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Two Polymorphisms in the Peroxisome Proliferator-Activated Receptor- Gene Are Associated with Severe Overweight among Obese Women¹

Departments of Clinical Nutrition (R.V., K.S., M.U.) and Medicine (R.M., J.P., M.L.), University of Kuopio, 70211 Kuopio; and the Eating Disorder Unit, University Hospital of Helsinki (A.R.), 00250 Helsinki, Finland; the Division of Medical Genetics, University of Washington (S.S.D.), Seattle, Washington 98195-7360; and INSERM U-325, Institut Pasteur de Lille (J.A.), Lille, France

Address all correspondence and requests for reprints to: Raisa Valve, M.Sc., Department of Clinical Nutrition, University of Kuopio, 70211 Kuopio, Finland. E-mail: raisa.valve{at}uku.fi

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Peroxisome proliferator-activated receptor- (PPAR) is a nuclear receptor that regulates adipocyte differentiation. Variations in the PPAR gene may affect the function of the PPAR and, therefore, body adipocity. We investigated the frequencies of the Pro¹²Ala polymorphism in exon B and the silent CAC478CAT polymorphism in exon 6 of the PPAR gene and their effects on body weight, body composition, and energy expenditure in obese Finns. One hundred and seventy obese subjects [29 men and 141 women; body mass index (BMI), 35.7 ± 3.8 kg/m²; age, 43 ± 8 yr; mean ± SD) participated in the study. The frequencies of the Ala¹² allele in exon B and CAT478 allele in exon 6 were not significantly different between the obese and population-based control subjects (0.14 vs. 0.13 and 0.19 vs. 0.21, respectively). The polymorphisms were associated with increased BMI [Pro¹²Pro, 34.5 ± 3.8; Pro¹²Ala, 34.8 ± 3.1; Ala¹²Ala, 39.2 ± 4.6 kg/m² (P = 0.011); CAC478CAC, 34.5 ± 3.8; CAC478CAT, 34.5 ± 3.3; CAT478CAT, 37.7 ± 4.1 kg/m² (P = 0.046)]. In addition, the women with both Ala¹²Ala and CAT478CAT genotypes (n = 5) were significantly more obese compared with the women having both Pro¹²Pro and CAC478CAC genotypes (n = 85; BMI, 40.6 ± 3.3 vs. 34.4 ± 3.9 kg/m²; P = 0.001), and they had increased fat mass (46.8 ± 9.1 vs. 36.8 ± 7.5 kg; P = 0.005). In conclusion, the Pro¹²Ala and CAC478CAT polymorphisms in the PPAR gene are associated with severe overweight and increased fat mass among obese women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
OBESITY results from the combined effects of genetic and nongenetic factors (1). Cumulative positive energy balance leads to the development of obesity, and variants in the genes that regulate adipocyte metabolism may predispose individuals to develop obesity. One of the candidate genes is a nuclear hormone receptor called peroxisome proliferator-activated receptor- (PPAR). PPAR activates adipocyte differentiation and mediates the expression of fat cell-specific genes (2, 3). There are three PPAR isoforms of the gene, PPAR1, PPAR2, and PPAR3, which are formed by alternative promoters and differential splicing (4, 5, 6). PPAR1 is expressed at low levels in several tissues, PPAR2 is expressed almost exclusively in adipose tissue, whereas PPAR3 seems to be expressed in colon and adipose tissue (5, 6, 7, 8). Obesity and nutritional factors influence the expression of the PPAR2 isoform (9).

Recently, three variants in the PPAR gene have been identified (10, 11, 12, 13). In middle-aged and elderly Finnish subjects of normal weight or slightly overweight, Pro¹²Ala substitution was shown to be associated with lower body mass index and improved insulin sensitivity (13). In addition, the Ala¹² variant exhibited lower affinity and trans-activation capacity than the wild-type allele variant. The researchers suggested that the Ala¹² isoform may result in less efficient stimulation of PPAR target genes and favor low levels of adipose tissue mass accumulation. In contrast, in two cohorts of obese Caucasians [body mass index (BMI) range, 18.6–43.2 and 24.2–76.8 kg/m²], the Pro¹²Ala polymorphism was associated with increased BMI (14). Also, a rare Pro¹¹⁵Gln variant has been shown to be associated with increased BMI among obese subjects, an effect attributed to a constitutively active PPAR protein accelerating cell differentiation (12). The CAC478CAT polymorphism was not associated with body mass index or other variables related to obesity (11). However, the obese subjects bearing at least one CAT478 allele had higher leptin levels than other obese subjects with similar BMIs, suggesting that the PPAR gene may influence the levels of plasma leptin in obese subjects (11). These interesting findings prompted us to investigate the association of the three known polymorphisms in the PPAR gene with body weight, fatness, and basal metabolic rate (BMR) in obese Finns.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

