C.L. is employed by AstraZeneca and holds stocks in AstraZeneca, Affymetrix, Merck, and Amgen. K.S. holds stocks in Pfizer and AstraZeneca. L.S. obtained lecture and consulting fees from Merck and Sanofi-Aventis. B.C. is employed by AstraZeneca. The Mölndal Metabolic study has previously been supported by grants from Hoffmann-La Roche (to L.S.).

First Published Online September 25, 2007

Abbreviations: BF, Body fat; BMC, bone mineral content; BMI, body mass index; BMR, basal metabolic rate; CIDEA, cell death-inducing DNA fragmentation factor--like effector A; DEXA, dual-energy x-ray absorptiometry; FFM, fat-free mass; HDL, high-density lipoprotein; hs-CRP, highly sensitive C-reactive protein; LRP10, low-density lipoprotein receptor-related protein 10; LTM, lean tissue mass; MetS–, did not meet the criteria for metabolic syndrome; MetS+, met the criteria for metabolic syndrome; OGTT, oral glucose tolerance test; PPIA, peptidyl-prolyl isomerase A; TG, triglyceride; UCP1, uncoupling protein 1; VLCD, very low calorie diet; WHR, waist-to-hip ratio.

Received May 22, 2007.

Accepted September 18, 2007.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Sell H, Deshaies Y, Richard D 2004 The brown adipocyte: update on its metabolic role. Int J Biochem Cell Biol 36:2098–2104[CrossRef][Medline]
2. Kopecky J, Clarke G, Enerbäck S, Spiegelman B, Kozak LP 1995 Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest 96:2914–2923[Medline]
3. Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, Langin D 2003 Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 278:33370–33376[Abstract/Free Full Text]
4. Inohara N, Koseki T, Chen S, Wu X, Nunez G 1998 CIDE, a novel family of cell death activators with homology to the 45 kDa subunit of the DNA fragmentation factor. EMBO J 17:2526–2533[CrossRef][Medline]
5. Zhou Z, Yon Toh S, Chen Z, Guo K, Ng CP, Ponniah S, Lin SC, Hong W, Li P 2003 CIDEA-deficient mice have lean phenotype and are resistant to obesity. Nat Genet 35:49–56[Medline]
6. Dahlman I, Kaaman M, Jiao H, Kere J, Laakso M, Arner P 2005 The CIDEA gene V115F polymorphism is associated with obesity in Swedish subjects. Diabetes 54:3032–3034[Abstract/Free Full Text]
7. Lin SC, Li P 2004 CIDE-A, a novel link between brown adipose tissue and obesity. Trends Mol Med 10:434–439[CrossRef][Medline]
8. Nordström EA, Ryden M, Backlund EC, Dahlman I, Kaaman M, Blomqvist L, Cannon B, Nedergaard J, Arner P 2005 A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-)-like effector A (CIDEA) in adipocyte lipolysis and obesity. Diabetes 54:1726–1734[Abstract/Free Full Text]
9. Dahlman I, Linder K, Arvidsson Nordström E, Andersson I, Liden J, Verdich C, Sorensen TI, Arner P 2005 Changes in adipose tissue gene expression with energy-restricted diets in obese women. Am J Clin Nutr 81:1275–1285[Abstract/Free Full Text]
10. Sjöholm K, Palming J, Olofsson LE, Gummesson A, Svensson PA, Lystig TC, Jennische E, Brandberg J, Torgerson JS, Carlsson B, Carlsson LM 2005 A microarray search for genes predominantly expressed in human omental adipocytes: adipose tissue as a major production site of serum amyloid A. J Clin Endocrinol Metab 90:2233–2239[Abstract/Free Full Text]
11. Palming J, Sjöholm K, Jernås M, Lystig TC, Gummesson A, Romeo S, Lönn L, Lönn M, Carlsson B, Carlsson LM 2007 The expression of NAD(P)H:quinone oxidoreductase 1 is high in human adipose tissue, reduced by weight loss, and correlates with adiposity, insulin sensitivity, and markers of liver dysfunction. J Clin Endocrinol Metab 92:2346–2352[Abstract/Free Full Text]
12. Behre CJ, Gummesson A, Jernås M, Lystig TC, Fagerberg B, Carlsson B, Carlsson LM 2007 Dissociation between adipose tissue expression and serum levels of adiponectin during and after diet-induced weight loss in obese subjects with and without the metabolic syndrome. Metabolism 56:1022–1028[CrossRef][Medline]
13. 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197
14. Larsson I, Berteus Forslund H, Lindroos AK, Lissner L, Näslund I, Peltonen M, Sjöström L 2004 Body composition in the SOS (Swedish obese subjects) reference study. Int J Obes Relat Metab Disord 28:1317–1324[CrossRef][Medline]
15. Henning B, Löfgren R, Sjöström L 1996 Chamber for indirect calorimetry with improved transient response. Med Biol Eng Comput 34:207–212[CrossRef][Medline]
16. Jernås M, Palming J, Sjöholm K, Jennische E, Svensson PA, Gabrielsson BG, Levin M, Sjögren A, Rudemo M, Lystig TC, Carlsson B, Carlsson LM, Lönn M 2006 Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J 20:1540–1542[Abstract/Free Full Text]
17. Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159[Medline]
18. Gabrielsson BG, Johansson JM, Jennische E, Jernås M, Itoh Y, Peltonen M, Olbers T, Lönn L, Lönroth H, Sjöström L, Carlsson B, Carlsson LM, Lönn M 2002 Depot-specific expression of fibroblast growth factors in human adipose tissue. Obes Res 10:608–616[Medline]
19. Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M 2001 Minimum Information About a Microarray Experiment (MIAME)-toward standards for microarray data. Nat Genet 29:365–371[CrossRef][Medline]
20. Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T, Orth AP, Vega RG, Sapinoso LM, Moqrich A, Patapoutian A, Hampton GM, Schultz PG, Hogenesch JB 2002 Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA 99:4465–4470[Abstract/Free Full Text]
21. Sjöholm K, Palming J, Lystig TC, Jennische E, Woodruff TK, Carlsson B, Carlsson LM 2006 The expression of inhibin beta B is high in human adipocytes, reduced by weight loss, and correlates to factors implicated in metabolic disease. Biochem Biophys Res Commun 344:1308–1314[CrossRef][Medline]
22. Gabrielsson BG, Olofsson LE, Sjögren A, Jernås M, Elander A, Lönn M, Rudemo M, Carlsson LM 2005 Evaluation of reference genes for studies of gene expression in human adipose tissue. Obes Res 13:649–652[Medline]
23. Zeger SL, Liang KY 1986 Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42:121–130[CrossRef][Medline]
24. Rotnitzky A, Jewell NP 1990 Hypothesis testing of regression parameters in semiparametric generalized linear models for cluster correlated data. Biometrika 77:485–497[Abstract/Free Full Text]
25. Viguerie N, Vidal H, Arner P, Holst C, Verdich C, Avizou S, Astrup A, Saris WH, Macdonald IA, Klimcakova E, Clement K, Martinez A, Hoffstedt J, Sorensen TI, Langin D 2005 Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets. Diabetologia 48:123–131[CrossRef][Medline]

