Corticosteroid Binding Globulin Gene Polymorphism Influences Cortisol Driven Fat Distribution in Obese Women

Hypothalamo‐pituitary‐adrenal axis has been reported to influence fat mass distribution in obesity. We investigated the hypothesis that corticosteroid‐binding globulin (CBG) polymorphism could influence obesity, metabolic, or hypothalamo‐pituitary adrenal (HPA) axis activity parameters. In 44 obese pre‐menopausal women, a microsatellite located within the CBG gene was analyzed, providing three genotypes: 86/86 (n = 29), 86/90 (n = 14), and 90/90 (n = 1). No significant difference was found for obesity, metabolic, and HPA axis activity parameters between the genotypes 86/86 and 86/90. Looking for differences in correlations between HPA axis activity parameters and obesity or metabolic parameters between the two genotypes, genotype 86/90 showed a strong correlation between salivary cortisol after dexamethasone (0.25 mg) suppression test and waist‐to‐hip ratio (r = ?0.84, p = 0.0007), whereas this correlation was weaker for genotype 86/86 (r = ?0.34, p = 0.09). These data were completed with an analysis of the BclI polymorphism of the glucocorticoid receptor (GR) gene. There was an association between this GR polymorphism and both awakening salivary cortisol and postdexamethasone salivary cortisol but no association for obesity or metabolic parameters. We concluded that CBG gene polymorphisms might modulate the influence of the HPA axis on the fat mass distribution in this population.     

Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression.

Glucocorticoid receptor gene polymorphisms are associated with glucocorticoid hypersensitivity and visceral obesity. Perturbations in HPA axis sensitivity to glucocorticoids implicated in the pathogenesis of major depression may result from functional alterations in the glucocorticoid receptor gene. We 1) examined the prevalence of genotype distribution of specific polymorphisms of the glucocorticoid receptor gene (Bcl1, N363S, rs33388, rs33389) in a subset of women from the P.O.W.E.R. Study (which enrolled 21- to 45-year-old premenopausal women with major depression and healthy controls) and 2) explored whether such polymorphisms were associated with visceral obesity and insulin resistance. Women with major depression had a higher body mass index, a higher waist:hip ratio, and more body fat than did controls. No differences were observed in plasma and urinary cortisol or in insulin sensitivity. The G/G genotype of the Bcl1 polymorphism was significantly more common (p<0.03) in women with major depression (n=52) than in controls (n=29). In addition, GG homozygotes (depressed n=10; controls n=2) had higher waist:hip ratios than did non-GG carriers (p<0.02). N363S, rs33388, and rs33389 polymorphisms were not different between groups. In conclusion, premenopausal women with both major depression and the GG genotype of the Bcl1 polymorphism had greater abdominal obesity compared with non-GG carriers.     

Resistin levels are related to fat mass,but not to body mass index in children

The relationship of resistin levels with obesity remains unclear. The aim of this study was to determine resistin levels in prepubertal children and adolescents and evaluate their association with anthropometric parameters and body composition. The study population included 420 randomly selected 6–8-year-old children and 712 children aged 12–16 years. Anthropometric data were measured and body mass index (BMI) and waist-to-hip and waist-to-height ratios were calculated. Body composition was assessed using an impedance body composition analyzer. Serum resistin levels were determined using a multiplexed bead immunoassay. Resistin levels were not significantly different between sexes. No significant differences in serum resistin concentrations were found between obese, overweight, and normal weight children at any age, and no significant correlations were observed between resistin concentrations and weight or BMI. However, resistin levels showed a significant positive correlation with fat mass in 12–16-year-old children, particularly in girls. In addition to describing serum resistin levels in prepubertal children and adolescents, our study suggests that resistin is related to body fat rather than to BMI in adolescents.     

Circulating cortisol‐associated signature of glucocorticoid‐related gene expression in subcutaneous fat of obese subjects

Objective:

Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor.

Design and Methods:

To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24‐h urinary‐free cortisol (UFC) were compared with their clinical parameters, serum cytokine levels, and mRNA expression of 93 receptor action‐regulating and 93 glucocorticoid‐responsive genes in abdominal subcutaneous fat.