All subjects participating in this study were Finnish. The Finnish population is genetically relatively homogenous, originating mainly from southern (European) and eastern (Asian) immigration 2000 yr ago (15, 16). Screening for the previously reported mutations of the PPAR gene were performed in 170 (29 men and 141 women) unrelated obese subjects participating in a weight reduction study (17). The subjects were recruited from primary health care in Kuopio and Helsinki. Their mean age was 43 ± 8 yr (mean ± SD), and their BMI was 34.7 ± 3.8 kg/m² (range, 28.6–43.8 kg/m²).

All subjects had normal liver, kidney, and thyroid functions, and none had a history of excessive alcohol intake. None of the subjects was taking drugs known to affect BMR or glucose metabolism, and none had diabetes evaluated by fasting serum glucose or an oral glucose tolerance test.

The frequencies of the polymorphisms of the PPAR gene among the study subjects were compared with those in a group of 107 (50 men and 57 women) population-based nondiabetic control subjects who were recruited from 180,000 inhabitants of the county of Kuopio in eastern Finland (18).

The protocol was approved by the ethics committees of the Universities of Kuopio and Helsinki, and all subjects gave their informed consent.

Analytical methods

All measurements were made in the morning after a 12-h fast using standardized methods. The obese subjects were advised to continue their normal diet and avoid alcohol intake and vigorous exercise before the visit. Weight was measured by electric scales. BMI was calculated from the following formula: BMI = weight (kilograms)/height² (meters). Waist circumference was measured at the level midway between the lateral lower rib margin and the iliac crest. Hip circumference was measured at the level of the major trochanters through the pubic symphysis. Energy intake was calculated from 4-day food records in 112 obese subjects. Body composition was determined by bioelectrical impedance (RJL Systems, Inc., Detroit, MI). The BMR was measured by indirect calorimetry (Deltatrac, TM Datex, Helsinki, Finland) after a 12-h fast as previously reported in detail (19). Gas exchange was measured for 30 min, of which the first 10 min were discarded, and the mean value of the last 20 min was used in the calculations. The energy production rate (calories per min) was calculated according to Ferrannini as follows BMR (kilocalories per min) = 3.91 x VO₂ (milliliters per min) + 1.10 x VCO₂ (milliliters per min) - 3.34 x N (milligrams per min) (20) and expressed as kilocalories per day. Urinary nitrogen was measured in samples obtained from 119 subjects. For each subject, the adjusted BMR (adjBMR) (21) was calculated as follows: (the group mean BMR) + (measured BMR - the predicted BMR), where the group mean BMR is the mean absolute metabolic rate calculated according to Ferrannini (kilocalories per day), the measured BMR is the rate (kilocalories per day) measured in each subject, and the predicted BMR is the calculated rate (kilocalories per day) obtained by using the individual lean body mass and age in the linear regression equation generated from the initial examinations of 170 subjects. Serum glucose was analyzed by kinetic photometry with glucose dehydrogenase (22). RIA methods were used for the analyses of serum insulin (CIS-Bio International, Gif-sur-Yvette, France) and serum leptin (Linco Research, Inc., St. Louis, MO). Serum triglyceride levels were assayed using an automated enzymatic method (Roche Molecular Biochemicals, Mannheim, Germany).

