The Concentration of β-Carotene in Human Adipocytes,but Not the Whole-Body Adipocyte Stores,Is Reduced in Obesity

We have examined the concentration of β-carotene in the fat of isolated abdominal subcutaneous adipocytes obtained from lean (BMI<23 kg/m²), non-obese with higher BMI (23≤BMI<28 kg/m²), obese (BMI≥28 kg/m²), and from a group of obese subjects with type 2 diabetes. The concentration of β-carotene was 50% lower in the adipocytes from the obese and obese/diabetic groups compared with the lean and non-obese groups. Interestingly, the total amount of β-carotene in the adipocyte stores of each subject was constant among all groups. Triacylglycerol constituted 92±1% (by weight) of the adipocyte lipids in the lean group and this was increased to 99±2% in the obese group with diabetes (p<0.05). The concentration of cholesteryl esters was in all cases <0.1 g per 100 g of total lipids, demonstrating that mature human adipocytes have negligible stores of cholesteryl ester. Our findings demonstrate that adipocyte concentrations of β-carotene are reduced in obese subjects. The lower concentrations in adipocytes from subjects with type 2 diabetes apparently reflect subjectś obesity. Our finding that whole-body stores of β-carotene in adipocytes are constant raises new questions regarding what function it serves, as well as the mechanisms for maintaining constant levels in the face of varied adipose tissue mass among individuals over a period of time.     

Calprotectin — A Novel Marker of Obesity

Background

The two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes.

Methodology/Principal Findings

Plasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-α or neutrophil number.

Conclusions/Significance

Plasma calprotectin is a marker of obesity in individuals without type 2 diabetes.     

Pediatric Obesity and Vitamin D Deficiency: A Proteomic Approach Identifies Multimeric Adiponectin as a Key Link between These Conditions

Key circulating molecules that link vitamin D (VD) to pediatric obesity and its co-morbidities remain unclear. Using a proteomic approach, our objective was to identify key molecules in obese children dichotomized according to 25OH-vitamin D (25OHD) levels. A total of 42 obese children (M/F = 18/24) were divided according to their 25OHD3 levels into 25OHD3 deficient (VDD; n = 18; 25OHD<15 ng/ml) or normal subjects (NVD; n = 24; >30 ng/ml). Plasma proteomic analyses by two dimensional (2D)-electrophoresis were performed at baseline in all subjects. VDD subjects underwent a 12mo treatment with 3000 IU vitamin D3 once a week to confirm the proteomic analyses. The proteomic analyses identified 53 “spots” that differed between VDD and NVD (p<0.05), amongst which adiponectin was identified. Adiponectin was selected for confirmational studies due to its tight association with obesity and diabetes mellitus. Western Immunoblot (WIB) analyses of 2D-gels demonstrated a downregulation of adiponectin in VDD subjects, which was confirmed in the plasma from VDD with respect to NVD subjects (p<0.035) and increased following 12mo vitamin D3 supplementation in VDD subjects (p<0.02). High molecular weight (HMW) adiponectin, a surrogate indicator of insulin sensitivity, was significantly lower in VDD subjects (p<0.02) and improved with vitamin D3 supplementation (p<0.042). A direct effect in vitro of 1α,25-(OH)2D3 on adipocyte adiponectin synthesis was demonstrated, with adiponectin and its multimeric forms upregulated, even at low pharmacological doses (10⁻⁹ M) of 1α,25-(OH)2D3. This upregulation was paralleled by the adiponectin interactive protein, DsbA-L, suggesting that the VD regulation of adiponectin involves post-transciptional events. Using a proteomic approach, multimeric adiponectin has been identified as a key plasma protein that links VDD to pediatric obesity.     

Effects of Proportions of Dietary Macronutrients on Glucocorticoid Metabolism in Diet-Induced Obesity in Rats

Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and inactivation by 5α- and 5β-reductases. A low carbohydrate diet increases hepatic 11β-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum ‘Western’ diet (37% fat, n = 36) for 22 weeks, then randomised to continue this diet (n = 12) or to switch to either a low carbohydrate (n = 12) or a moderate carbohydrate (n = 12) diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12) throughout. The low and moderate carbohydrate diets decreased hepatic 11β-HSD1 mRNA compared with the Western diet (both 0.7±0.0 vs 0.9±0.1 AU; p<0.01), but did not alter 11β-HSD1 in adipose tissue. 5α-Reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11β-HSD1 activity (1.6±0.1 vs 2.8±0.1 nmol/mcg protein/hr; p<0.001) and increased 5α-reductase and 5β-reductase mRNAs (1.9±0.3 vs 1.0±0.2 and 1.6±0.1 vs 1.0±0.1 AU respectively; p<0.01) in the liver, and reduced 11β-HSD1 mRNA and activity (both p<0.01) in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue), a low carbohydrate diet does not increase hepatic 11β-HSD1 in obese rats as occurs in humans.     