Results and Conclusions:

AM cortisol levels did not correlate with mRNA expression of the all genes examined, whereas PM cortisol levels, AM/PM cortisol ratios, and 24‐h UFC were associated with distinct sets of these genes. Body mass index did not significantly correlate with the four cortisol parameters employed. These results suggest that physiologic levels of AM serum cortisol do not solely represent biological effects of circulating cortisol on the expression of glucocorticoid‐related genes in subcutaneous adipose tissue, whereas PM levels, amplitude, and net amounts of the diurnally fluctuating serum cortisol have distinct effects. Through the genes identified in this study, glucocorticoids appear to influence intermediary metabolism, energy balance, inflammation, and local circadian rythmicity in subcutaneous fat. Our results may also explain in part the development of metabolic abnormality and obesity in subjects under stress or patients with melancholic/atypical depression who demonstrate elevated levels of PM serum cortisol.     

Environmental and Genetic Factors Influence the Relationship Between Circulating IL‐10 and Obesity Phenotypes

Interleukin‐10 (IL‐10) is a centrally operating anti‐inflammatory cytokine that plays a crucial role in the regulation of the innate immune system. It has strong inactivating properties on the inflammatory host response and has been related with viral persistence. We aimed to evaluate the association among circulating IL‐10, obesity phenotypes, IL‐10 and IL‐10R1 gene polymorphisms, and the environmental exposure to viral infection. IL‐10 ?819C/T gene promoter and IL‐10 receptor‐1 ?243A/G gene polymorphisms were studied in 760 subjects, whereas the former was also investigated in a replication study of 676 subjects. The association of circulating IL‐10 levels (enzyme‐linked immunosorbent assay) with the serum IgG against adenoviruses and enteroviruses was evaluated in a subset of 189 subjects. Circulating levels of IL‐10 were increased in obese people and were positively associated with weight, BMI, waist, waist‐to‐hip ratio, fat mass, systolic pressure, and, interestingly, the titer of adenoviruses and enteroviruses. Obese subjects with adenovirus titer over the median had the highest circulating IL‐10 concentration. Both obesity and adenovirus titer were independently associated with IL‐10 variance. Nonmorbid obese T carriers for the ?819CT IL‐10 gene polymorphism had significantly higher BMI and waist circumference, and those with normal fasting glucose had increased fasting triglycerides. G carriers for the ?536AG IL‐10R1 gene polymorphism had higher systolic and diastolic pressures, and IL‐10 levels; and obese G carriers had an increased waist‐to‐hip ratio. In summary, circulating IL‐10 levels were associated not only with obesity status but also with genetic factors and with the exposure to environmental pathogens.     

Genetic variation in two proteins of the endocannabinoid system and their influence on body mass index and metabolism under low fat diet.

The endocannabinoid system (ECS) plays an important and not yet fully understood role in hypothalamic and peripheral regulation of food intake, obesity, and metabolism. Two frequent single nucleotide polymorphisms (snp) have been identified in members of the ECS: the 1359 G/A variant in the cannabinoid receptor 1 ( CB1) and the P129T polymorphism in fatty acid amide hydrolase ( FAAH), a key degradation enzyme of endocannabinoids. -While for the 1359 G/A variant an association has been shown only with psychiatric diseases such as drug-abusing schizophrenia, the P129T polymorphism has recently been proved to be correlated to a higher body mass index (BMI) in a group of black and white Americans. However, no knowledge exists as to whether these variants affect the outcome of a low fat diet in obese subjects. Therefore, we genotyped a group of 451 obese and dyslipidaemic participants and observed the biometric and metabolic outcome of a 6 week low fat diet. While no significance was seen for the 1359 G/A variant, carriers of the P129T mutation in FAAH had a significantly greater decrease in triglycerides and total cholesterol as compared to wild type. The reason for our findings remains to be elucidated, however, a hepatic downregulation of endocannabinoid tone may contribute to the observed outcome in studied subjects.     

