Obesity-related Phenotypes Research Articles

Heritability of Obesity-related Phenotypes and Association with Adiponectin Gene Polymorphisms in the Chinese National Twin Registry

The purpose of this study was to estimate the heritability of obesity-related phenotypes and investigate the association of adiponectin gene polymorphisms +45T>G and +276G>T with these measures in Chinese twins. 1260 twin pairs were recruited from two cities through the Chinese National Twin Registry System from 2001 to 2005. Two SNPs at the adiponectin locus (+45T>G and +276G>T) were genotyped. Structural equation modeling (SEM) was used to estimate heritability and the best-fitting variance component model. The regular association among all twins was analysed with generalised estimating equations (GEE). Sib-transmission/disequilibrium test (TDT) within dizygotic (DZ) twin pairs discordant for their genotype was performed using SEM. Additive genetic, common and unique environmental (ACE) model-based heritability of body mass index (BMI) was 61%, while additive genetic and unique environmental (AE)-model-based heritability of waist circumference (WC) and waist-hip ratio (WHR) were 75% and 61%, respectively. There was no association of adiponectin gene +45T>G and +276G>T genotypes with obesity-related phenotypes in all twins or discordant DZ twins. Our twins data did not support that there was an association between adiponectin gene polymorphisms +45T>G and +276G>T and the obesity-related phenotypes. Further studies are required to better understand the role of adiponectin gene polymorphisms in obesity.

Association of the MC4R V103I Polymorphism With Obesity: A Chinese Case–control Study and Meta‐analysis in 55,195 Individuals

Recently, large-scaled studies suggested a negative association of the infrequent allele of the melanocortin-4 receptor (MC4R) V103I polymorphism with obesity. We conducted a Chinese case-control study, meta-analysis in East Asians and in all populations, in order to further assess the association between the V103I polymorphism and reduced body weight and to explore whether the association varies among different ethnic groups. We conducted a case-control study to analyze this polymorphism in 2,012 children of two independent study groups from Beijing, China, no association was found between the V103I polymorphism and obesity or obesity-related phenotypes (P > 0.10). In the meta-analysis of 3,526 individuals from six East Asian studies, I103 carriers had a 31% lower risk for obesity (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.50-0.94, P = 0.02). Subsequently, we performed a large meta-analysis of the six East Asian studies and 31 studies of other ethnic groups, involving 55,195 individuals with 19,822 obese cases and 35,373 nonobese controls. In total, the individuals with I103 allele had a 21% lower risk for obesity (OR = 0.79, 95% CI: 0.71-0.88, P < 0.0001). In conclusion, this study confirmed and extended the previous findings, suggesting the MC4R V103I polymorphism is negatively associated with human obesity. It provides significant evidence for the association in East Asian populations. Further large-scaled studies in East Asian populations are needed to validate the association.

Relationship between variants of the leptin gene and obesity and metabolic biomarkers in Brazilian individuals

The relationship between variants of the leptin gene (LEP) and obesity and metabolic biomarkers was investigated in Brazilian individuals. One-hundred-ten obese (BMI > 30 kg/m(2)) and 100 non-obese individuals (145 women and 65 men, aged 49 +/- 14 years) were randomly selected. Plasma leptin, glycemia, serum lipid measurements and LEP -2548G>A and 3'HVR polymorphisms were analyzed. The LEP -2548GG genotype was associated with a 2.2% and 2.0% increase in BMI (p = 0.009) and plasma leptin (p = 0.031), respectively. 3'HVR I/II (classes I/I+I/II) genotypes contributed with 1.8% of BMI values (p = 0.046). LEP I/G combined genotypes (I/IGG, I/IGA and I/IIGG) were associated with obesity, and increased BMI, waist circumference, leptin and triglycerides (p < 0.05). These relationships were found in women (p < 0.05) but not in men. LEP I/G combined genotypes were not associated with hypertension, hyperglycemia, dyslipidemia and coronary artery disease. LEP I/G combined genotypes are associated with obesity-related metabolic biomarkers and phenotype in a gender-dependent manner.