Natural Killer Cells in Obesity: Impaired Function and Increased Susceptibility to the Effects of Cigarette Smoke

Background

Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independantly associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects.

Methodology and Principal Findings

Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg/m²) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +/− 13% vs 42% +/−12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01).

Conclusions/Significance

Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.     

The Impact of Full-Length,Trimeric and Globular Adiponectin on Lipolysis in Subcutaneous and Visceral Adipocytes of Obese and Non-Obese Women

Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5''-AMP-activated protein kinase) in adiponectin-dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 µg/ml of: A) full-length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti-lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti-lipolytic activity in obese SCAAT and VAT, respectively.     

Can Certain Genotypes Predispose to Poor Asthma Control in Children? A Pharmacogenetic Study of 9 Candidate Genes in Children with Difficult Asthma

Objective

We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control.

Methods

A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma.

Key Results

The results indicated that LTA4H A-9188>G, TNFα G-308>A and IL-4Rα A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4Rα A1199>C, IL-4Rα T1570>C and IL-4Rα A1727>G and CA haplotype of TNFα C-863>A and TNFα G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively).

Conclusions and Clinical Relevance

The study revealed multiple SNPs and haplotypes in LTA4H, TNFα and IL4-Rα genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.     

Insulin Sensitivity from Preschool to School Age in Patients with Severe Obesity

Background

Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age.

Research design and methods

Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) ≥99° percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); β-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test.

Results

After a median follow-up of 2.23 (1–4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8–11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R² = 0.309; p = 0.002; β = −0.556), ISSI-2 (R² = 0.465; p<0.0001; β = −0.682), and BMI z-score (R² = 0.246; p = 0.008; 0.496), respectively.

Conclusions

In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation.     

The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

Objective

Several studies have reported the existence of a subgroup of obese individuals with normal metabolic profiles. It remains unclear what factors are responsible for this phenomenon. We proposed that adipocyte size might be a key factor in the protection of metabolically healthy obese (MHO) individuals from the adverse effects of obesity.

Subjects

Thirty-five patients undergoing bariatric surgery were classified as MHO (n = 15) or metabolically unhealthy obese (MUO, n = 20) according to cut-off points adapted from the International Diabetes Federation definition of the metabolic syndrome. Median body mass index (BMI) was 48 (range 40–71).

Results

There was a moderate correlation between omental adipocyte size and subcutaneous adipocyte size (r = 0.59, p<0.05). The MHO group had significantly lower mean omental adipocyte size (80.9±10.9 µm) when compared with metabolically unhealthy patients (100.0±7.6 µm, p<0.0001). Mean subcutaneous adipocyte size was similar between the two groups (104.1±8.5 µm versus 107.9±7.1 µm). Omental, but not subcutaneous adipocyte size, correlated with the degree of insulin resistance as measured by HOMA-IR (r = 0.73, p<0.0005), as well as other metabolic parameters including triglyceride/HDL-cholesterol ratio and HbA1c. Twenty-eight patients consented to liver biopsy. Of these, 46% had steatohepatitis and fibrosis. Fifty percent (including all the MHO patients) had steatosis only. Both omental and subcutaneous adipocyte size were significantly associated with the degree of steatosis (r = 0.66, p<0.0001 and r = 0.63, p<0.005 respectively). However, only omental adipocyte size was an independent predictor of the presence or absence of fibrosis.

Conclusion

Metabolically healthy individuals are a distinct subgroup of the severely obese. Both subcutaneous and omental adipocyte size correlated positively with the degree of fatty liver, but only omental adipocyte size was related to metabolic health, and possibly progression from hepatic steatosis to fibrosis.     

REV-ERB ALPHA Polymorphism Is Associated with Obesity in the Spanish Obese Male Population

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m²) and 418 lean (BMI 23.27±1.5 kg/m²). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity.     

Serum Retinol-Binding Protein 4 as a Marker for Cardiovascular Disease in Women

Background

Elevated serum level of retinol-binding protein 4 (RBP4) has been associated with obesity-related co-morbidities including insulin resistance, dyslipidemia and hypertension.