Effects of β2‐Adrenergic Receptor Gene Variants on Adiposity: The HERITAGE Family Study

We investigated whether the Arg16Gly and Gln27Glu polymorphisms of the β2‐adrenergic receptor gene were associated with body‐fat and fat‐distribution phenotypes measured before and in response to a 20‐week endurance‐training program. BMI, fat mass (FAT), percentage of body fat (%FAT), sum of eight skinfolds (SF8), and abdominal fat areas assessed by computed tomography were measured in adult sedentary white and black participants of the HERITAGE Family Study. Evidence of gene‐by‐obesity interaction was found in whites for several adiposity phenotypes measured before training. Analyses performed separately in nonobese and obese subjects revealed that obese men carrying the Glu27 allele have lower fat accumulation (BMI, FAT, and %FAT) than noncarriers. Among white obese women, Gly16Gly homozygotes had a lower fat accumulation (BMI, FAT, and SF8) than Arg16Gly and Arg16Arg carriers. In response to endurance training, white women with the Arg16Arg genotype exhibited a greater reduction in BMI, FAT, and %FAT. Results observed in blacks were mostly negative. These results suggest that polymorphisms in the β2‐adrenergic receptor gene influence the amount of body fat in white obese men (Gln27Glu) and women (Arg16Gly), as well as the changes in adiposity in response to endurance training in white women (Arg16Gly).     

Association of A-604G <Emphasis Type="Italic">ghrelin</Emphasis> gene polymorphism and serum ghrelin levels with the risk of obesity in a mexican population

Obesity is a metabolic disorder that has a multifactorial etiology and affects millions of people worldwide. Ghrelin, a hormone coded by the GHRL gene, plays a role in human body composition and appetite. Single nucleotide polymorphisms (SNPs) of the GHRL gene have been associated with obesity and metabolic disorders. To evaluate the association of A-604G SNP of GHRL promoter region with serum ghrelin levels and the risk of obesity in a Mexican population. Two hundred and fifty individuals were enrolled and classified as obese or control subjects (CS) according to BMI. DNA samples, anthropometric measurements and biochemical parameters were obtained from all subjects. The A-604G SNP was genotyped using PCR-RFLPs technique. Ghrelin levels were measured using a commercial enzyme immunoassay. The G/G genotype was more frequent among obese individuals (p?<?0.0001) when compared to CS. The G/A genotype and A allele were associated with protection against obesity (OR 0.29, p?<?0.0001; OR 0.39, p?<?0.0001 respectively), the A allele remained significant after adjusting for age and gender (OR: 0.25, p?<?0.0001). Serum ghrelin levels were higher in obese patients (p?=?0.004) than in CS, however, significance was lost after adjustment for age (p?=?0.088). The G/G genotype was associated with higher levels of serum ghrelin (p?=?0.02) independently of the effect of age. The G/G genotype of the A-604G SNP in the GHRL gene is associated with altered serum ghrelin levels and obesity. The A allele was also associated with protection against obesity in this study.     

Genetic variation in the cannabinoid receptor gene (CNR1) (G1359A polymorphism) and their influence on anthropometric parameters and metabolic parameters under a high monounsaturated vs. high polyunsaturated fat hypocaloric diets

An intragenic polymorphism (1359 G/A) of the cannabinoid receptor 1 (CNR1) gene was reported as a common polymorphism in Caucasian populations (rs1049353). Intervention studies with this polymorphism have yield contradictories results. We decide to investigate the role of polymorphism (G1359A) of (CNR1) gene on metabolic parameters and weight loss secondary to a high monounsaturated fat and high polyunsaturated fat hypocaloric diets in obese subjects. A population of 258 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 3-month period in which subjects received 1 of 2 diets (diet M: high monounsaturated fat diet vs diet P: high polyunsaturated fat diet). One hundred and sixty five patients (63.9%) had the genotype G1359G and 93 (36.1%) patients (A allele carriers) had G1359A (78 patients,30.3%) or A1359A (15 patients,5.8%) genotypes. In subjects with both genotypes, body mass index, weight, fat mass, waist circumference and systolic blood pressures decreased with both diets. With the diet-type M and in both genotype groups, biochemical parameters remained unchanged. After the diet type P and in subjects with both genotypes, glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, insulin and homeostasis model assessment for insulin resistance (HOMA-IR) levels decreased. In G1359G genotype subjects after both diets, leptin levels decreased. The finding of this study is the association of the A allele with a lack of improvement on leptin levels. Subjects with both genotypes and after a high polyunsaturated fat hypocaloric diet showed a significant improvement of LDL cholesterol, total cholesterol, HOMA-IR and insulin levels.     

