Mutation screening and association studies of the human uncoupling protein 3 gene in normoglycemic and diabetic morbidly obese patients.
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Adult↗
Biomedical subjects
B Guy-Grand
Publications and source records attributed to B Guy-Grand.
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.
The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
Adult↗
Leptin receptor gene in a large cohort of massively obese subjects: no indication of the fa/fa rat mutation. Detection of an intronic variant with no association with obesity.
The massive obesity caused in rodents by the disruption of the leptin-receptor signal through genetic defects at the level of either leptin (OB) or leptin receptor (OB-R) has raised the question of the relevance of these genes to morbid obesity in humans. In this study, we screened a large population of massively obese subjects for the presence of a leptin receptor mutation homologous to that of fa/fa rats, a single base substitution changing glutamine 269, a highly conserved glutamine found at position 270 in the human sequence. After polymerase chain reaction (PCR) amplification of a DNA region encompassing the end of exon 5, intron 5, and the beginning of exon 6, we performed restriction fragment length polymorphism analysis. Within the limitations of this approach where only mutations introducing restriction sites (5 of 8 possibilities) could be assessed, no evidence of mutation at the codon gln 270 was found in 343 massively obese subjects. However, a new OB-R gene variant in intron 5 was revealed by MaeII digestion of the PCR products. MaeII/hOB-R genotyping revealed no difference in the distribution of the genotypes between obese subjects and a group of 79 unrelated nonobese control subjects. In addition, no significant association between various obesity-related metabolic phenotypes and the presence of MaeII/hOB-R alleles was found. Thus, our results did not support a significant role for the MaeII/hOB-R gene variant in the development of the obese phenotype in the population we studied.
Adult↗
Plasma leptin and hunger ratings in healthy humans.
Leptin, the ob gene product, is considered as a signal involved in the regulation of energy stores through centrally mediated effects on ingestive behavior and metabolism. To investigate the relationships between appetite-related sensations and circulating leptin in humans, 12 healthy male volunteers were served two test lunches (1200 kcal, 38% carbohydrate, 50% fat, 12% protein) with comparable palatability but resulting in different postprandial hunger ratings, and plasma leptin concentrations were monitored during 8 h after meal ingestion. Whereas postprandial hunger ratings (assessed by visual analog scales) and plasma insulin patterns differed significantly between meals, no significant difference in postprandial plasma leptin concentrations was observed between the two meals. A moderate but significant increase in mean plasma leptin was found over time. We conclude that postprandial plasma leptin concentrations do not significantly differ between two meals inducing different effects on hunger subjective feelings. These data are in agreement with a role for leptin in the regulation of energy balance as a long-term adiposity-related signal rather than a short-term meal-related factor.
Adult↗
A frameshift mutation in human MC4R is associated with a dominant form of obesity.
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Adult↗
A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.
Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen-q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.
Alleles↗
A polymorphism in the 5' untranslated region of the human ob gene is associated with low leptin levels.
OBJECTIVE: To search the human ob gene for mutations and evaluate their role in massive obesity. DESIGN: Direct mutation screening of the gene and case-control association study. Multivariate analyses for evaluation of differences in clinical parameters. SUBJECTS: Primary mutation screening: 24 morbidly obese subjects (body mass index (BMI) > 40 kg/m2). Association study: 395 unrelated morbidly obese subjects (BMI > 40 kg/m2), 121 lean, non-diabetic control individuals, 72 women of a random sample with an average BMI 32.5 kg/m2. RESULTS: We report the finding of a DNA variant in exon 1 of the human ob gene (A --> G substitution, base + 19). This variant showed a prevalence of 62% in our study population. Association analyses under different genetic models (dominant, co-dominant, recessive) showed no significant evidence for an association of this variant with BMI. However, obese individuals homozygous for the G-allele showed significantly lower leptin concentrations compared to obese patients either heterozygous or homozygous for the A-allele after correction for BMI. CONCLUSION: Recent linkage studies have shown evidence for linkage of the hsob locus with obesity. Our study provides further evidence that a defect in the ob gene in linkage disequilibrium with the G-allele of exon 1 might be involved in obesity by affecting leptin concentrations.
