The finding of new genetic polymorphism of UCP-1 A-1766G and its effects on body fat accumulation

A-1766G polymorphism, for the first time, has been found in the sequencing of pooled and individual genomic DNA of Korean subjects at the 5' flanking region of the UCP-1 gene. The effects of new polymorphism on body fat were elucidated among 387 Korean female subjects. It was shown that the genotypes AA, AG, and GG were consisted of 57.4%, 37.7%, and 4.9%, respectively, which was in agreement with Hardy-Weinberg equilibrium (P=0.327). The frequency of major A allele was 0.762 and that of minor G allele was 0.238. It is found that the waist-hip ratio (WHR) (P=0.008), body fat mass (P=0.023), and percent body fat (P=0.014) are significantly higher in the AG/GG type compared to the AA type. When the subjects were analyzed using computerized tomography, there were significant increases in the AG/GG type compared to the AA type in the abdominal subcutaneous fat (P=0.015) and the abdominal visceral fat (P=0.013), respectively. A-1766G is approximately 2 kb downstream from the well-known A-3826G polymorphism, and no linkage between them was found (D'=0.929, R(2)=0.283). Three haplotypes (frequency >0.05) were examined from two polymorphisms and studied for their physiological effects. It was found that haplotype [GG] was significantly associated with increased body fat, while haplotype [GA] was associated with decreased body fat.     

Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity

Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4-42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = -0.30; all P ≤ 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors.     

Increased intramyocellular lipid accumulation in HIV-infected women with fat redistribution.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance. Increased intramyocellular lipid (IMCL) concentrations are thought to contribute to insulin resistance, being linked to metabolic and body composition variables. We examined 46 women: HIV infected with fat redistribution (n = 25), and age- and body mass index-matched HIV-negative controls (n = 21). IMCL was measured by 1H-magnetic resonance spectroscopy, and body composition was assessed with computed tomography, dual-energy X-ray absorptiometry (DEXA), and magnetic resonance imaging. Plasma lipid profile and markers of glucose homeostasis were obtained. IMCL was significantly increased in tibialis anterior [135.0 +/- 11.5 vs. 85.1 +/- 13.2 institutional units (IU); P = 0.007] and soleus [643.7 +/- 61.0 vs. 443.6 +/- 47.2 IU, P = 0.017] of HIV-infected subjects compared with controls. Among HIV-infected subjects, calf subcutaneous fat area (17.8 +/- 2.3 vs. 35.0 +/- 2.5 cm2, P < 0.0001) and extremity fat by DEXA (11.8 +/- 1.1 vs. 15.6 +/- 1.2 kg, P = 0.024) were reduced, whereas visceral abdominal fat (125.2 +/- 11.3 vs. 74.4 +/- 12.3 cm2, P = 0.004), triglycerides (131.1 +/- 11.0 vs. 66.3 +/- 12.3 mg/dl, P = 0.0003), and fasting insulin (10.8 +/- 0.9 vs. 7.0 +/- 0.9 microIU/ml, P = 0.004) were increased compared with control subjects. Triglycerides (r = 0.39, P = 0.05) and extremity fat as percentage of whole body fat by DEXA (r = -0.51, P = 0.01) correlated significantly with IMCL in the HIV but not the control group. Extremity fat (beta = -633.53, P = 0.03) remained significantly associated with IMCL among HIV-infected patients, controlling for visceral abdominal fat, abdominal subcutaneous fat, and antiretroviral medications in a regression model. These data demonstrate increased IMCL in HIV-infected women with a mixed lipodystrophy pattern, being most significantly associated with reduced extremity fat. Further studies are necessary to determine the relationship between extremity fat loss and increased IMCL in HIV-infected women.     

Validity and reliability of dual-energy X-ray absorptiometry for the assessment of abdominal adiposity.