PLIN1 gene: fat keeper and prevention switcher

it has long been recognized that the ability to become an elite athlete has a strong genetic basis. Support for this notion does not require the use of sophisticated laboratory genetic analyses, but just being a passive spectator of sporting events. When it comes to athletics (specifically, track

Copy number variation at leptin receptor gene locus associated with metabolic traits and the risk of type 2 diabetes mellitus

BackgroundRecent efforts have been made to link complex human traits and disease susceptibility to DNA copy numbers. The leptin receptor (LEPR) has been implicated in obesity and diabetes. Mutations and genetic variations of LEPR gene have been discovered in rodents and humans. However, the association of DNA copy number variations at the LEPR gene locus with human complex diseases has not been reported. In an attempt to study DNA copy number variations associated with metabolic traits and type 2 diabetes mellitus (T2DM), we targeted the LEPR gene locus in DNA copy number analyses.ResultsWe identified DNA copy number variations at the LEPR gene locus among a Korean population using genome-wide SNP chip data, and then quantified copy numbers of the E2 DNA sequence in the first two exons overlapped between LEPR and LEPROT genes by the quantitative multiplex PCR of short fluorescent fragment (QMPSF) method. Among the non-diabetic subjects (n = 1,067), lower E2 DNA copy numbers were associated with higher fasting glucose levels in men (p = 1.24 × 10-7) and women (p = 9.45 × 10-5), as well as higher total cholesterol levels in men (p = 9.96 × 10-7). In addition, the significant association between lower E2 DNA copy numbers and lower level of postprandial 2hr insulin was evident only in non-diabetic women, whereas some obesity-related phenotypes and total cholesterol level exhibited significant associations only in non-diabetic men. Logistic regression analysis indicated that lower E2 DNA copy numbers were associated with T2DM (odds ratio, 1.92; 95% CI, 1.26~2.96; p < 0.003) in our nested case-control study. Interestingly, the E2 DNA copy number exhibited a negative correlation with LEPR gene expression, but a positive correlation with LEPROT gene expression.ConclusionsThis work suggests that a structural variation at the LEPR gene locus is functionally associated with complex metabolic traits and the risk of T2DM.

Influence of maternal educational level on the association between the rs3809508 neuromedin B gene polymorphism and the risk of obesity in the HELENA study

Neuromedin B (NMB) is a bombesin-like peptide, which inhibits food intake and modulates stress-related behaviour. An NMB gene polymorphism (P73T) has been earlier associated with obesity and abnormal eating behaviour in adults. The association between four NMB polymorphisms and obesity-related phenotypes was investigated in the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional study (n=1144, 12-17-year-old European adolescents). This population was genotyped for the NMB rs1107179, rs17598561, rs3809508 and rs1051168 (P73T) polymorphisms. Obesity was defined according to Cole et al. (BMJ 2000; 320:1240-1243) criteria; eating behaviour was assessed by the Eating Behaviour and Weight Problems Inventory for Children (EWI-C) and the food choices and preferences questionnaires. Familial socioeconomic status (SES) was assessed through the parents' educational level. Only the genotype distribution of rs3809508 differed according to obesity status, as the TT genotype was more frequent in obese than in non-obese adolescents (8.6% vs 3.1%, P=0.05; adjusted odds ratio for obesity (95% confidence interval): 2.85 (1.11-7.31), P=0.03). Moreover, TT subjects had higher body mass index (22.8+/-4.4 kg m(-2) vs 21.3+/-3.7 kg m(-2), P=0.02), waist circumference (75.8+/-9.7 cm vs 72.2+/-9.3 cm, P=0.006), waist-to-hip ratio (0.84+/-0.14 vs 0.79+/-0.07, P<0.0001) and waist-to-height ratio (0.47+/-0.06 vs 0.44+/-0.55, P=0.002) than C allele carriers. The effects of this single nucleotide polymorphism on all anthropometric values were influenced by the maternal SES, in that a low maternal educational level aggravated the phenotype of adolescents carrying the TT genotype (interactions: P<0.02). No association with EWI-C scores was found, although sweet craving was a more frequent cause of between-meal food intake in TT subjects than in C allele carriers (24.3% vs 9.2%, P=0.01). In European adolescents, the TT genotype of the NMB rs3809508 polymorphism was associated with a higher risk of obesity. Moreover, the effects of this polymorphism on anthropometric values were influenced by the maternal educational level.