Screening of the mutations in the PPAR gene

DNA was prepared from peripheral blood leukocytes by proteinase K-phenol-chloroform extraction method. Exon B of the PPAR gene was amplified by PCR with the forward primer 5'-GACAAAATATCAGTGTGAATTACAGC-3' and the reverse primer 5'-CCCAATAGCCGTATCTGGAAGG-3' (product size, 167 bp), and exon 6 of the PPAR gene was amplified with the forward primer 5'-CCGCCCAGGTTTGCTGAATGTG-3' and the reverse primer 5'-CAGTGGCTGAGGACTCTCTG-3' (product size, 267 bp). PCR was performed in a 6-µL volume containing 50 ng genomic DNA, 3 pmol of each primer, 10 mmol/L Tris-HCl (pH 8.8), 50 mmol/L KCl, 1.5 mmol/L MgCl₂, 0.1% Triton X-100, 100 µmol/L deoxy (d)-NTP, 0.25 U DNA polymerase (Dynazyme DNA Polymerase, Finnzymes, Espoo, Finland), and either 0.55 µCi [³²P]dCTP (for exon B) or 0.25 µCi [³³P]dCTP (for exon 6). PCR conditions for exon B were denaturation at 94 C for 4 min, followed by 35 cycles of denaturation at 94 C for 30 s and annealing at 66 C for 1 min, with a final extension at 72 C for 6 min. PCR conditions for the exon 6 were denaturation at 94 C for 3 min, followed by 35 cycles of denaturation at 94 C for 30 s, annealing at 66 C for 30 s, and extension at 72 C for 40 s, with a final extension at 72 C for 6 min. Variants were detected by single strand conformation polymorphism analysis. PCR products were first diluted 4- to 10-fold with 0.1% SDS and 10 mmol/L ethylenediamine tetraacetate and then mixed (1:1) with loading dye mix (95% formamide, 20 mmol/L ethylenediamine tetraacetate, 0.05% bromophenol blue, and 0.05% xylene cyanol). After denaturing at 98 C for 3 min, samples were immediately placed on ice. Two microliters of each sample were loaded onto nondenaturing polyacrylamide gels (acrylamide/N,N'-methylene-bis-acrylamide ratio, 49:1; 6% for exon B and 5% for exon 6) containing 10% glycerol. Samples were run at temperatures that were shown to discriminate among the variants in the previously sequenced (23) samples of exon B (37–38 C) and exon 6 (31–35 C) most accurately. The gel was dried and autoradiographed overnight at -70 C with intensifying screens. The Pro¹¹⁵Gln mutation was screened by PCR-restriction fragment length polymorphism assays as previously described (12).

Statistical analysis

All calculations were performed using the SPSS/WIN program version 6.0 (SPSS, Inc., Chicago, IL). Data are presented as the mean ± SD. Statistical significance of the differences between the groups was evaluated by ² test, ANOVA, or Student’s t test. Student’s t test with Bonferroni correction was used for comparison of two groups of interest if the ANOVA showed significant differences among the groups. The linkage disequilibrium between the exon B and exon 6 polymorphisms of the PPAR gene and obesity were studied with the program EH (estimating haplotype frequencies) (24). Food records were analyzed by the Nutrica computer program based on Finnish nutrient databases (The Social Insurance Institution, Helsinki, Finland).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
None of the subjects had the Pro¹¹⁵Gln mutation. The frequencies of the Ala¹² allele in exon B and the CAT478 allele in exon 6 were not significantly different between the obese and population-based control subjects (0.14 vs. 0.13 and 0.19 vs. 0.21, respectively). The two polymorphisms were in linkage disequilibrium in both study populations (P < 0.001) i.e. the rare alleles (Ala¹² and CAT478) and the common alleles (Pro¹² and CAC478) occurred together more often in the same haplotype than expected by chance. The linkage disequilibrium coefficient was 0.06, which was 50% of the maximal value in both groups. The estimated haplotype frequencies did not differ between obese and control subjects. As among the obese subjects none of the men had the Ala¹²Ala genotype, and only one man had the CAT478CAT genotype in the PPAR gene, further statistical analysis included obese women (n = 141) only.

Obese women with the Ala¹²Ala genotype had increased BMI, lean body mass, fat mass, and waist and hip circumferences compared with the women with the Pro¹²Pro or Pro¹²Ala genotypes (Table 1). Age, percentage of body fat; serum glucose, insulin, and leptin; adjBMR; and energy intake were similar among the three groups. The obese women with the CAT478CAT genotype in exon 6 had increased BMI and waist circumference compared with the women with the CAC478CAC or CAC478CAT genotypes (Table 1). There were no differences in other variables studied among the three genotypes. Furthermore, the women with both the Ala¹²Ala and CAT478CAT genotypes were severely obese and had increased fat mass and waist and hip circumferences compared with the women with the Pro¹²Pro and CAC478CAC genotypes (Table 2 and Fig. 1).