A number of methods exist for the estimation of abdominal obesity, ranging from waist-to-hip ratio to computed tomography (CT). Although dual-energy X-ray absorptiometry (DXA) was originally used to measure bone density and total body composition, recent improvements in software allow it to determine abdominal fat mass. Sixty-five men and women aged 18-72 yr participated in a series of studies to examine the validity and reliability of the DXA to accurately measure abdominal fat. Total body fat and abdominal regional fat were measured by DXA using a Lunar DPX-IQ. Multislice CT scans were performed between L1 and L4 vertebral bodies (region of interest) using a Picker PQ5000 CT scanner, and volumetric analyses were carried out on a Voxel Q workstation. Both abdominal total tissue mass (P = 0.02) and abdominal fat mass (P < 0.0001) in the L1-L4 region of interest were significantly lower as measured by DXA compared with multislice CT. However, Bland-Altman analysis demonstrated good concordance between DXA and CT for abdominal total tissue mass (i.e., limits of agreement = -1.56-2.54 kg) and fat mass (i.e., limits of agreement = -0.40-1.94 kg). DXA also showed excellent reliability among three different operators to determine total, fat, and lean body mass in the L1-L4 region of interest (intraclass correlations, R = 0.94, 0.97, and 0.89, respectively). In conclusion, the DXA L1-L4 region of interest compared with CT proved to be both reliable and accurate method to determine abdominal obesity.     

Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is characterized by abnormalities of lipid metabolism, glucose homeostasis, and fat distribution. Overaccumulation of intramuscular lipid may contribute to insulin resistance in this population. We examined 63 men: HIV positive with lipodystrophy (n = 22), HIV positive without lipodystrophy (n = 20), and age- and body mass index-matched HIV-negative controls (n = 21). Single-slice computed tomography was used to determine psoas muscle attenuation and visceral fat area. Plasma free fatty acids (FFA), lipid profile, and markers of glucose homeostasis were measured. Muscle attenuation was significantly decreased in subjects with lipodystrophy [median (interquartile range), 55.0 (51.0-58.3)] compared with subjects without lipodystrophy [57.0 (55.0-59.0); P = 0.05] and HIV-negative controls [59.5 (57.3-64.8); P < 0.01]. Among HIV-infected subjects, muscle attenuation correlated significantly with FFA (r = -0.38; P = 0.02), visceral fat (r = -0.49; P = 0.002), glucose (r = -0.38; P = 0.02) and insulin (r = -0.60; P = 0.0001) response to a 75-g oral glucose tolerance test. In forward stepwise regression analysis with psoas attenuation as the dependent variable, visceral fat (P = 0.02) and FFA (P < 0.05), but neither body mass index, subcutaneous fat, nor antiretroviral use, were strong independent predictors of muscle attenuation (r2 = 0.39 for model). Muscle attenuation (P = 0.02) and visceral fat (P = 0.02), but not BMI, subcutaneous fat, FFA, or antiretroviral use, were strong independent predictors of insulin response (area under the curve) to glucose challenge (r2 = 0.47 for model). These data demonstrate that decreased psoas muscle attenuation due to intramuscular fat accumulation may contribute significantly to hyperinsulinemia and insulin resistance in HIV-lipodystrophy patients. Further studies are needed to assess the mechanisms and consequences of intramuscular lipid accumulation in HIV-infected patients.     

The alpha 2-adrenergic receptor gene and body fat content and distribution: the HERITAGE Family Study

BACKGROUND: Among adrenergic receptor subtypes that regulate lipid mobilization, the alpha2-adrenergic receptor is involved in the inhibition of fatty acid mobilization from adipose tissue. A C-1291G polymorphism is located in the alpha2-adrenergic receptor gene (ADRA2A) but no association with body fat accumulation has been reported yet. MATERIALS AND METHODS: Body mass index (BMI), fat mass (FAT), percentage body fat (%FAT), trunk-to-extremity skinfold ratio (TER), sum of eight skinfolds (SF8), and abdominal subcutaneous (ASF), visceral (AVF), and total (ATF) fat areas assessed by CT scan have been measured in adult sedentary white (n = 503) and black (n = 276) subjects participating in the HERITAGE Family Study. Association between the C-1291G polymorphism and each phenotype was tested separately in men and women of each race using ANCOVA with the effects of age as covariate in addition to the effects of BMI for TER and of FAT for AVF, ASF, and ATF. RESULTS: The allele frequencies of the ADRA2A C-1291G polymorphism differed between races. No association was observed in white subjects, except for a moderate effect of the polymorphism accounting for less than 1% of the variance in AVF and ATF in women. In black subjects, however, the G-1291 allele was found to be associated with an increase of TER in men (3.8% of variance accounted for by the polymorphism), while in black women it was associated with a decrease in TER (2.9%) and in AVF (2.5%). CONCLUSION: These results suggest a role for the ADRA2A gene in determining the propensity to store fat in the abdominal area, independently of total body fatness.     

