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Original Studies |
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
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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(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 |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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(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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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Footnotes |
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Received April 1, 1999.
Revised June 25, 1999.
Accepted July 6, 1999.
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References |
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(mPPAR ) gene: alternative promoter use and different splicing yield
two PPAR isoforms. Proc Natl Acad Sci USA. 92:7921–7925. gene: organization, promoter analysis, and expression. J
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mRNA: a distinct PPAR mRNA subtype transcribed from an independent
promoter. FEBS Lett. 438:55–60.[CrossRef][Medline]
in
humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes. 46:1319–1327.[Abstract]
(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.) gene in diabetic Caucasians: identification of a Pro12Ala
PPAR-2 missense mutation. Biochem Biophys Res Commun. 241:270–274.
gene influences plasma leptin levels in obese humans. Hum Mol
Genet. 7:435–440.2 is associated with decreased receptor activity, lower body mass
index and improved insulin sensitivity. Nat Genet. 20:284–287.[CrossRef][Medline]
2 gene with obesity in two Caucasian population. Diabetes. 47:1806–1808.[Medline]
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differential activity of PPAR-1 and -2 isoforms and influence of
insulin. J Biol Chem. 272:20230–20235.2 gene on adiposity, fat
distribution, and insulin sensitivity in Japanese men. Biochem Biophys
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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]
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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]
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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]
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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]
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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]
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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]
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W.-C. Hsueh, S. A. Cole, A. R. Shuldiner, B. A. Beamer, J. Blangero, J. E. Hixson, J. W. MacCluer, and B. D. Mitchell Interactions Between Variants in the {beta}3-Adrenergic Receptor and Peroxisome Proliferator-Activated Receptor-{gamma}2 Genes and Obesity Diabetes Care, April 1, 2001; 24(4): 672 - 677. [Abstract] [Full Text]
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M. Stumvoll, H. G. Wahl, K. Löblein, R. Becker, F. Machicao, S. Jacob, and H. Häring Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene Is Associated With Increased Antilipolytic Insulin Sensitivity Diabetes, April 1, 2001; 50(4): 876 - 881. [Abstract] [Full Text]
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J.'a. Luan, P. O. Browne, A.-H. Harding, D. J. Halsall, S. O’Rahilly, V.K. K. Chatterjee, and N. J. Wareham Evidence for Gene-Nutrient Interaction at the PPAR{gamma} Locus Diabetes, March 1, 2001; 50(3): 686 - 689. [Abstract] [Full Text]
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S. J. Hasstedt, Q.-F. Ren, K. Teng, and S. C. Elbein Effect of the Peroxisome Proliferator-Activated Receptor-{{gamma}}2 Pro12Ala Variant on Obesity, Glucose Homeostasis, and Blood Pressure in Members of Familial Type 2 Diabetic Kindreds J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 536 - 541. [Abstract] [Full Text]
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 K.-i. Inoue, H. Sano, J. Kelly, I. B. Hirsch, and S. Cooper Troglitazone-Induced Pulmonary Edema Arch Intern Med, March 27, 2000; 160(6): 871 - 872. [Full Text] [PDF]
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