View this table: [in this window] [in a new window]   Table 1. Characteristics of obese women according to the Pro12Ala and CAC478CAT polymorphisms in the PPAR2 gene

View this table: [in this window] [in a new window]   Table 2. Characteristics of obese women with the Pro12Ala and CAC478CAT polymorphisms of the PPAR gene

View larger version (20K): [in this window] [in a new window]   Figure 1. BMI in obese women according to the Pro12Ala and CAC478CAT polymorphisms in the PPAR gene. Values are the mean ± SD.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

We found that the obese women with the Ala¹²Ala and CAT478CAT genotypes in the PPAR gene were severely obese compared with the women with the Pro¹²Pro and CAC478CAC genotypes. Obviously, as a result of increased body weight, the obese women with the Ala¹²Ala and CAT478CAT genotypes had increased body fat mass and circumferences of waist and hip, the effects of the Ala¹² and CAT478 variants on the number and size of adipocytes need to be investigated further. The two polymorphisms were in linkage disequilibrium, and therefore, we cannot determine whether one or both of them is significant. Previous studies support the importance of the Pro¹²Ala polymorphism affecting body weight (13, 14).

In two Caucasian populations with a wide range of BMI (18.6–76.8 kg/m²), the Ala¹² variant has been shown to be associated with increased body weight and BMI. These associations were most pronounced in very obese subjects and were more distinct in women than in men (14). Alanine in codon 12 is within the domain that enhances ligand-independent activation of PPAR2 (25), and the Pro¹²Ala substitution may change the structure of the protein and alter its function. However, in Japanese men (BMI range, 17.1–41.0 kg/m²), the Ala¹² variant was not associated with the degree of obesity (26). Furthermore, among normal weight or slightly overweight subjects the Ala¹² variant was associated with lower than average BMI (13). The Ala¹² variant was shown to have lower affinity and trans-activation capacity than the Pro¹² variant in several cell lines, including 3T3-L1 preadipocytes. It is possible that the function of the Ala¹² variant may vary in the different cell types, such as human adipocytes, and might also be influenced by other genetic and environmental factors. In general, the messenger ribonucleic acid expression of PPAR2 is increased in adipose tissue of obese subjects, and a low calorie diet down-regulates the expression (9). Therefore, the functional importance of the Pro¹²Ala substitution may be dependent on our energy reserves, which could explain the contradictory associations of the Ala¹² variant with BMI in obese and normal weight subjects.

In our study, the rare Pro¹¹⁵Gln mutation was not found in any subjects. This mutation has been shown to be associated with increased body weight in obese subjects and resulted in 2.5 times greater accumulation of triglycerides than that in wild-type cell lines (12). Interestingly, the Pro¹¹⁵Gln mutation renders PPAR constitutively active, because it interferes with an inhibitory phosphorylation of Ser¹¹⁴. In combination, the Pro¹²Ala mutant, which renders PPAR less active and is associated with reduced BMI (13), and the increased BMI observed in carriers of the constitutively active Pro¹¹⁵Gln, are in vivo proof of an important role of the PPAR gene in adipose tissue homeostasis.

In a recent study of the French population, the CAT478 allele was not associated with increased body weight (11). However, obese subjects (BMI, >30 kg/m²) bearing at least one CAT478 allele had higher plasma leptin levels than subjects without it, and this increase was not associated with an elevated BMI. Consistent with these observations, the obese women with the CAT478CAT genotype in our study had higher BMI and slightly higher leptin concentrations than the other obese women studied. However, higher leptin levels were entirely due to increased adipose tissue mass.

Insulin stimulates ligand-independent activation of PPAR and may promote adipocyte differentiation (25). In our study, the women with the Ala¹²Ala and CAT478CAT genotypes did not have significantly elevated serum glucose and insulin concentrations despite the presence of severe obesity. Insulin resistance develops with increasing body weight (27), and insulin-sensitive subjects are more likely to gain weight than insulin-resistant ones (28, 29, 30). In a previous study, the obese subjects with the Ala¹² variant had slightly lower fasting insulin levels than others (14). Our observations are also consistent with the report by Deeb et al. (13), demonstrating that in normal weight and mildly obese subjects the Ala¹² variant was associated with lower BMI and higher insulin sensitivity. As this difference disappeared after adjusting for BMI, the researchers suggested that the Ala¹² variant influences primarily the amount of adipose tissue mass.