Determinants of coronary flow velocity reserve in healthy young men

The objective of this study was to identify risk markers for attenuated coronary flow velocity reserve (CFVR) that exist in healthy young men without evident atherosclerotic risk factors. Coronary blood flow velocity was measured with transthoracic Doppler echocardiography at baseline and during adenosine infusion in 37 healthy nonsmoking men [mean age, 27 yr (SD 4.0)]. Body composition and distribution of fat tissue were assessed with anthropometric measures and regulation of fat metabolism by determination of adiponectin and leptin levels. Physical performance capacity was tested with ergospirometry. The mean body mass index was 23 kg/m2 (SD 1.9), waist-to-hip ratio was 0.84 (SD 0.04), and CFVR was 3.5 (SD 0.61). Obesity indexes at study outset, leptin, adiponectin, maximal load (Max load in W/kg) and maximal oxygen consumption (Vo2 peak in ml x kg(-1) x min(-1)) in ergospirometry, rate-pressure product, and heart rate at rest were significantly associated with CFVR. In multivariate analysis, Max load (in W/kg) and waist-to-hip ratio were the only independent predictors of CFVR. We found no relationship between CFVR and serum lipids or body mass index. We conclude that abdominal fat accumulation and low aerobic fitness are independently associated with CFVR in men.     

Relationships of resting energy expenditure with body fat distribution and abdominal fatness in Japanese population

Body fat distribution and abdominal fatness are indicators of risks for coronary heart disease. However, the relationships between resting energy expenditure (REE) and the body fat distribution or the abdominal fatness are unclear. We examined the relationships of REE with whole-body fat distribution (waist, hip and waist-to-hip ratio: WHR) and abdominal fatness (intra-abdominal fat: IF and subcutaneous fat: SF) after adjustment for body composition. 451 men and 471 women were subdivided into two groups, 40-59 years: middle-aged group and 60-79 years: elderly group. REE was measured by an indirect calorimetry system. Percentage of fat mass (%FM), fat mass (FM) and fat-free mass (FFM) were assessed by a dual-energy x-ray absorptiometry method. The IF area (IFA) and SF area (SFA) at the level of the umbilicus were measured using computed tomography. Circumference of waist and hip were measured in a standing position. The WHR, waist circumference and SFA did not significantly (p>0.05) associate with the REE after adjusting for FM, FFM and age in any of the groups. The adjusted REE was significantly and inversely correlated with hip (r=-0.159, p<0.05) and IFA (r=-0.131, p<0.05) in the elderly men. These results suggest that lower REE may contribute to greater hip and IFA rather than WHR and waist in elderly men.     

ACDC/Adiponectin and PPAR‐γ Gene Polymorphisms: Implications for Features of Obesity