Genetic Variance in the Spinocerebellar Ataxia Type 2 (ATXN2) Gene in Children with Severe Early Onset Obesity

BackgroundExpansion of a CAG repeat in the coding region of exon 1 in the ATXN2 gene located in human chromosome 12q24.1 causes the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2). In contrast to other polyglutamine (polyQ) disorders, the SCA2 repeat is not highly polymorphic in central European (CEU) controls with Q22 representing 90% of alleles, and Q23 contributing between 5–7% of alleles. Recently, the ATXN2 CAG repeat has been identified as a target of adaptive selection in the CEU population. Mouse lines deficient for atxn2 develop marked hyperphagia and obesity raising the possibility that loss-of-function mutations in the ATXN2 gene may be related to energy balance in humans. Some linkage studies of obesity related phenotypes such as antipsychotic induced weight gain have reported significant lod scores on chromosome 12q24. We tested the hypothesis that rare loss-of-function ATXN2 variants cause obesity analogous to rare mutations in the leptin, leptin receptor and MC4R genes.Methodology/Principal FindingsWe sequenced the coding region of ATXN2 including intron-exon boundaries in 92 severely obese children with a body mass index (BMI) >3.2 standard deviations above age- and gender-adjusted means. We confirmed five previously identified single nucleotide polymorphisms (SNPs) and three new SNPs resulting in two synonymous substitutions and one intronic polymorphism. Alleles encoding >Q22 were overrepresented in our sample of obese children and contributed 15% of alleles in children identified by their parents as white. SNP rs695872 closely flanking the CAG repeat showed a greatly increased frequency of C/C homozygotes and G/C heterozygotes compared with reported frequencies in the CEU population.Conclusions/SignificanceAlthough we did not identify variants leading to novel amino acid substitutions, nonsense or frameshift mutations, this study warrants further examination of variation in the ATXN2 gene in obesity and related phenotypes in a larger case-control study with emphasis on rs695872 and CAG repeat structure.

A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans

BackgroundA genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (INSIG2) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.MethodsWe studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise r2 of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.ResultsWe did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.ConclusionAlthough rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of INSIG2 in obesity related traits as we found significant association of another tagSNP in INSIG2 with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.

Obesity-Related Dyslipidemia Associated with FAAH , Independent of Insulin Response, in Multigenerational Families of Northern European Descent

A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained for the FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.

Are endocannabinoid type 1 receptor gene (CNR1) polymorphisms associated with obesity and metabolic syndrome in postmenopausal Polish women?

Abstract Objective: The aim of this study was to determine whether genetic variation at the cannabinoid receptor-1 (CNR1) locus could have an effect on adiposity, fat distribution and obesity-related metabolic disorders in Polish postmenopausal women.Design and Subjects: The A3813G, G1422A and A4895G single nucleotide polymorphisms of CNR1 were genotyped in 348 randomly selected postmenopausal women aged 50-60 years recruited from the Wroclaw city population. Measurements: CNR1 genotypes, anthropometric measures (BMI, WC, body fat distribution by DEXA) and metabolic parameters (glucose, lipid profile, insulin FIRI) were determined. Results: The 3813G allele was not significantly associated with higher body mass, BMI, WC, total fat, or fat percentage, but was associated with higher android fat deposit (2971.78 &amp;177; 1655.08 &amp;177; 2472.64 &amp;177; 1300.53, p = 0.007) and percentage of android fat (37.59 &amp;177; 8.45 vs. 35.66 &amp;177; 7.63, p = 0.062). The 1422A allele was associated with higher total fat (31587.72 &amp;177; 9161.28 g vs. 26078.26 &amp;177; 7552.14 g, p = 0.019), fat percentage (40.51 &amp;177; 5.66% vs. 37.51 &amp;177; 4.99%, p = 0.052), and percentage of android fat (40.86 &amp;177; 9.73% vs. 36.09 &amp;177; 7.70%, p = 0.047). No associations were observed for the A4895G variant. Conclusions: There is an association of variants of CNR1 with obesity-related phenotypes in Polish postmenopausal women. As CB1 is a drug target for obesity, pharmacogenetic receptor gene analysis of obesity treatment by endocannabinoid blockade may be of interest to identify the best responders.