Adult↗
Satiating effect of proteins in healthy subjects: a comparison of egg albumin, casein, gelatin, soy protein, pea protein, and wheat gluten.
The influence of six dietary protein types (egg albumin, casein, gelatin, soy protein, pea protein, and wheat gluten) on satiety and food intake was investigated. Twelve healthy subjects ingested six protein-manipulated lunches (approximately 5.2 MJ, 22% of energy as protein) according to a within-subjects design. Test meals were controlled for energy, macronutrients, fiber, and palatability. Nearly 65% of total protein varied between sessions. After lunch, satiety was assessed for 8 h and energy and macronutrients intakes were measured for 24 h. Blood was collected for determination of postprandial plasma glucose and insulin responses. Results showed no effect of the type of protein on satiety, on 24-h energy or macronutrient intakes, or on postprandial plasma glucose and insulin concentrations. These findings differ in part from those obtained previously in humans, which suggested that proteins may be differentiated in terms of their satiating capacities. We conclude that varying the protein source in a mixed meal does not affect food behavior in healthy humans, probably because coingestion of carbohydrate and fat with protein buffers the kinetics of the physiologic mechanisms implicated in postprandial satiety after a protein load.
Adult↗
Preferential cholesteryl ester acceptors among triglyceride-rich lipoproteins during alimentary lipemia in normolipidemic subjects.
Triglyceride-rich lipoproteins (TRLs), namely chylomicrons (CMs), VLDL, and their remnants, are implicated in the atherogenic features of postprandial lipemia. In human plasma, cholesteryl ester transfer protein (CETP) mediates the heteroexchange of neutral lipids, ie, triglycerides (TG) and cholesteryl esters (CE), between distinct subpopulations of apoB- and of apoAI-containing lipoproteins. In fasting normolipidemic plasma, CETP plays an antiatherogenic role by promoting preferential CE redistribution from HDL to LDL particles of intermediate subclass with optimal binding affinity for the cellular LDL receptor. While the relative proportions and chemical compositions of donor and acceptor lipoproteins are known to influence CETP activity, elevated levels of TRL present during alimentary lipemia have been proposed to be associated with enhanced CETP activity. To identify the preferential CE acceptor particles among postprandial TRL subfractions, we investigated the effects of a typical Western meal (1200 kcal, 14% protein; 38% carbohydrate; and 48% fat, monounsaturated/polyunsaturated ratio 4:1) on the rates of postprandial CE transfer from HDL to apoB-containing lipoproteins in normolipidemic subjects (n=13). Two hours postprandially, plasma levels of TRL were significantly elevated (140 versus 51 mg/dL at baseline, P=.0001). Total rates of CE transferred (88 +/- 7 microg x h[-1] x mL[-1]) from HDL to apoB-containing lipoproteins were not significantly modified by alimentary lipemia over a period of 8 hours. Quantitatively, LDL accepted 64+/-5 microg CE per hour per milliliter plasma from HDL, whereas CM (Sf>400), VLDL1 (Sf 60 to 400), VLDL2 (Sf 20 to 60), and IDL (Sf 12 to 20) accepted 5+/-3, 16+/-3, 1.4+/-0.3, and 1.5+/-0.2, respectively. Quantitatively, VLDL1 was the major CE acceptor among TRLs (P=.0001); thus, VLDL1, but not CMs, represented the major CE acceptor among TRLs. Qualitatively however, VLDL2 and IDL displayed a higher capacity to accept CE from HDL (51.6+/-4.1 and 46.3+/-2.8 microg CE transferred per hour per milligram lipoprotein, respectively; P<.005) compared with CM, VLDL1, and LDL (12.6+/-2.8, 34.7+/-4.2, and 22.7+/-2.0 microg CE transferred per hour per milligram lipoprotein, respectively). In conclusion, elevated postprandial TRL levels are not associated with enhanced total CE transfer to these particles. Furthermore, the qualitative features of postprandial CE transfer from HDL to CM and VLDL1 were not related to the relative TG content of these particles. The CETP-facilitated enrichment of VLDL1 in CE therefore identifies them as potentially atherogenic particles during the postprandial phase.