Objective: The main purpose of this study was to investigate associations of single‐nucleotide polymorphisms (SNPs) in the adipocyte C1q and collagen domain‐containing (ACDC) gene and its regulator, the nuclear peroxisome proliferator‐activated receptor (PPAR)‐γ gene, with body fat mass and its topographical distribution in postmenopausal women. Research Methods and Procedures: Participants were 1501 healthy women, 60 to 85 years old, who were genotyped for four SNPs in the ACDC gene (−11391G/A, −11377C/G, +45T/G, +276G/T) and the Pro12Ala SNP in the PPAR‐γ gene. Total body fat mass and the central to peripheral fat mass ratio (CFM/PFM ratio) were measured using DXA. Adiponectin and homeostasis model assessment of insulin resistance were measured in 287 subjects. Results: The −11377C/G SNP was associated with adiponectin (p < 0.001) and the CFM/PFM ratio (p = 0.005); the G allele being associated with low adiponectin and high CFM/PFM ratio. Similar associations of adiponectin (p = 0.0001) and the CFM/PFM ratio (p = 0.002) characterized the 1_2 (G_G) promoter haplotype (11391G/A_−11377C/G). Genotype variation of SNP Pro12Ala was associated with total body fat mass (p = 0.04); women with GG being the most obese (p = 0.01). The Ala/Ala (GG) genotype of Pro12Ala SNP interacted with the CC genotype of SNP‐11377C/G in the determination of BMI (p = 0.001), when analyzed using a codominant model. Discussion: Polymorphisms in the ACDC gene are associated with body fat distribution, whereas the Pro12Ala polymorphism in PPAR‐γ is associated with overall adiposity, apparently in interaction with an ACDC promoter SNP.     

Novel Obesity Risk Loci Do Not Determine Distribution of Body Fat Depots: A Whole‐body MRI/MRS study

A recent meta‐analysis of genome‐wide association studies has identified six new risk‐loci for common obesity. We studied whether these risk loci influence the distribution of body fat depots. We genotyped 1,469 nondiabetic subjects for the single‐nucleotide polymorphisms (SNPs) TMEM18 rs6548238, KCTD15 rs11084753, GNPDA2 rs10938397, SH2B1 rs7498665, MTCH2 rs10838738, and NEGR1 rs2815752. We assessed BMI, waist circumference, total body fat, and lean body mass (bioimpedance). All subjects underwent an oral glucose tolerance test (OGTT) for estimation of insulin sensitivity. In 332 subjects, we measured total adipose tissue (TAT), visceral adipose tissue (VAT), nonvisceral adipose tissue (NVAT), liver fat content, and intramyocellular lipids (IMCLs) using whole‐body magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). In the dominant inheritance model, the risk alleles of TMEM18 rs6548238 and MTCH2 rs10838738 were nominally associated with higher BMI (P = 0.04, both). The risk allele of TMEM18 rs6548238 was additionally associated with higher waist circumference and total body fat (P ≤ 0.03), the risk allele of NEGR1 rs2815752 with higher waist circumference (P = 0.05) and unexpectedly with lower BMI (P = 0.01). In the MR cohort, we found an association of the risk allele of SH2B1 rs7498665 with higher VAT (P = 0.009) and of GNPDA2 rs10938397 with increased IMCLs (P = 0.03). After Bonferroni correction for multiple comparisons (corrected α‐level: P = 0.0085), none of the SNPs was significantly associated with measures of adiposity or body fat distribution (all P > 0.009, dominant inheritance model). Therefore, our results suggest that these new obesity SNPs, despite their influence on BMI, are neither associated with a metabolically unfavorable nor with a favorable body composition.     

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.     

Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30 +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2). min(-1)) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with magnetic resonance imaging at the L(4-5) level. Basal endogenous glucose production (EGP), hepatic insulin resistance index (basal EGP x FPI), and total glucose disposal (TGD) during the first and second insulin clamp steps were similar in male and female subjects. VF (159 +/- 9 vs. 143 +/- 9 cm2) and DSF (199 +/- 14 vs. 200 +/- 15 cm(2)) were not different in male and female subjects. SSF (104 +/- 8 vs. 223 +/- 15 cm2) was greater (P < 0.0001) in female vs. male subjects despite similar body mass index (31 +/- 1 vs. 30 +/- 1 kg/m2) and total body fat mass (31 +/- 2 vs. 33 +/- 2 kg). In male T2DM, TGD during the first insulin clamp step (1st TGD) correlated inversely with VF (r = -0.45, P < 0.01), DSF (r = -0.46, P < 0.01), and SSF (r = -0.39, P < 0.05). In males, VF (r = 0.37, P < 0.05), DSF (r = 0.49, P < 0.01), and SSF (r = 0.33, P < 0.05) were correlated positively with hepatic insulin resistance. In females, the first TGD (r = -0.45, P < 0.05) and hepatic insulin resistance (r = 0.49, P < 0.05) correlated with VF but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral adiposity is associated with both peripheral and hepatic insulin resistance, independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance.     

Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study.

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index (P = 0.01), fat mass (P = 0.01), and percent body fat (P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat (P = 0.05) and a greater increase in post-heparin LPL activity (P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.     

Effects of short-term dehydroepiandrosterone supplementation on body composition in young athletes

Dehydroepiandrosterone (DHEA) is often promoted as a slimming and weight/fat loss agent and ingestion of DHEA may have hypolipidemic and anti-obesity properties. The main aim of this study was to examine the effects of acute DHEA intake on body composition and serum steroid hormones in young athletes. Twenty young (19 to 22 years) male soccer players were allocated into two randomly assigned trials in double-blind design by ingesting 100-mg daily oral DHEA or as placebo (PLA) for 28 days. Body mass was not affected by 4 weeks of DHEA supplementation (P > 0.05). No significant changes in body mass index (BMI), waist-to-hip ratio (WHR) and body fat or total muscle mass for the two groups were detected at the end of the trial (P > 0.05). There was no within- or between-group difference in arm fat index (AFI) and corrected mid-upper-arm muscle area (cAMA) (P > 0.05). Treatment with DHEA resulted in a significant increase of total testosterone, estradiol and DHEA-S levels in treated subjects versus the placebo group (P < 0.05). Results of this study suggest that DHEA supplementation has no beneficial effects on body composition in young competitive athletes.     

Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women

We examined expression and activity of steroid aldoketoreductase (AKR) 1C enzymes in adipose tissue in women. AKR1C1 (20alpha-hydroxysteroid dehydrogenase; 20alpha-HSD), AKR1C2 (3alpha-HSD-3), and AKR1C3 (17beta-HSD-5) are involved mainly in conversion of progesterone to 20alpha-hydroxyprogesterone and inactivation of dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol. Abdominal subcutaneous and omental adipose tissue biopsies were obtained during abdominal hysterectomies in seven women with low visceral adipose tissue (VAT) area and seven age- and total body fat mass-matched women with visceral obesity. Women with elevated VAT areas were characterized by significantly higher omental adipose tissue 20alpha-HSD and 3alpha-HSD-3 mRNA abundance compared with women with low VAT accumulations (1.4- and 1.6-fold differences, respectively; P < 0.05). Omental and subcutaneous adipose tissue 3alpha-HSD activities were significantly higher in women with high vs. low VAT areas (P < 0.05 for both comparisons). Total and visceral adiposities were positively associated with omental 20alpha-HSD mRNA level (r = 0.75, P < 0.003 for fat mass; r = 0.57, P < 0.04 for VAT area) and omental 3alpha-HSD-3 mRNA level (r = 0.68, P < 0.01 for fat mass; r = 0.74, P < 0.003 for VAT area). Enzyme activities in both depots were also positively correlated with adiposity measures. Omental adipose tissue enzyme expression and activity were positively associated with omental adipocyte size and LPL activity. In conclusion, mRNA abundance and activity of AKR1C enzymes in abdominal adipose tissue compartments are positive correlates of adiposity in women. Increased progesterone and/or dihydrotestosterone reduction in abdominal adipose tissue may impact locally on fat cell metabolism.     