Genetic Variation in the FAAH Gene and Metabolic Syndrome–related Phenotypes

TO THE EDITOR: We read with great interest the article “Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community” by Lieb et al. about a lack of association of common variants of the CNR1 and FAAH genes with surrogate measures of adiposity in a large community-based sample of individuals (1). The authors performed a comprehensive analysis of common variation across these two genes and observed no evidence for association of any variant with BMI, waist circumference, and visceral adipose tissue volume. In a smaller (n = 420) but well-characterized sample of adult men of self-reported European ancestry (aged 34.4 ± 0.4 years, mean ± s.e.), selected from a population-based study in Argentinean people, we explored the role of the C/T rs6703669-FAAH variant in the genetic susceptibility of metabolic syndrome–related phenotypes. The variant was selected as a tagSNP capturing common variation in the promoter region of the gene (pair-wise approach at r2 = 0.8, minor allele frequency >10%). Genotyping was performed by allele-specific PCR and genotypes were in Hardy–Weinberg equilibrium. In agreement with Lieb et al., we found no evidence of association between the variant and any of the obesity-related phenotypes: BMI as a continuous trait (logarithmically transformed) P = 0.9, waist circumference P = 0.25, obesity status as a discrete trait P = 0.24, and measurement of body fat content by bioelectrical impedance P = 0.4. Nevertheless, when we analyzed the serum lipid variables in relation to the rs6703669, a significant association was observed with plasma levels of triglycerides: homozygous CC 105.1 ± 5.9, heterozygous CT 131.3 ± 7.5 and homozygous TT 119.2 ± 15.5 mg/dl, P < 0.015, adjusted by log-transformed age and BMI. Accordingly, hypertriglyceridemia evaluated as a discrete trait (plasma triglycerides ≥150 mg/dl), also showed significant association with the variant (OR per T allele: 1.31, 95% CI 1.04–1.66, P < 0.022). Finally, we evaluated the possible association of the rs6703669 and other metabolic syndrome–related phenotypes and observed a significant association with arterial hypertension (dichotomized as a discrete trait): OR per T allele: 1.43, 95% CI 1.06–1.95, P = 0.01, after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3). This study was partially supported by PICT 05-25920 (Agencia Nacional de Promoción Científica y Tecnológica). A.L.B., S.S., C.G., and C.J.P. belong to Consejo Nacional de Investigaciones Científicas y Técnicas. A.L.B. is recipient of a Health Ministry Fellowship (Beca Ramón Carrillo-Arturo Oñativia Ministerio de Salud y Ambiente de la Nación) Convocatoria 2008. The authors declared no conflict of interest.

Association analyses of the INSIG2polymorphism in the obesity and cholesterol levels of Korean populations

BackgroundWhile INSIG2 has been reported to be associated with BMI in many populations, conflicting results have prevented consensus over its role. In analyses of mice and cell cultures the gene has been found to be involved in the regulation of cholesterol synthesis; however, no relationship has been found with cholesterol metabolism in human epidemiological research. Therefore, this study attempts to assess the effect of rs7566605 near INSIG2 on both obesity- and cholesterol-related traits in Koreans.MethodsThe rs7566605 polymorphism was genotyped with 2,364 Koreans, and associations with obesity- and cholesterol-related traits were analyzed statistically via an ANOVA or T-test.ResultsReplication of an association with BMI, WHR, fat mass, fat percent, and abdominal fat area failed, and the C allele of rs7566605 was not associated significantly with total cholesterol, HDL cholesterol, or triglyceride. However, it was found in a meta-analysis of a dominant model that the C allele of rs7566605 appeared to affect the level of the total cholesterol, especially in female subjects.ConclusionWe failed to show associations of rs7566605 with cholesterol- and obesity-related phenotypes, although we newly suggest the possible involvement of INSIG2 with the plasma level of the total cholesterol in women.

Severe obesity is associated with novel single nucleotide polymorphisms of theESR1 and PPARγ locus in Han Chinese