Adult↗
Mutation screening of the human UCP 2 gene in normoglycemic and NIDDM morbidly obese patients: lack of association between new UCP 2 polymorphisms and obesity in French Caucasians.
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Adult↗
Plasma leptin and acute serotoninergic stimulation of the corticotropic axis in women who are normal weight or obese.
In some recent studies, glucocorticoid treatment was associated with rapid induction of obese (ob) gene expression in adipose tissue of normal rats and in isolated adipocytes. We studied the effect of acute stimulation of the corticotropic axis on plasma leptin, the ob gene product, in 7 women of normal weight and 12 women with obesity. Under double-blind, placebo-controlled conditions, a single 12.5-mg dose of clomipramine, a serotonin uptake inhibitor, was administered intravenously in 15 minutes. Mean basal plasma leptin was increased more than 3-fold in subjects with obesity compared with subjects of normal weight (35.1 +/- 4.9 ng/mL vs. 8.9 +/- 1.4 ng/mL, p = 0.001). Whereas corticotropin (ACTH) and cortisol responses were increased in women who were obese compared with women who were lean, no significant effect of clomipramine infusion was found on plasma leptin concentrations measured during the following 150 minutes in both groups. There was a strong positive correlation between basal plasma leptin concentrations and body mass index (r = 0.92, p < 0.0001). In six subjects with obesity studied after a moderate weight loss, mean basal plasma leptin was significantly decreased (43.7 +/- 6.4 ng/mL before vs. 28.0 +/- 8.1 ng/mL after, p = 0.04), but the hormonal response pattern to clomipramine administration was unchanged. We conclude that, at least in the short term, an acute stimulation of the corticotropic axis does not seem to increase leptin secretion in humans, as shown by the response to the serotoninergic agent clomipramine.
Adolescent↗
Genetic studies of neuropeptide Y and neuropeptide Y receptors Y1 and Y5 regions in morbid obesity.
Synthesis and release of neuropeptide Y (NPY) are both regulated by leptin binding to its hypothalamic receptor mediating some of the effects of leptin on food intake. Moreover, NPY administration is a powerful stimulant of feeding behaviour. Thus, we investigated the potential implication of NPY, NPY-Y1 and -Y5 subtype receptors [rNPY-Y1/-Y5] in the development of human obesity. Two complementary genetic approaches were used: 1) linkage analyses between obesity and polymorphic markers located nearby NPY and rNPY-Y1/-Y5 genes (respectively on chromosomes 7p15.1 and 4q[31.3-32]) in 93 French Caucasian morbidly obese families; 2) single strand conformation polymorphism (SSCP) scanning of the coding region of the NPY and rNPY-Y1 genes performed in 50 unrelated obese patients ascertained on the basis of a body mass index of 27 kg/m2 or more and a family history of obesity. No evidence of linkage between morbid obesity or obesity-related quantitative traits and NPY and rNPY-Y1/ Y5 regions was found in this population. Moreover, SSCP scanning revealed no mutation in the coding region of NPY and rNPY-Y1 genes among obese subjects. These results suggest that NPY and NPY-Y1/ Y5 receptors are unlikely to be implicated in the development of human morbid obesity, at least in the French Caucasian population.
Alleles↗
Genetic studies of the leptin receptor gene in morbidly obese French Caucasian families.