Homocysteine Levels in Patients with Schizophrenia on Clozapine Monotherapy

We tested the hypothesis that homocysteine levels are higher in blood of schizophrenic subjects on clozapine monotherapy than in healthy controls and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. Regarding the whole group, homocysteine levels were significantly higher in men (17.0 ± 3.4 vs. 12.1 ± 4.0 μmol/L, p = 0.009). Homocysteine levels correlated with waist circumference (R = 0.58, p = 0.003), waist-to-hip ratio (R = 0.57, p = 0.003), basal metabolic rate (R = 0.48, p = 0.01), lean body mass [kg] (R = 0.53, p = 0.008), body water [L] (R = 0.53, p = 0.008) and triglycerides (R = 0.57, p = 0.003). There were no significant differences of homocysteine levels for impaired fasting glucose, abdominal obesity, obesity/overweight, and dyslipidemia. Homocysteine levels did not correlate with age, treatment duration, clozapine dose, weight, body mass index, abdominal circumference, blood pressure, total body fat, cholesterol, high density lipoproteins, low density lipoproteins, uric acid, calcium, glucose, insulin, homoeostasis model assessment of insulin resistance 1, and homoeostasis model assessment of insulin resistance 2. We did not find significant differences in blood homocysteine levels between subjects with schizophrenia and controls. Association with waist circumference may support homocysteine role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of homocysteine than women.     

A single nucleotide polymorphism on the promoter of eotaxin1 associates with its mRNA expression and asthma phenotypes

Eotaxin1 plays a pivotal role in eosinophil-associated inflammation. Previously, we demonstrated 14 single-nucleotide polymorphisms (SNPs) in the human eotaxin1 gene and the association between the EOT+67G>A allele and the level of IgE. In this study, we investigated the association between the SNPs and plasma eotaxin1 levels, peripheral blood eosinophil counts, and PC20 methacholine values in normal and asthmatic subjects, and the effects of SNPs on the process of eotaxin1 production. The EOT-576C>T and EOT-384A>G polymorphisms and haplotypes (ht1 and ht4) were significantly associated with plasma eotaxin1 levels in the asthmatics (p < 0.001-0.040). The log [plasma eotaxin1] values correlated with the log [serum total IgE] values in the asthmatics and the normal controls (p = 0.012 and p = 0.004, respectively), and with the log [PC20 methacholine] values in the asthmatics (p = 0.014). A DNA-protein complex was formed with EOT-384A>G, but not with the other SNPs of the promoter. The interaction was stronger with the minor allele than with the common allele, and was reduced upon TNF-alpha exposure. TNF-alpha-stimulated PBMCs from the asthmatics with the minor allele homozygote expressed significantly lower levels of eotaxin1 mRNA than those from individuals with the common allele. The EOT+67G>A polymorphism, which substitutes alanine with threonine, did not affect eotaxin1 production or activity. Our data suggest that the EOT-384A>G SNP participates in the regulation of eotaxin1 expression by providing a potential binding site for a repressor, and that the ANOVA of EOT-384A>G may predict asthma phenotypes.     

Subcutaneous abdominal preadipocyte differentiation in vitro inversely correlates with central obesity

Expansion of adipose tissue mass results from increased number and size of adipocyte cells. We hypothesized that subcutaneous abdominal preadipocytes in obese individuals might have an intrinsically higher propensity to differentiate into adipocytes. Thus we investigated the relationship between obesity and the level of in vitro preadipocyte differentiation in Pima Indians. Subcutaneous abdominal stromal vascular fractions containing preadipocytes were cultured from 58 nondiabetic subjects [31 M/27 F, 30 +/- 6 yr, body fat 34 +/- 8% by dual-energy X-ray absorptiometry (means +/- SD)]. The average percentage of preadipocyte differentiation (PDIFF; cell count by microscopy) was 11 +/- 11% (range 0.2-51%). PDIFF correlated negatively with percent body fat (r = -0.35, P = 0.006) and waist circumference (r = -0.45, P = 0.0004). Multiple regression analysis indicated that waist circumference (P = 0.01), sex (P = 0.01), and percent body fat (P = 0.05) were significant determinants of PDIFF. Molecular characterization of predifferentiated cultured cells was performed by real-time PCR measurements of glucocorticoid receptor-alpha (GRalpha), insulin-like growth factor I receptor (IGF-IR), peroxisome proliferator-activated receptor-gamma (PPARgamma), enhancer-binding protein GATA-3, CCAAT/enhancer-binding protein-alpha undifferentiated protein (CUP/AP-2alpha), and endothelial cell-specific marker 2 (ECSM2). The mRNA concentrations of GRalpha correlated with PDIFF (r = 0.29, P = 0.03), but the others did not (IGF-IR, r = 0.003, P = 1.0; PPARgamma, r = -0.1, P = 0.5; GATA-3, r = 0.02, P = 0.9; CUP/AP-2alpha, r = -0.2, P = 0.1; ECSM2, r = 0.04, P = 0.7). Contrary to our hypothesis, the results may indicate a blunted in vitro differentiation potential of preadipocytes in centrally obese individuals. The lower differentiation potential of preadipocytes in the obese subjects might be due, at least partly, to decreased glucocorticoid receptor expression.     