Objectives

The present study examined the relationship between serum level of RBP4 and various risk factors related to cardiovascular disease (CVD) in men and women.

Methods

284 subjects (139 males, 145 females), grouped into healthy (n = 60), obese diabetes (n = 60), non-obese diabetes (n = 60), obese non-diabetes (n = 60) and patients with CVD (n = 44), were assessed for anthropometric and biochemical parameters related to obesity, diabetes and CVD. In addition, serum levels of several adipokines, including fatty acid binding protein 4 (FABP4) and lipocalin 2 (LCN2) and RBP4 were measured using specific immunoassays.

Results

Serum RBP4 level correlated significantly with principal component derived from known risk factors of CVD (β = 0.20±0.06, P = 0.002). Significance of this correlation was limited to women (β = 0.20±0.06, P = 0.002) and it persisted even after adjusting for BMI (β = 0.19±0.06, P = 0.002). Overall (n = 284) serum RBP4 values significantly correlated with FABP4 (R = 0.19, p = 0.001). Serum FABP4 level of CVD subjects was significantly higher than healthy control (P = 0.001) and non-obese diabetes (P = 0.04) groups, but this difference was attributable to differences in BMI. Serum LCN2 level correlated well with RBP4 (R = 0.15, P = 0.008) and FABP4 (R = 0.36, P<0.001), but did not differ significantly between CVD and other groups.

Conclusions

Results of this study indicate a significant correlation between serum RBP4 and various established risk factors for CVD and suggest RBP4 may serve as an independent predictor of CVD in women.     

Twenty-Four Hour Total and Dietary Fat Oxidation in Lean,Obese and Reduced-Obese Adults with and without a Bout of Exercise

Background

It has been hypothesized that obese and reduced-obese individuals have decreased oxidative capacity, which contributes to weight gain and regain. Recent data have challenged this concept.

Objective

To determine (1) whether total and dietary fat oxidation are decreased in obese and reduced-obese adults compared to lean but increase in response to an acute exercise bout and (2) whether regular physical activity attenuates these metabolic alterations.

Design

We measured 24-hr total (whole-room calorimetry) and dietary fat (¹⁴C-oleate) oxidation in Sedentary Lean (BMI = 21.5±1.6; n = 10), Sedentary Obese (BMI = 33.6±2.5; n = 9), Sedentary Reduced-Obese (RED-SED; BMI = 26.9±3.7; n = 7) and in Physically Active Reduced-Obese (RED-EX; BMI = 27.3±2.8; n = 12) men and women with or without an acute exercise bout where energy expended during exercise was not replaced.

Results

Although Red-SED and Red-EX had a similar level of fatness, aerobic capacity and metabolic profiles were better in Red-EX only compared to Obese subjects. No significant between-group differences were seen in 24-hr respiratory quotient (RQ, Lean: 0.831±0.044, Obese: 0.852±0.023, Red-SED: 0.864±0.037, Red-EX: 0.842±0.039), total and dietary fat oxidation. A single bout of exercise increased total (+27.8%, p<0.0001) and dietary (+6.6%, p = 0.048) fat oxidation across groups. Although exercise did not impact RQ during the day, it decreased RQ during sleep (p = 0.01) in all groups. Red-EX oxidized more fat overnight than Red-SED subjects under both resting (p = 0.036) and negative energy balance (p = 0.003) conditions, even after adjustment for fat-free mass.

Conclusion

Obese and reduced-obese individuals oxidize as much fat as lean both under eucaloric and negative energy balance conditions, which does not support the hypothesis of reduced oxidative capacity in these groups. Reduced-obese individuals who exercise regularly have markers of metabolic health similar to those seen in lean adults. Both the acute and chronic effects of exercise were primarily observed at night suggesting an important role of sleep in the regulation of lipid metabolism.     

Vitamin D Receptor Gene Polymorphisms and Prognosis of Breast Cancer among African-American and Hispanic Women

Background

Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). Although African-Americans have the lowest levels of serum vitamin D, there is a dearth of information on VDR gene polymorphisms and breast cancer among African-Americans and Hispanics. This study examines whether VDR gene polymorphisms are associated with breast cancer in these cohorts.

Methods

Blood was collected from 232 breast cancer patients (Cases) and 349 non-cancer subjects (Controls). Genotyping for four polymorphic variants of VDR (FokI, BsmI, TaqI and ApaI) was performed using the PCR-RFLP method.