Family studies have shown that in some populations up to 75% of the variation of body mass index can be explained by genetic factors. However, in humans, no major obesity gene has been identified to date. In contrast, there are a number of genetically well defined animal models for obesity. In two of those models (ob/ob and db/db), defects in the same pathway are responsible for obesity. Recently, some evidence has been found for the OB gene also being involved in human obesity. In this study we investigated the potential role of the OB receptor (OBR) in the etiology of massive obesity in humans using familial linkage analyses and case-control association studies. The typing of two microsatellite markers (D1S198 and D1S209), flanking the OBR gene, in 256 sib pairs showed no evidence for linkage with obesity. In order to be able to detect small gene effects, association studies with a 3'-UTR insertion/deletion polymorphism were carried out. The results of these analyses remained non-significant (chi 2 = 3.442, P = 0.18). However, subjects heterozygous for the insertion/deletion polymorphism showed a slight trend towards lower insulin values 30 min after an oral glucose load compared to homozygous individuals (P = 0.02). In summary, our results do not support a major role of the human OBR gene in the development of morbid obesity in our population.
Adult↗
Whole-body protein turnover in humans fed a soy protein-rich vegetable diet.
OBJECTIVES: This study was designed to compare the whole-body protein turnover in humans after the ingestion of a soy protein-rich vegetable diet with that of a control group fed a western animal protein-rich diet. SUBJECTS: Twelve male volunteers were divided into two groups of six subjects who were given for two weeks either a 85% vegetable protein diet (diet VP) or a control western animal protein-rich diet (diet AP). INTERVENTIONS: Whole-body protein turnover was estimated at the end of the two-week controlled diet period using the [15N]-glycine end-product method. Nitrogen flux rates were determined in the fed state (1.3 g protein/kg) over a 9 h period after the dose of [15N]-glycine was given. RESULTS: After the 9 h of the test, the urinary ammonia excretion was significantly higher in the group receiving the diet AP than that in the group receiving the diet VP (P < 0.05). In contrast, there was no significant difference for both total nitrogen and urea nitrogen excretions. Both the protein synthesis and the protein breakdown were similar in both groups. In the same way, the net protein deposition measured in the fed state during 9 h was similar for both diets at 0.07 g/kg/h. CONCLUSIONS: Young adults fed 1.3 g/kg/d of either meat or vegetable protein-rich diet for two weeks did not show a different protein turnover.
Adult↗
Association of poorly controlled diabetes with low serum leptin in morbid obesity.
OBJECTIVES: Leptin may be involved in the regulation of body weight, food intake, and energy expenditure. In view of a possible link between leptin concentrations and diabetes that has been suggested in obese rodents, we investigated the potential relationship between serum leptin concentrations and hyperglycaemia in French patients with morbid obesity. SUBJECTS: Fasting leptin concentrations were measured in 241 morbidly obese patients with various degrees of glucose tolerance in a cross-sectional study. RESULTS: Fasting serum leptin concentrations did not differ between normoglycaemia (NG, 61.5 +/- 24.0 ng/ml) and glucose intolerant morbidly obese subjects (IGT, 56.5 +/- 18.5 ng/ml) and were slightly lower in those with controlled diabetes (55.1 +/- 30.3 ng/ml, P = 0.06 when compared to NG subjects). In contrast, leptin concentrations were 30% lower in patients with poorly controlled diabetes (43.0 +/- 22.2 ng/ml, P = 0.001 vs NG subjects). Leptin concentrations were negatively correlated with fasting glucose in all groups combined (p = -0.24, P = 0.0001) and particularly in NIDDM subjects (p = 0.31, P = 0.0054). Although leptin concentrations were higher in women than in men, similar significant correlation with fasting glucose was found when females were analyzed separately. A positive correlation was found with BMI (p = 0.25, P = 0.0001) in all groups. Multivariate analysis revealed that fasting glucose was independently associated with serum leptin concentrations (F = 12.5, P = 0.0005). Sex, age, BMI, waist/hip ratio, fasting glucose and insulin, total cholesterol and triglycerides, tested in the model, explained 42% of the leptin variability in this population. CONCLUSIONS: Poorly controlled diabetes was accompanied by a significant reduction of serum leptin concentrations in morbidly obese subjects. We suggest that a relative leptin deficiency (lower than expected for the BMI) associated with insulin deficiency in this population might contribute to a vicious cycle maintaining (or even worsening) obesity itself and/or its metabolic complications.