血清视黄醇结合蛋白-4同儿童肥胖和代谢综合征组分的关系

目的:探讨儿童血清视黄醇结合蛋白-4(retinol-binding protein4,RBP-4),视黄醇,甲状腺素运载蛋白(transthyretin,TTR)等维生素A相关指标与肥胖、胰岛素抵抗以及代谢综合征组分之间的关系。方法:分别随机选取本地区13-15岁体检学生,其中正常对照组和单纯性肥胖组儿童各50例,测定其血清RBP-4、视黄醇、TTR水平;利用空腹胰岛素和定量胰岛索敏感性检测指标评价其胰岛素抵抗;同时测定代谢综合征部分组分水平和亚临床炎症指标。结果:仅5%的青少年存在维生素A营养不足状态。排除年龄、性别、感染等因素的影响后,血清RBP-4水平、视黄醇、RBP-4/TTR摩尔比值以及RBP-4/视黄醇摩尔比值与体重指数、体脂含量以及体脂的中心分布(WHR)等密切相关;RBP-4与代谢综合征组分的甘油三酯水平则存在明显的正相关,而RBP-4/视黄醇摩尔比值则与空腹胰岛素水平存在显著的正相关。结论:RBP-4可能通过视黄醇依赖和/或非视黄醇依赖的方式参与肥胖和代谢综合征的病理过程。     

Abdominal Adipose Tissue was Associated with Glomerular Hyperfiltration among Non- Diabetic and Normotensive Adults with a Normal Body Mass Index

Glomerular hyperfiltration is recognized as an early marker of progressive kidney dysfunction in the obese population. This study aimed to identify the relationship between glomerular hyperfiltration and body fat distribution measured by computed tomography (CT) in healthy Korean adults. The study population included individuals aged 20–64 years who went a routine health check-up including an abdominal CT scan. We selected 4,378 individuals without diabetes and hypertension. Glomerular filtration rate was estimated using the CKD-EPI equation, and glomerular hyperfiltration was defined as the highest quintile of glomerular filtration rate. Abdominal adipose tissue areas were measured at the level of the umbilicus using a 16-detector CT scanner, and the cross-sectional area was calculated using Rapidia 2.8 CT software. The prevalence of glomerular hyperfiltration increased significantly according to the subcutaneous adipose tissue area in men (OR = 1.74 (1.16–2.61), P for trend 0.016, for the comparisons of lowest vs. highest quartile) and visceral adipose tissue area in women (OR = 2.34 (1.46–3.75), P for trend < 0.001) in multivariate analysis. After stratification by body mass index (normal < 23 kg/m², overweight ≥ 23 kg/m²), male subjects with greater subcutaneous adipose tissue, even those in the normal BMI group, had a higher prevalence of glomerular hyperfiltration (OR = 2.11 (1.17–3.80), P for trend = 0.009). Among women, the significance of visceral adipose tissue area on glomerular hyperfiltration resulted from the normal BMI group (OR = 2.14 (1.31–3.49), P for trend = 0.002). After menopause, the odds ratio of the association of glomerular hyperfiltration with subcutaneous abdominal adipose tissue increased (OR = 2.96 (1.21–7.25), P for trend = 0.013). Subcutaneous adipose tissue areas and visceral adipose tissue areas are positively associated with glomerular hyperfiltration in healthy Korean adult men and women, respectively. In post-menopausal women, visceral adipose tissue area shows significant positive association with glomerular hyperfiltration as in men.