Biomedical subjects

Robert Dent

Publications and source records attributed to Robert Dent.

6 recordsLinked to original sources

PubMed2005

A PYY Q62P variant linked to human obesity.

Peptide YY (PYY) has been implicated in the control of food intake through functional studies in rodents and humans. To investigate whether genetic alterations within this gene result in abnormal weight in humans, we sequenced its coding exons and splice sites in a large cohort of extremely obese [n = 379; average body mass index (BMI), 49.0 kg/m2] and lean (n = 378; average BMI, 19.5 kg/m2) individuals. In total, three rare non-synonymous variants were identified, only one of which, PYY Q62P, exhibited familial segregation with body mass. Through serendipity, previous studies based on cell culture revealed this precise variant to have altered receptor-binding selectivity in vitro. We further show, using mouse peptide injection experiments, that while the wild-type PYY peptide reduces food intake, the mutant PYY 62P had an insignificant effect in reducing food intake in vivo. Taken together, these results are the first to support that rare sequence variants within PYY can influence human susceptibility to obesity.

Amino Acid Sequence↗

PubMed2005

Lack of support for the association between GAD2 polymorphisms and severe human obesity.

The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (-243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase-GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the -243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83-1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the -243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90-1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the -243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity.

Adolescent↗

PubMed2004

Adipogenic and antiapoptotic protein levels in human adipose stromal cells after weight loss.

OBJECTIVE: Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. However, current strategies to achieve sustained weight loss are often unsuccessful. Fat reaccumulation might be favored by enhanced adipose cell differentiation or survival in the postreduced state. RESEARCH METHODS AND PROCEDURES: We measured adipogenic and apoptotic protein expression in subcutaneous abdominal adipose stromal-vascular cells from 10 obese patients (7 women and 3 men) that were obtained before and after a 16% weight loss in a medically supervised weight loss program. RESULTS: After weight loss, protein expression was 2.4-fold higher (p < 0.005) for p42 C/CAAT enhancer binding protein alpha, but there was no change for peroxisome proliferator-activated receptor gamma1; both of these are adipogenic regulators. For neuronal apoptosis inhibitory protein, a protein associated with adipose cell apoptotic resistance, there was a rise of 1.7-fold (p < 0.02). DISCUSSION: Alterations in C/CAAT enhancer binding protein alpha and neuronal apoptosis inhibitory protein expression occurred in human adipose stromal-vascular cells after weight loss in a pilot study of 10 patients. It will be important for future studies to directly examine whether the adipogenic and antiapoptotic capacity of these cells is changed after weight loss.

Adipose Tissue↗

PubMed2004

Effect of weight reduction on respiratory function and airway reactivity in obese women.

BACKGROUND: Population-based studies have documented an association between obesity and an increased prevalence of asthma in women. METHODS: We prospectively studied 58 obese women with a body mass index of > 30 kg/m(2), 24 of whom had asthma, who were enrolled in an intensive 6-month weight loss program to determine whether loss of body mass would be correlated with improvements in bronchial reactivity, lung function, and disease-specific health status. RESULTS: Patients lost an average of 20 kg over the 6-month period. For every 10% relative loss of weight, the FVC improved by 92 mL (p = 0.05) and the FEV(1) improved by 73 mL (p = 0.04), however, bronchial reactivity did not significantly change with weight loss (p = 0.23). Patients who lost > 13% of their pretreatment weight experienced improvements in FEV(1) (p = 0.01), FVC (p = 0.02), and total lung capacity (p = 0.05) compared to patients in the lowest quartile who failed to lose significant amounts of weight. Neither group experienced any significant change in methacholine responsiveness (p = 0.57). Patients who completed the 6-month weight loss program experienced improvements in respiratory health status, irrespective of weight loss. CONCLUSION: We concluded that weight loss can improve lung function in obese women, however, the improvements appear to be independent of changes in airway reactivity.

Adult↗

PubMed2002

The effect of participation in a weight loss programme on short-term health resource utilization.

Obese people consume significantly greater amounts of health resources. This study set out to determine if health resource utilization by obese people decreases after losing weight in a comprehensive medically supervised weight management programme. Four hundred and fifty-six patients enrolled in a single-centred, multifaceted weight loss programme in a universal health care system were studied. Patient information was anonymously linked with administrative databases to measure health resource utilization for 1 year before and after the programme. Mean body mass index (BMI) decreased by more than 15%. The mean annual physician visits (pre = 9.6, post = 9.4) did not change significantly after the programme. However, patients saw a significantly fewer number of different physicians per year following the programme (pre = 4.5, post = 3.9; P < 0.001). Mean annual number of emergency visits (pre = 0.2; post = 0.2) and hospital admissions (pre = 0.05; post = 0.08) did not change. Neither baseline BMI, nor its change during the programme, influenced changes in health resource utilization. Our study suggests that weight loss in a supervised weight management programme does not necessarily decrease short-term health resource utilization. Further study is required to determine if patients who maintain their weight loss experience a decrease in health utilization.

Adult↗

PubMed2002

Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women.

Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P = 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5' flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects.

Body Weight↗