The exact mechanisms by which PPAR variants could affect adipose tissue mass are not known. Adipocyte differentiation involves a complex regulatory pathway controlled by coordinated expression of specific regulatory genes and transcription factors. Therefore, several unknown mechanisms may modify the role of the Pro¹²Ala and CAC478CAT polymorphisms of the PPAR gene in adipogenesis. The changes in the activity and/or structure of the PPAR gene in vivo may change the activity of other transcription factors and the expression of target genes in differentiating cells. These alterations in the pathway of adipocyte differentiation may lead to obesity.

In conclusion, obese women with Ala¹²Ala and CAT478CAT genotypes in the PPAR gene were severely obese and had increased fat mass. The effects of these polymorphisms on adipose tissue metabolism need to be studied further in both lean and obese subjects, because the importance of these polymorphisms in the PPAR gene appears to be different in obese and normal weight subjects.

	Footnotes

 
¹ This work was supported by grants from the Research Council for Health, the Academy of Finland, Kuopio University Hospital, the Jenny and Antti Wihuri Foundation, the Finnish Cultural Foundation, INSERM, Institut Pasteur de Lille, Hoffmann-La Roche (Basel, Switzerland), and NIH Grant HL-30086 (to S.S.D.).

Received April 1, 1999.

Revised June 25, 1999.

Accepted July 6, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Bouchard C, ed. 1994 Genetics of obesity. Boca Raton: CRC Press.
2. Spiegelman B, Flier J. 1996 Adipogenesis and obesity: rounding out the big picture. Cell. 87:377–389.[CrossRef][Medline]
3. Fajas L, Fruchart JC, Auwerx J. 1998 Transcriptional control of adipogenesis. Curr Opin Cell Biol. 10:165–173.[CrossRef][Medline]
4. Zhu Y, Qi C, Korenberg J, et al. 1995 Structural organization of mouse peroxisome proliferator-activated receptor (mPPAR ) gene: alternative promoter use and different splicing yield two PPAR isoforms. Proc Natl Acad Sci USA. 92:7921–7925.[Abstract/Free Full Text]
5. Fajas L, Auboeuf D, Raspe E, et al. 1997 The human PPAR gene: organization, promoter analysis, and expression. J Biol Chem. 272:18779–18789.[Abstract/Free Full Text]
6. Fajas L, Fruchart JC, Auwerx J. 1998 PPAR3 mRNA: a distinct PPAR mRNA subtype transcribed from an independent promoter. FEBS Lett. 438:55–60.[CrossRef][Medline]
7. Auboeuf D, Rieusset J, Fajas L, et al. 1997 Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor- in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes. 46:1319–1327.[Abstract]
8. Ricote M, Huang J, Fajas L, et al. 1998 Expression of the peroxisome proliferator-activated receptor (PPAR) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density protein. Proc Natl Acad Sci USA. 95:7614–7619.[Abstract/Free Full Text]
9. Vidal-Puig A, Considine R, Jimenez-Linan M, et al. 1997 Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 99:2416–2422.[Medline]
10. Yen C-J, Beamer B, Negri C, et al. Molecular scanning of the human peroxisome proliferator activated receptor (hPPAR) gene in diabetic Caucasians: identification of a Pro12Ala PPAR-2 missense mutation. Biochem Biophys Res Commun. 241:270–274.
11. Meirhaeghe A, Fajas L, Helbecque N, et al. 1998 A genetic polymorphism of the peroxisome proliferator-activated receptor gene influences plasma leptin levels in obese humans. Hum Mol Genet. 7:435–440.[Abstract/Free Full Text]
12. Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn R. 1998 Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 339:953–959.[Abstract/Free Full Text]
13. Deeb S, Fajas L, Nemoto M, et al. 1998 A Pro12Ala substitution in the human peroxisome proliferator activated receptor 2 is associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 20:284–287.[CrossRef][Medline]
14. Beamer B, Yen C-J, Andersen R, et al. 1998 Association of the Pro12Ala variant in the peroxisome proliferator activated receptor 2 gene with obesity in two Caucasian population. Diabetes. 47:1806–1808.[Medline]
15. De la Chapelle A. 1993 Disease gene mapping in isolated human population; the example of Finland. J Med Genet. 30:857–865.[Free Full Text]
16. Kittles R, Perola M, Peltonen L, et al. 1998 Dual origins of Finns revealed by Y chromosome haplotype variation. Am J Hum Genet. 62:1171–1179.[CrossRef][Medline]
17. Uusitupa M, Karhunen L, Franssila-Kallunki A, et al. 1996 Apolipoprotein E phenotype modifies metabolic and hemodynamic abnormalities related to central obesity in women. Am J Clin Nutr. 64:131–136.[Abstract/Free Full Text]
18. Uusitupa M, Niskanen L, Siitonen O, Voutilainen E, Pyörälä K. 1993 Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 36 1175–1184.
19. Laakso M, Uusitupa M, Takala J, Majander H, Reijonen T, Penttilä I. 1988 Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects. Metabolism. 37:1092–1100.[CrossRef][Medline]
20. Ferrannini E. 1988 The theoretical bases of indirect calorimetry: a review. Metabolism. 37:287–301.[CrossRef][Medline]
21. Ravussin E, Lillioja S, Knowler W. 1988 Reduced rate of energy expenditure as a risk factor for body weight gain. N Engl J Med. 318:467–472.[Abstract]
22. Rindfrey H, Helger R, Lang H. 1977 Kinetic determination of glucose concentrations with glucose hydrogenase. J Clin Chem Clin Biochem. 15:217–220.[Medline]
23. Kretz K, Carson G, O’Brien J. 1989 Direct sequencing from low melt agarose with Sequenase. Nucleic Acids Res. 17:5864.[Free Full Text]
24. Terwilliger J, Ott J, eds. 1994 Handbook of human genetic linkage. Baltimore: John Hopkins University Press; 188–203.
25. Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig A, Flier J. 1997 Ligand-independent activation domain in the N-terminus of peroxisome proliferator-activated receptor : differential activity of PPAR-1 and -2 isoforms and influence of insulin. J Biol Chem. 272:20230–20235.[Abstract/Free Full Text]
26. Mori Y, Kim-Motoyama H, Katakura T, et al. 1998 Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun. 251:195–198.[CrossRef][Medline]
27. Sigal R, Warram J. 1996 The interaction between obesity and diabetes. Curr Opin Endocrinol Diabetes. 3:3–9.
28. Swinburn B, Nyomba B, Saad M, et al. 1991 Insulin resistance associated with lower rates of weight gain in Pima Indians. J Clin Invest. 88:168–173.
29. Valdez R, Mitchell B, Haffner S, et al. 1994 Predictors of weight change in a bi-ethnic population: the San Antonio Heart Study. Int J Obes Relat Metab Disord. 18:85–91.[Medline]
30. Hoag S, Marshall J, Jones R, Hamman R. 1995 High fasting insulin levels associated with lower rates of weight gain in persons with normal glucose tolerance: the San Luis Valley Diabetes Study. Int J Obes Metab Disord. 19:175–180.[Medline]