Results

An increased association of the VDR-Fok1 f allele with breast cancer was observed in African-Americans (OR = 1.9, p = 0.07). Furthermore, the FbTA, FbtA and fbtA haplotypes were associated with breast cancer among African-Americans (p<0.05). Latinas were more likely to have the VDR-ApaI alleles (Aa or aa) (p = 0.008). The VDR-ApaI aa genotype was significantly associated with poorly-differentiated breast tumors (p = 0.04) in combined Cases. Kaplan-Meier survival analysis showed decreased 5-year disease-free-survival (DFS) in breast cancer patients who had the VDR-Fok1 FF genotype (p<0.05). The Cox regression with multivariate analysis revealed the independent predictor value of the VDR-FokI polymorphism for DFS. The other three variants of VDR (BsmI, TaqI and ApaI) were not associated with disease outcome.

Conclusions

VDR haplotypes are associated with breast cancer in African-Americans, but not in Hispanic/Latinas. The VDR-FokI FF genotype is linked with poor prognosis in African-American women with breast cancer.     

The Associations between Anthropometric Indices and Obstructive Sleep Apnea in a Korean Population

Background

Obesity is a major risk factor for the development of obstructive sleep apnea (OSA). Although clinical and epidemiological studies have shown that OSA and obesity are strongly associated, few Asian studies have examined the associations between anthropometric obesity indices and OSA, especially in the Korean population. The purpose of this study was to evaluate the influence of anthropometric obesity indices on OSA in a Korean population.

Methods

Anthropometric indices, including neck circumference, waist circumference, and body mass index, were assessed in 383 consecutive subjects with suspected OSA.

Results

Of the 383 subjects assessed, 316 (82.5%) were diagnosed with OSA. Neck circumference (r = 0.518), waist circumference (r = 0.570), and body mass index (r = 0.512) were correlated with the apnea-hypopnea index (p<0.001, for all). After adjusting for age, sex, alcohol consumption, and smoking, a logistic regression model showed that neck circumference [odds ratio (OR), 1.414; p<0.001)], waist circumference (OR, 1.114; p<0.001), and body mass index (OR, 1.364; p<0.001) were associated with OSA. The linear regression model showed that neck circumference (β = 3.748, p<0.001), waist circumference (β = 1.272, p<0.001), and body mass index (β = 3.082, p<0.001) were associated with apnea-hypopnea index. The cut-off values for predicting OSA were determined as 34.5 cm for neck circumference, 76.5 cm for waist circumference, and 23.05 kg/m² for body mass index for females, and 38.75 cm for neck circumference, 88.5 cm for waist circumference, and 24.95 kg/m² for body mass index for males.

Conclusion

Increased anthropometric indices were significantly associated with the presence and severity of OSA in a Korean population. In addition, this study demonstrated the cut-off values for body mass index, waist circumference, and neck circumference for increased OSA risk.     

VEGF,HIF-1α Expression and MVD as an Angiogenic Network in Familial Breast Cancer

Angiogenesis, which plays an important role in tumor growth and progression of breast cancer, is regulated by a balance between pro- and anti-angiogenic factors. Expression of vascular endothelial growth factor (VEGF) is up-regulated during hypoxia by hypoxia-inducible factor-1α (HIF-1α). It is known that there is an interaction between HIF-1α and BRCA1 carrier cancers, but little has been reported about angiogenesis in BRCA1-2 carrier and BRCAX breast cancers. In this study, we investigated the expression of VEGF and HIF-1α and microvessel density (MVD) in 26 BRCA1-2 carriers and 58 BRCAX compared to 77 sporadic breast cancers, by immunohistochemistry. VEGF expression in BRCA1-2 carriers was higher than in BRCAX cancer tissues (p = 0.0001). Furthermore, VEGF expression was higher in both BRCA1-2 carriers and BRCAX than the sporadic group (p<0.0001). VEGF immunoreactivity was correlated with poor tumor grade (p = 0.0074), hormone receptors negativity (p = 0.0206, p = 0.0002 respectively), and MIB-1-labeling index (p = 0.0044) in familial cancers (BRCA1-2 and BRCAX). The percentage of nuclear HIF-1α expression was higher in the BRCA1-2 carriers than in BRCAX cancers (p<0.05), and in all familial than in sporadic tumor tissues (p = 0.0045). A higher MVD was observed in BRCA1-2 carrier than in BRCAX and sporadic cancer tissues (p = 0.002, p = 0.0001 respectively), and in all familial tumors than in sporadic tumors (p = 0.01). MVD was positively related to HIF-1α expression in BRCA1-2 carriers (r = 0.521, p = 0.006), and, in particular, we observed a highly significant correlation in the familial group (r = 0.421, p<0.0001). Our findings suggest that angiogenesis plays a crucial role in BRCA1-2 carrier breast cancers. Prospective studies in larger BRCA1-2 carrier series are needed to improve the best therapeutic strategies for this subgroup of breast cancer patients.     