Impact of adiponectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men

The aim of this study was first to examine the relationships between adiponectin gene (Apm1) polymorphisms and anthropometric indices as well as plasma adiponectin and lipoprotein/lipid levels, and then to investigate whether the presence of visceral obesity or insulin resistance may modulate the impact of these polymorphisms on metabolic risk variables. Molecular screening of the Apm1 gene was achieved, and a sample of 270 unrelated men recruited from the greater Quebec City area and selected to cover a wide range of body fatness values was genotyped. Sequencing of the Apm1 gene revealed two previously reported polymorphisms (c.45T>G and c.276G>T) as well as two newly identified genetic variations (-13752delT and -13702G>C). Carriers of the c.276T allele had higher LDL-cholesterol and lower HDL-triglyceride concentrations than did 276G/G homozygotes (P=0.02 and P=0.01, respectively). Carriers of the c.45G allele exhibited higher plasma adiponectin concentrations than did 45T/T homozygotes (P=0.04). After dividing each genotype group into subgroups for visceral AT, homozygotes for the normal allele at position -13752delT, carriers of the c.45G allele, and carriers of the c.276T allele had similar total apolipoprotein B (apoB) concentrations, whether they were viscerally obese or not. These results suggest that some Apm1 gene polymorphisms influence plasma adiponectin concentrations and lipoprotein/lipid levels. In addition, the impact of these polymorphisms is modulated by the presence of visceral obesity.     

Il6 gene promoter polymorphism (-174G/C) influences the association between fat mass and cardiovascular risk factors

During the last decades, the prevalence of obesity has increased rapidly among young people. A polymorphism in the promoter region of the IL6 gene (-174G/C), has been previously reported to be involved in obesity and metabolic syndrome development. Therefore, the aim of the study was to examine whether the IL6-174G/C polymorphism influence the association of body fat with low-grade inflammatory markers and blood lipids and lipoproteins in Spanish adolescents. 504 Spanish adolescents participating in the AVENA study were genotyped for the-174G/C polymorphism of the IL6 gene. Anthropometric and body composition measurements were taken and blood samples were collected for plasma molecules determinations. No differences between genotypes were observed in anthropometric values, body composition measurements and plasma markers concentration. Physical activity level differ between genotypes with subjects carrying the C allele of the polymorphism being significantly (p<0.05) more active than GG subjects. The association between body fat mass and plasma glucose was influenced by the -174G/C polymorphism of the IL6 gene. Subjects carrying the C allele of the mutation seem to have higher values of lipoprotein (a) and C-reactive protein as their percentage of body fat mass increase. Our results suggest that this promoter polymorphism influences the association between adiposity and some plasma markers.     

IL6 and IL1B polymorphisms are associated with fat mass in older men: the MrOS Study Sweden

There is growing evidence that immune functions are linked to the regulation of body fat. Our studies of knockout mice indicate that both endogenous interleukin (IL)-6 and IL-1 can suppress mature-onset obesity. We now investigated whether four common polymorphisms of the IL6 and IL1 systems are associated with the fat mass measured with dual-energy X-ray absorptiometry (DXA) in elderly men (n = 3,014). The study subjects were from the Swedish part of the MrOS multicenter population study and 69-81 years of age. The IL6 -174 G>C (Minor allele frequency (MAF) = 48%) gene promoter polymorphism was associated with the primary outcome total fat mass (P = 0.006) and regional fat masses, but not with lean body mass. The IL1B -31T>C (MAF = 34%) polymorphism was also associated with total fat (P = 0.007) and regional fat masses, but not lean body mass. The IL-1 receptor antagonist (IL-1ra) gene (IL1RN) +2018 T>C (MAF = 27%) polymorphism (in linkage disequilibrium (LD) with a well-studied variable number tandem repeat of 86 base pair (bp)) and IL1B +3953 C>T (MAF = 26%) polymorphism were not associated with total fat mass. In conclusion, the IL-1 and IL-6 systems, shown to suppress mature-onset obesity in experimental animals, contain gene polymorphisms that are associated with fat, but not lean, mass in elderly men.     

Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity

As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all.     