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				T. Temelkova-Kurktschiev, M. Hanefeld, G. Chinetti, C. Zawadzki, S. Haulon, A. Kubaszek, C. Koehler, W. Leonhardt, B. Staels, and M. Laakso Ala12Ala Genotype of the Peroxisome Proliferator-Activated Receptor {gamma}2 Protects against Atherosclerosis J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4238 - 4242. [Abstract] [Full Text] [PDF]

				K. Z. Al-Shali, A. A. House, A. J.G. Hanley, H. M.R. Khan, S. B. Harris, B. Zinman, M. Mamakeesick, A. Fenster, J. D. Spence, and R. A. Hegele Genetic Variation in PPARG Encoding Peroxisome Proliferator-Activated Receptor {gamma} Associated With Carotid Atherosclerosis Stroke, September 1, 2004; 35(9): 2036 - 2040. [Abstract] [Full Text] [PDF]

				E. S. Tai, D. Corella, M. Deurenberg-Yap, X. Adiconis, S. K. Chew, C. E. Tan, and J. M. Ordovas Differential effects of the C1431T and Pro12Ala PPAR{gamma} gene variants on plasma lipids and diabetes risk in an Asian population J. Lipid Res., April 1, 2004; 45(4): 674 - 685. [Abstract] [Full Text] [PDF]

				F. Orio Jr., G. Matarese, S. Di Biase, S. Palomba, D. Labella, V. Sanna, S. Savastano, F. Zullo, A. Colao, and G. Lombardi Exon 6 and 2 Peroxisome Proliferator-Activated Receptor-{gamma} Polymorphisms in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5887 - 5892. [Abstract] [Full Text] [PDF]

				S Masud and S Ye Effect of the peroxisome proliferator activated receptor-{gamma} gene Pro12Ala variant on body mass index: a meta-analysis J. Med. Genet., October 1, 2003; 40(10): 773 - 780. [Full Text] [PDF]