Genetic Polymorphisms of Estrogen Receptors α and β and the Risk of Developing Prostate Cancer

Estrogen may be involved in the development of prostate cancer. The association between genetic polymorphisms of estrogen receptors α (ESR1) and β (ESR2) and prostate cancer risk was examined in a nested case-control study in Washington County, Maryland. Incident prostate cancer cases (n = 269) were matched to one or two controls (n = 440) by age, sex, race, and date of blood donation. Associations between estrogen receptor genotypes or dietary intake and the development of prostate cancer were examined in conditional logistic regression models. Results from this study showed that six single base-pair polymorphisms (SNPs) of ESR1 (rs1801132, rs2077647, rs746432, rs2273206, rs851982, rs2228480) and four SNPs of ESR2 (rs4986938, rs928554, rs8018687, rs number not available for ESR2 5696 bp 3′ of STP A>G) were not significantly associated with prostate cancer risk, either by allelic or genotypic frequencies. However, an interactive association with BMI was observed in the relationship between prostate cancer risk and genotypes of ESR2 38 bp 3′ of STP G>A (rs4986938) (p = 0.031). An interaction between intake level of phytoestrogen and genotypes of ESR1 Ex1-192G>C (rs746432) and between intake level of phytoestrogen and genotypes of ESR1 Ex8+229G>A (rs2228480) and risk of prostate cancer was observed (p = 0.0009 and p = 0.044, respectively). In conclusion, selected genetic polymorphisms of ESR1 and ESR2, overall, were not associated with prostate cancer risk. However, a variation in risk by BMI and phytoestrogen intake was implicated.     

Association between Milk and Milk Product Consumption and Anthropometric Measures in Adult Men and Women in India: A Cross-Sectional Study

Background

The nutritional aetiology of obesity remains unclear, especially with regard to the role of dairy products in developing countries.

Objective

To examine whether milk/milk product consumption is associated with obesity and high waist circumference among adult Indians.

Methods

Information on plain milk, tea, curd and buttermilk/lassi consumption assessed using a Food Frequency Questionnaire was obtained from the cross-sectional sib-pair designed Indian Migration Study (3698 men and 2659 women), conducted at four factory locations across north, central and south India. The anthropometric measures included were Body Mass Index (BMI) and Waist Circumference (WC). Mixed-effect logistic regression models were conducted to accommodate sib-pair design and adjust for potential confounders.

Results

After controlling for potential confounders, the risk of being obese (BMI≥25 kg/m²) was lower among women (OR = 0.57;95%CI:0.43−0.76;p≤0.0001) and men (OR = 0.67;95%CI: 0.51−0.87;p = 0.005), and the risk of a high WC (men: >90 cm; women: >80 cm) was lower among men (OR = 0.71;95%CI:0.54−0.93;p = 0.005) and women (OR = 0.79;95%CI:0.59−1.05;p>0.05) who consume ≥1 portions of plain milk daily than those who do not consume any milk. The inverse association between daily plain milk consumption and obesity was also confirmed in sibling-pair analyses. Daily tea consumption of ≥1 portion was associated with obesity (OR = 1.51;95%CI:1.00−2.25;p>0.050) and high WC (OR = 1.65;95%CI:1.08−2.51;p>0.019) among men but not among women but there was no strong evidence of association of curd and buttermilk/lassi consumption with obesity and high waist circumference among both men and women.

Conclusions

The independent, inverse association of daily plain milk consumption with the risk of being obese suggests that high plain milk intake may lower the risk of obesity in adult Indians. However, this is an observational finding and uncontrolled confounding cannot be excluded as an explanation for the association. Therefore, confirmatory studies are needed to clarify this relationship.     

Extracellular Matrix Biomarker,Fibulin-1, Is Closely Related to NT-proBNP and Soluble Urokinase Plasminogen Activator Receptor in Patients with Aortic Valve Stenosis (The SEAS Study)

Background

Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS).

Methods

In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo.