Background:A large number of potential obesity loci have been reported. At least 18 genes have been replicated in a minimum of 5 studies on obesity-related phenotypes. Fourteen additional genes have been associated with obesity in Asians. Objectives:Our objectives were to examine how many common variants of these candidate genes are associated with severe obesity in Han Chinese and how they are combined to exert their effects. Design:In total, 304 severely obese patients [body mass index (BMI; in kg/m2) ≥39] and 304 control subjects (BMI ≤ 24) participated in a 2-staged association study. Subsequently, 220 additional severely obese patients (BMI ≥ 35) and 338 controls (BMI ≤ 24) were recruited to replicate the results. All of the controls were age-, sex-, education- and residence-matched. Finally, a pooled analysis was carried out based on all 514 cases and 606 controls with complete information. Results:The first-stage association analysis in 94 cases and 94 controls found 18 potentially associated single nucleotide polymorphisms (SNPs) (P = 0.01–0.1). The significance of 3 novel common SNPs, 1 onESR1 and 2 onPPARγ, were confirmed in the second stage and replicated further with odds ratios ranging from 1.89 to 2.24. The combined effect of these 3 genes was stronger (odds ratio: 5.27; 95% CI: 2.25, 12.32) than that from any individual gene. Conclusions:Severe obesity in Han Chinese was associated with 3 novel common SNPs forESR1 and PPARγ. These 2 genes collectively result in a >5-fold risk of severe obesity. This information may contribute to the assessment of risk of severe obesity.

Leptin, Insulin, and Obesity‐related Phenotypes: Genetic Influences on Levels and Longitudinal Changes

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity-related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8-10 years apart. We estimated that polygenes explained 30-50% of the adjusted leptin and insulin levels and 30-70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h(2) = 0.45) and small-to-moderate heritability estimates for changes in insulin and other obesity-related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20-30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20-25% of the additive genetic variance in insulin-anthropometric pairs of variables.

Associations Among Slipped Capital Femoral Epiphysis, Tibia Vara, and Type 2 Juvenile Diabetes

Clinical consequences of obesity are numerous and include slipped capital epiphysis of the femur, tibia vara, impaired mobility, insufficient muscle strength, glucose intolerance, type 2 diabetes, hyperlipidemia, nonalcoholic fatty liver disease, cholelithiasis, hypertension, sleep apnea, polycystic ovary disease, increased cardiorespiratory effort, and pseudotumor cerebri, among others. Because slipped capital femoral epiphysis, tibia vara, and type 2 diabetes are observed commonly in obese children, a degree of multiple disease occurrence in a patient would be anticipated; however, the senior author has never observed an obese adolescent who presented at the initial diagnosis with a coexistence of slipped capital femora epiphysis, tibia vara, or type 2 diabetes, so, possibly, these constellations of comorbidities may represent unique obesity phenotypes. We reviewed the population consisting of all consecutive patients with newly diagnosed slipped capital femoral epiphysis or tibia vara from 2000 to 2006 and a selected group of patients with type 2 diabetes treated at the Alfred I. duPont Hospital for Children, Wilmington, DE. There were 57 cases of slipped capital femoral epiphysis, 41 cases of tibia vara, and 53 cases of type 2 diabetes. The tibia vara group had the highest body mass index (BMI; 40.81 [13.01]); the diabetes group (BMI, 35.76 [7.04]) and the slipped capital femoral epiphysis group (BMI, 29.08 [7.07]) had the lowest BMI. There was no significant difference in age at the disease onset and height between groups. There was no overlap of disease at initial presentation among slipped capital femoral epiphysis, adolescent tibia vara, and type 2 diabetes. We observed 3 separate obesity-related phenotypes in adolescents with no overlap of disease at initial presentation among slipped capital femoral epiphysis, adolescent tibia vara, and type 2 diabetes.

Several obesity- and nutrient-related gene polymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB Study

Part of the heterogeneity of the obesity phenotype may originate from genetic differences between obese individuals that may influence energy expenditure (EE). To examine if common single-nucleotide polymorphisms (SNPs) in genes related to obesity-associated phenotypes are associated with postabsorptive resting energy expenditure (REE) and postprandial REE in obese individuals. Postabsorptive REE and 3-h postprandial REE (liquid test meal containing 95% fat, energy content 50% of estimated REE) were measured in 743 obese individuals from eight clinical centres in seven European countries. The analysis assessed the association of genotypes of 44 SNPs in 28 obesity-related candidate genes with postabsorptive REE and postprandial REE taking into consideration the influence of body composition, habitual physical activity, insulin sensitivity, circulating thermogenic hormones and metabolites. After adjustment for fat-free mass (FFM), age, sex and research centre, SNPs in CART, GAD2, PCSK1, PPARG3, HSD11B1 and LIPC were significantly associated with postabsorptive REE. SNPs in GAD2, HSD11B1 and LIPC remained significantly associated with postabsorptive REE after further adjustment for fat mass (FM). SNPs in CART, PPARG2 and IGF2 were significantly associated with postprandial REE after similar adjustments. These associations with postprandial REE remained significant after further adjustment for FM. FTO, UCP2 and UCP3 variants were not associated with postabsorptive or postprandial REE. Several gene polymorphisms associated with obesity-related phenotypes but not FTO and UCP variants may be responsible for some of the inter-individual variability in postabsorptive REE and fat-induced thermogenesis unaccounted for by FFM, FM, age and sex. The association between FTO and obesity that has been reported earlier may not be mediated directly through modulation of EE in obese individuals.