				M. Gurnell, D. B. Savage, V. K. K. Chatterjee, and S. O'Rahilly The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor {gamma} and Its Therapeutic Modulation J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2412 - 2421. [Abstract] [Full Text] [PDF]

				M. Kolehmainen, M. I. J. Uusitupa, E. Alhava, M. Laakso, and H. Vidal Effect of the Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor (PPAR) {gamma}2 Gene on the Expression of PPAR{gamma} Target Genes in Adipose Tissue of Massively Obese Subjects J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1717 - 1722. [Abstract] [Full Text] [PDF]

				M. Bluher, G. Lubben, and R. Paschke Analysis of the Relationship Between the Pro12Ala Variant in the PPAR-{gamma}2 Gene and the Response Rate to Therapy With Pioglitazone in Patients With Type 2 Diabetes Diabetes Care, March 1, 2003; 26(3): 825 - 831. [Abstract] [Full Text] [PDF]

				H. P. Koeffler Peroxisome Proliferator-activated Receptor {gamma} and Cancers Clin. Cancer Res., January 1, 2003; 9(1): 1 - 9. [Abstract] [Full Text] [PDF]

				L. Frederiksen, K. Brodbaek, M. Fenger, T. Jorgensen, K. Borch-Johnsen, S. Madsbad, and S. A. Urhammer Studies of the Pro12Ala Polymorphism of the PPAR-{gamma} Gene in the Danish MONICA Cohort: Homozygosity of the Ala Allele Confers a Decreased Risk of the Insulin Resistance Syndrome J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3989 - 3992. [Abstract] [Full Text] [PDF]

				M. Stumvoll and H. Haring The Peroxisome Proliferator-Activated Receptor-{gamma}2 Pro12Ala Polymorphism Diabetes, August 1, 2002; 51(8): 2341 - 2347. [Abstract] [Full Text] [PDF]

				V. I. Lindi, M. I.J. Uusitupa, J. Lindstrom, A. Louheranta, J. G. Eriksson, T. T. Valle, H. Hamalainen, P. Ilanne-Parikka, S. Keinanen-Kiukaanniemi, M. Laakso, et al. Association of the Pro12Ala Polymorphism in the PPAR-{gamma}2 Gene With 3-Year Incidence of Type 2 Diabetes and Body Weight Change in the Finnish Diabetes Prevention Study Diabetes, August 1, 2002; 51(8): 2581 - 2586. [Abstract] [Full Text] [PDF]

				J. G. Eriksson, V. Lindi, M. Uusitupa, T. J. Forsen, M. Laakso, C. Osmond, and D. J.P. Barker The Effects of the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene on Insulin Sensitivity and Insulin Metabolism Interact With Size at Birth Diabetes, July 1, 2002; 51(7): 2321 - 2324. [Abstract] [Full Text] [PDF]

				R. Walczak and P. Tontonoz PPARadigms and PPARadoxes: expanding roles for PPAR{gamma} in the control of lipid metabolism J. Lipid Res., February 1, 2002; 43(2): 177 - 186. [Abstract] [Full Text] [PDF]

				M. Hara, S. Y. Alcoser, A. Qaadir, K. K. Beiswenger, N. J. Cox, and D. A. Ehrmann Insulin Resistance Is Attenuated in Women with Polycystic Ovary Syndrome with the Pro12Ala Polymorphism in the PPAR{gamma} Gene J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 772 - 775. [Abstract] [Full Text] [PDF]

				B. J. Nicklas, E. F.C. van Rossum, D. M. Berman, A. S. Ryan, K. E. Dennis, and A. R. Shuldiner Genetic Variation in the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene (Pro12Ala) Affects Metabolic Responses to Weight Loss and Subsequent Weight Regain Diabetes, September 1, 2001; 50(9): 2172 - 2176. [Abstract] [Full Text] [PDF]

				N. Stefan, A. Fritsche, H. Häring, and M. Stumvoll Effect of Experimental Elevation of Free Fatty Acids on Insulin Secretion and Insulin Sensitivity in Healthy Carriers of the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene Diabetes, May 1, 2001; 50(5): 1143 - 1148. [Abstract] [Full Text]

W.-C. Hsueh, S. A. Cole, A. R. Shuldiner, B. A. Beamer, J. Blangero, J. E