This article has been cited by other articles:

				A. Saiki, M. Olsson, M. Jernas, A. Gummesson, P. G. McTernan, J. Andersson, P. Jacobson, K. Sjoholm, B. Olsson, S. Yamamura, et al. Tenomodulin Is Highly Expressed in Adipose Tissue, Increased in Obesity, and Down-Regulated during Diet-Induced Weight Loss J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3987 - 3994. [Abstract] [Full Text] [PDF]

				K. Kos, S. Wong, B. Tan, A. Gummesson, M. Jernas, N. Franck, D. Kerrigan, F. H. Nystrom, L. M.S. Carlsson, H. S. Randeva, et al. Regulation of the Fibrosis and Angiogenesis Promoter SPARC/Osteonectin in Human Adipose Tissue by Weight Change, Leptin, Insulin, and Glucose Diabetes, August 1, 2009; 58(8): 1780 - 1788. [Abstract] [Full Text] [PDF]

				J. A. Timmons, B. K. Pedersen, N. Stefan, C. Pfannenberg, H.-U. Haring, F. Villarroya, P. Domingo, M. Giralt, H. A. Jacene, R. L. Wahl, et al. The Importance of Brown Adipose Tissue N. Engl. J. Med., July 23, 2009; 361(4): 415 - 421. [Full Text] [PDF]

				J. Laurencikiene, B. M. Stenson, E. Arvidsson Nordstrom, T. Agustsson, D. Langin, B. Isaksson, J. Permert, M. Ryden, and P. Arner Evidence for an Important Role of CIDEA in Human Cancer Cachexia Cancer Res., November 15, 2008; 68(22): 9247 - 9254. [Abstract] [Full Text] [PDF]

				M. Hallberg, D. L. Morganstein, E. Kiskinis, K. Shah, A. Kralli, S. M. Dilworth, R. White, M. G. Parker, and M. Christian A Functional Interaction between RIP140 and PGC-1{alpha} Regulates the Expression of the Lipid Droplet Protein CIDEA Mol. Cell. Biol., November 15, 2008; 28(22): 6785 - 6795. [Abstract] [Full Text] [PDF]

				M. Prentki and S. R. M. Madiraju Glycerolipid Metabolism and Signaling in Health and Disease Endocr. Rev., October 1, 2008; 29(6): 647 - 676. [Abstract] [Full Text] [PDF]

				P. Keller, J. T. Petrie, P. De Rose, I. Gerin, W. S. Wright, S.-H. Chiang, A. R. Nielsen, C. P. Fischer, B. K. Pedersen, and O. A. MacDougald Fat-specific Protein 27 Regulates Storage of Triacylglycerol J. Biol. Chem., May 23, 2008; 283(21): 14355 - 14365. [Abstract] [Full Text] [PDF]

				J. Y. Kim, K. Liu, S. Zhou, K. Tillison, Y. Wu, and C. M. Smas Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E654 - E667. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gummesson, A. Articles by Carlsson, L. M. S. Search for Related Content PubMed PubMed Citation Articles by Gummesson, A. Articles by Carlsson, L. M. S. Related Collections Metabolism Obesity