Results

During treatment, fibulin-1 became more closely associated with NT-proBNP (β_year0 = 0.10, p = 0.08, β_year1 = 0.16, p = 0.005, β_year4 = 0.22, p<0.001) and suPAR (β_year0 = 0.05, p = 0.34, β_year1 = 0.16, p = 0.006, β_year4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (β_year0 = −0.14, p = 0.005, β_year1 = −0.08, p = 0.11, β_year4 = −0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.R_year0 ² = 0.19, Adj.R_year1 ² = 0.22, Adj.R_year4 ² = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm²/m² (median value), fibulin-1 was more closely associated to NT-proBNP (β_year0 = 0.25, β_year1 = 0.21, β_year4 = 0.22, all p<0.01), and suPAR (β_year0 = 0.09, p = 0.26, β_year1 = 0.23, β_year4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation.

Conclusions

Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.     

Pulmonary and Cardiac Function in Asymptomatic Obese Subjects and Changes following a Structured Weight Reduction Program: A Prospective Observational Study

Background

The prevalence of obesity is rising. Obesity can lead to cardiovascular and ventilatory complications through multiple mechanisms. Cardiac and pulmonary function in asymptomatic subjects and the effect of structured dietary programs on cardiac and pulmonary function is unclear.

Objective

To determine lung and cardiac function in asymptomatic obese adults and to evaluate whether weight loss positively affects functional parameters.

Methods

We prospectively evaluated bodyplethysmographic and echocardiographic data in asymptomatic subjects undergoing a structured one-year weight reduction program.

Results

74 subjects (32 male, 42 female; mean age 42±12 years) with an average BMI 42.5±7.9, body weight 123.7±24.9 kg were enrolled. Body weight correlated negatively with vital capacity (R = −0.42, p<0.001), FEV1 (R = −0.497, p<0.001) and positively with P 0.1 (R = 0.32, p = 0.02) and myocardial mass (R = 0.419, p = 0.002). After 4 months the study subjects had significantly reduced their body weight (−26.0±11.8 kg) and BMI (−8.9±3.8) associated with a significant improvement of lung function (absolute changes: vital capacity +5.5±7.5% pred., p<0.001; FEV1+9.8±8.3% pred., p<0.001, ITGV+16.4±16.0% pred., p<0.001, SR tot −17.4±41.5% pred., p<0.01). Moreover, P0.1/Pimax decreased to 47.7% (p<0.01) indicating a decreased respiratory load. The change of FEV1 correlated significantly with the change of body weight (R = −0.31, p = 0.03). Echocardiography demonstrated reduced myocardial wall thickness (−0.08±0.2 cm, p = 0.02) and improved left ventricular myocardial performance index (−0.16±0.35, p = 0.02). Mitral annular plane systolic excursion (+0.14, p = 0.03) and pulmonary outflow acceleration time (AT +26.65±41.3 ms, p = 0.001) increased.

Conclusion

Even in asymptomatic individuals obesity is associated with abnormalities in pulmonary and cardiac function and increased myocardial mass. All the abnormalities can be reversed by a weight reduction program.     

Age- and Sex-Dependent Association between FTO rs9939609 and Obesity-Related Traits in Chinese Children and Adolescents

Background

The associations between common variants in the fat mass- and obesity-associated (FTO) gene and obesity-related traits may be age-dependent and may differ by sex. The present study aimed to assess the association of FTO rs9939609 with body mass index (BMI) and the risk of obesity from childhood to adolescence, and to determine the age at which the association becomes evident.

Methods

Totally 757 obese and 2,746 non-obese Chinese children aged 6–18 years were genotyped for FTO rs9939609. Of these, a young sub-cohort (n = 777) aged 6–11 years was reexamined 6 years later. Obesity was defined using the sex- and age-specific BMI cut-offs recommended by the International Obesity Task Force.

Results

The associations of FTO rs9939609 with BMI and obesity did not appear until children reached 12–14 years. The variant was associated with an increased BMI in boys (β = 1.50, P = 0.004) and girls (β = 0.97, P = 0.018), respectively. Thereafter, the magnitude of association increased in girls at ages 15–18 years (β = 2.02, P<0.001), but not boys (β = 0.10, P>0.05). Age was found to interact with the variant on BMI (P<0.001) and obesity (P = 0.042) only in girls. In the sub-cohort, the associations of FTO rs9939609 with BMI (β = 1.07, P = 0.008) and obesity (OR = 2.09, 95% CI: 1.12, 3.91) were only observed 6 years later (ages 12–18 years) in girls, even after adjusting for baseline BMI.

Conclusions

The association between FTO rs9939609 and obesity-related traits may change from childhood to adolescence in Chinese individuals, and the association may start as early as age 12 years, especially in girls.