Validity of the body mass index and fat mass index as an indicator of obesity in children aged 3-5 year

The validity of the BMI and fat mass index (FMI) as indicators of obesity was evaluated in a group of 3-5 yr old (n=486) children. Bioelectrical impedance analysis (BIA) was measured (using 50 kHz and tetrapolar electrodes) in order to calculate percent fat mass (%FM) and FMI (fat mass/stature squared). For boys, obesity was defined as > or =20%FM. For girls, the cutoff for obesity was > or =25%FM. However, obesity was defined as a BMI at or above the 90th percentile of age- and sex-specific data in this study. The percentile cutoffs for FMI were the same as for BMI using the same sample. There were correlations between BMI or FMI and %FM, but there was no significant correlation between BMI or FMI and stature. Therefore, it appears that both the BMI and FMI in this study are far more useful indices with which to assess obesity, and are reasonable indicators of fatness. However, with the use of %FM by BIA as the criterion for obesity, BMI and FMI had high specificities (95.5-96.4% for BMI and 99.5-100% for FMI) and lower but variable sensitivities (30.4-37.5% for BMI and 42.9-68.8% for FMI). Thus, almost all children who were not obese were classified correctly. In contrast, many obese children were not correctly identified by BMI and FMI. Therefore, we conclude that BMI should be used with caution as an indicator of childhood obesity. The new recommendations based on the FMI approach for defining childhood obesity are associated with a level of sensitivity that is somewhat higher than that of the BMI approach. Caution should, however, be used in generalizing from the findings in this study, and a further investigation of the issue is required.     

Sex difference in the effect of puberty on the relationship between fat mass and bone mass in 926 healthy subjects, 6 to 18 years old

Objective: Understanding factors influencing bone mineral accrual is critical to optimize peak bone mass during childhood. The epidemic of pediatric obesity and reported higher incident of fracture risk in obese children led us to study the influence of fat mass on bone mineral content (BMC) in children. Research Methods and Procedures: Height; weight; pubertal stage; and BMC, non‐bone fat‐free mass (nbFFM), and fat mass (FM) by DXA were obtained in a multiethnic group of healthy children (444 girls/482 boys; 6 to 18 years old) recruited in the New York metropolitan area. Regression techniques were used to explore the relationship between BMC and FM, with age, height, nbFFM, pubertal stage, sex, and ethnicity as covariates. Results: Because there were significant sex interactions, separate regression analyses were performed for girls and boys. Although ln(nbFFM) was the greatest predictor of ln(BMC), ln(FM) was also a significant predictor in prepubertal boys and all girls but not in pubertal boys. This effect was independent of ethnicity. Discussion: FM was a determinant of BMC in all girls but in only prepubertal boys. Our study confirms nbFFM as the greatest predictor of BMC but is the first to find a sex difference in the effect of puberty on the relationship of FM to BMC. Our results suggest that, in two individuals of the same sex and weight, the one with greater fat mass will have lower BMC, especially pubertal boys. The implications of these findings for achievement of optimal peak bone mass in a pediatric population with an unprecedented incidence of overweight and “overfat” status remain to be seen.     

Bcl1 polymorphism of glucocorticoid receptor gene in patients with bronchial asthma with obesity

The objective of this investigation was to analyze possible association between Bcl1 polymorphism of glucocorticoid receptor gene and obesity in patients with bronchial asthma (BA). The study involved 188 patients with bronchial asthma and 95 apparently healthy adult individuals. Generally accepted assessments and examinations for BA diagnosis, and anthropometric, molecular-genetic and statistic methods of investigation were used in the research. It was found out that the patients with BA demonstrated higher body mass index (BMI) and higher ratio of fat centralization much more often, than the control group. Genotypes distribution for Bcl1 polymorphism in patients with BA showed a statistically significant difference between patients with different BMI unlike the control group. Comparison of genotype frequency for Bcl1 polymorphism in glucocorticoid receptor gene in individuals with different ratio of fat centralization in the control group and in the patients with BA separately showed statistically significant differences in the distribution of gene allelic variations only among the patients with BA. It was demonstrated that G/G genotype in the patients with visceral obesity was associated with BA.     

A single nucleotide polymorphism (SNP) in the leptin receptor is associated with BMI, fat mass and leptin levels in postmenopausal Caucasian women

The human leptin (obese) receptor gene contains a number of single nucleotide polymorphisms, including GLN223ARG, which changes an amino acid on the extracellular region common to all isoforms of the receptor. Here, we demonstrate that, in postmenopausal Caucasian women, genotypes at that locus are associated with differences in body mass index (BMI), fat mass and serum leptin levels. Measurement of serum leptin-binding activity indicates that this may reflect changed receptor function associated with genotype. These observations indicate that functional variations in the leptin receptor gene are important factors in the regulation of adiposity and BMI.