Adult↗
How the degree of unsaturation of dietary fatty acids influences the glucose and insulin responses to different carbohydrates in mixed meals.
The association of fats with carbohydrates results in a lower glucose response but the influence of the nature of the dietary fatty acids has not been investigated clearly. We examined the effect of the degree of dietary fatty acid unsaturation on the postprandial glucose and insulin responses to a mixed meal. Eight young normolipidemic men consumed four different meals in random order. The meals differed in the nature of their oils and in the type of their main carbohydrates. The meals contained either a high ratio of monounsaturated to polyunsaturated n-6 fatty acids (MUFA) or a low ratio (PUFA) and either potatoes or parboiled rice. Proteins and saturated and polyunsaturated n-3 fatty acid contents were not different among meals. Blood samples were collected every 30 min for 3 h after the test meal. The glucose response was significantly lower 30 min after the parboiled rice-PUFA meal than after parboiled rice-MUFA or potato-MUFA (P < 0.05) meals. The insulin response was lower after parboiled rice-PUFA than after potato-MUFA (P < 0.05) meals. Similarly, an effect of fat appeared after 30 min. Glucose responses (F = 1.4, P < 0.01) and insulin responses (F = 5.3, P < 0.05) to both carbohydrates were significantly lower with dietary PUFA compared with dietary MUFA. In conclusion, the degree of dietary fatty acid unsaturation (18:1 compared with 18:2) may influence the glucose and insulin responses to mixed meals.
Adult↗
Weight gain at the time of menopause.
The menopause is associated with changes in body composition: a decline in bone mineral content, a decrease in collagen synthesis, a loss of lean body mass and an increase in total and abdominal fat mass. Oestrogen deficiency seems to play a role in the menopause-related changes in body composition, but life styles (diet, exercise, smoking habits, alcohol consumption) are also involved. The time course of the decrease in lean mass deserves attention since it could justify specific actions, i.e. exercising or hormonal treatment, early during the perimenopausal period. A decrease in fat-free mass may be responsible for a decrease in energy expenditure favouring weight gain if the calorie intake is not reduced.
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Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians.
The sulfonylurea receptor (SUR) is a key component in glucose-stimulated insulin secretion. Obesity and NIDDM are frequently associated and share some metabolic abnormalities, suggesting that they might also share some susceptibility genes. Thus, the SUR encoding gene is a plausible candidate for a primary pancreatic beta-cell defect and thus for hyperglycemia and weight gain. Through association and linkage studies, we have investigated the potential role of the SUR gene in families with NIDDM and in two independent sets of morbidly obese families. The exon 22 T-allele at codon 761 was more common in patients with NIDDM (7.7%) and morbid obesity (7.8%) than in control subjects (1.8%, P = 0.030 and P = 0.023, respectively). This variant was associated with morbid obesity (odds ratio 3.71, P = 0.017) and NIDDM (odds ratio 2.20, P = 0.04; association dependent on BMI). Although the frequencies for intron 24 variant were similar in all groups, morbidly obese patients homozygous for the c-allele had a more deleterious form of obesity. Sib-pair linkage studies with NIDDM in French Caucasian families gave no evidence for linkage to the SUR locus. However, in one set of the obese families, we found an indication for linkage with a SUR-linked microsatellite marker (D11S419, P = 0.0032). We conclude that in Caucasians, the SUR locus may contribute to the genetic susceptibility to NIDDM and obesity.
ATP-Binding Cassette Transporters↗