Genotype-environment interaction in human obesity.

The data reviewed in this paper reveal that individual differences in the response to alterations in energy balance induced by diet or exercise are ubiquitous. These differences are observed in a variety of obesity-related phenotypes, including body weight, body fatness, and abdominal visceral fat. Although little is known about the causes of the heterogeneity in responsiveness to dietary habits or to regular exercise, the evidence accumulated so far suggests that genetic factors may play an important role in determining the response of body mass and body fat stores to chronic alterations in energy balance. It is likely that genetic variation at several genes contributes to this heterogeneity of responses and thus to the susceptibility to obesity. Research on the genetic and molecular basis of gene-environment interactions has become a major area of investigation. One can, therefore, anticipate that major advances will occur in the coming years with respect to the identification of the genetic and molecular causes of the susceptibility to the most common diseases, including obesity.

Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phosphodiesterase 4B.

The concept that obesity is an inflammatory state has changed our understanding of this condition and suggested that pharmacological interventions targeting inflammation may be useful strategies to improve metabolic complications of obesity. Phosphodiesterase 4 (PDE4) inhibitors exhibit profound antiinflammatory effects, but whether PDE4 inhibition suppresses obesity-induced inflammation is unknown. Among PDE4 isoforms, PDE4B is the major species mediating inflammatory responses. We therefore examined obesity-related phenotypes in mice deficient for PDE4B. Compared with wild-type littermates, PDE4B-null mice were leaner, with lower fat pad weights, smaller adipocytes, and decreased serum leptin levels on both chow and high-fat diets (HFDs). PDE4B deficiency suppressed TNF-alpha mRNA levels and macrophage infiltration in white adipose tissue in mice on HFD, but insulin sensitivity was unaltered. PDE4B-null mice on HFDs had increased locomotor activity. These results suggest a previously unappreciated role for PDE4B in the regulation of energy balance and that PDE4B inhibitors could have utility in treatment of obesity and for suppression of obesity-induced inflammation in white adipose tissue.

Association Analyses Between Type 2 Diabetes Genes and Obesity Traits in Pigs

To investigate candidate genes involved in human type 2 diabetes (T2D) for obesity-related phenotypes in pigs. Statistical association analyses of genes with fat deposition were realized in a pig reference family constructed by two breeds, Berkshire and Yorkshire. Extensive sequencing was then attempted to discover the causative polymorphism. Genes implied in human T2D development, TCF7L2, WFS1, FTO, SLC30A8, and GCKR, were mapped on Sus scrofa chromosomes 14, 8, 6, 4, and 3, respectively. Only TCF7L2 was significantly associated with five fat traits in pigs. Further investigation demonstrated that one haplotype (HapB), but not the HapA (homologous to the region for human T2D susceptibility where single-nucleotide polymorphism (SNP) rs7903146 is located), is significantly associated with the fat-related traits. In HapB, two SNPs in TCF7L2 exon 8 and intron 10 are significantly associated with five fat traits, and may be in linkage disequilibrium with the causative variant with additive effects on all four backfat traits, and the total lipid percentage. Pigs of genotype TT for the SNP in exon 8 have only one transcript isoform (the one without exon 4), and lower backfat depth. Candidate gene analyses could provide novel ideas about how these genes function in T2D susceptibility in human, and support that the pig can be a suitable model for human obesity and T2D research. Further replication of this research in other pig populations should be considered, so that the possibility of utilizing these genetic markers in pig breeding or in animal model research can be explored.

Association Study between Candidate Genes and Obesity-Related Phenotypes Using a Sample of Lumberjacks

Introduction: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. Methods: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. Results: Significant associations were found between carriers of the minor alleles of APOE-ε2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. Conclusion: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.