Randomized, multi-center trial of two hypo-energetic diets in obese subjects: high- versus low-fat content.

OBJECTIVE: To investigate whether a hypo-energetic low-fat diet is superior to a hypo-energetic high-fat diet for the treatment of obesity. DESIGN: Open-label, 10-week dietary intervention comparing two hypo-energetic (-600 kcal/day) diets with a fat energy percent of 20-25 or 40-45. SUBJECTS: Obese (BMI >or=30 kg/m(2)) adult subjects (n = 771), from eight European centers. MEASUREMENTS: Body weight loss, dropout rates, proportion of subjects who lost more than 10% of initial body weight, blood lipid profile, insulin and glucose. RESULTS: The dietary fat energy percent was 25% in the low-fat group and 40% in the high-fat group (mean difference: 16 (95% confidence interval (CI) 15-17)%). Average weight loss was 6.9 kg in the low-fat group and 6.6 kg in the high-fat group (mean difference: 0.3 (95% CI -0.2 to 0.8) kg). Dropout was 13.6% (n = 53) in the low-fat group and 18.3% (n = 70) in the high-fat group (P=0.001). Among completers, more subjects lost >10% in the low-fat group than in the high-fat group ((20.8%, n = 70) versus (14.7%, n = 46), P = 0.02). Fasting plasma total, low-density lipoprotein- and high-density lipoprotein-cholesterol decreased in both groups, but more so in the low-fat group than in the high-fat group. Fasting plasma insulin and glucose were lowered equally by both diets. CONCLUSIONS: The low-fat diet produced similar mean weight loss as the high-fat diet, but resulted in more subjects losing >10% of initial body weight and fewer dropouts. Both diets produced favorable changes in fasting blood lipids, insulin and glucose.

Recommendations regarding obesity surgery.

In France, 1,000 obese persons per month undergo a bariatric operation. Obesity surgery requires coordination and monitoring of aftercare. The French public health-care insurer asked the medical associations involved in obesity management to provide guidelines for obesity surgery. The recommendations were developed by the national associations of Obesity, Nutrition and Diabetes: the Association Française d'Etudes et de Recherches sur l'Obésité (AFERO), member of the EASO and IASO; the Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques (ALFEDIAM); the Société Française de Nutrition (SFN); and the Société Française de Chirurgie de l'Obésité (SOFCO). This article presents the short version of the guidelines.

Effects of orlistat on obesity-related diseases - a six-month randomized trial.

AIM: To assess the effect of orlistat on body weight and concomitant diseases in patients with body mass index (BMI) of > 28 kg/m2 and poorly controlled type 2 diabetes, hypertension or hypercholesterolaemia. METHODS: This trial was a six-month, randomized, double-blind, placebo-controlled study of orlistat 120 mg three times daily plus a mildly reduced-calorie diet. 1004 obese patients (BMI 28-40 kg/m2) were included by 253 private endocrinologists and received orlistat (n = 499) or placebo (n = 505). Patients were stratified by concomitant disorder (type 2 diabetes, n = 193; hypertension, n = 614; hypercholesterolaemia, n = 197). Body weight, anthropometry, lipid and glycaemic control parameters and blood pressure. RESULTS: After six months, orlistat produced a significantly greater weight loss than placebo in type 2 diabetes (-4.2% vs. -1.4%), hypertension (-6.2% vs. -1.9%) and hypercholesterolaemia (-5.5% vs. -2.3%) groups (p < 0.0001 for all). There was a greater decrease in HbA(1c) in the type 2 diabetes group (-0.54 vs. -0.18%; p = 0.002) and low-density lipoprotein (LDL)-cholesterol in the hypercholesterolaemia group (-11.7% vs. -4.5%; p = 0.004) with orlistat vs. placebo. Early weight loss (> or = 5% at 12 weeks) was associated with the highest weight loss in each group, and the highest decreases in HbA1c, LDL-cholesterol and diastolic blood pressure in patients with type 2 diabetes, hypercholesterolaemia and hypertension, respectively, at six months. The incidence of adverse events was similar for orlistat and placebo, except for certain generally well-tolerated gastrointestinal events that were more common with orlistat. CONCLUSION: Orlistat plus a mildly reduced-calorie diet produced clinically meaningful weight loss and improvements in risk factors in overweight and obese patients with poorly controlled type 2 diabetes, hypertension or hypercholesterolaemia.

Single nucleotide polymorphisms of protein tyrosine phosphatase 1B gene are associated with obesity in morbidly obese French subjects.

AIMS/HYPOTHESIS: The development of insulin resistance may contribute to the occurrence and progression of the metabolic syndrome associated with obesity. Components contributing to the insulin pathway and its regulation are good candidates for the molecular study of metabolic syndrome pathogenesis. Protein tyrosine phosphatase 1B (PTP 1B) is an important negative regulator of insulin. We investigated whether PTP 1B SNPs are associated with obesity and obesity-related traits as well as global metabolic syndrome in morbidly obese subjects. METHODS: Untranslated and coding regions of the PTP 1B gene were screened in groups of non-diabetic and diabetic obese subjects and in non-obese subjects. Unrelated morbidly obese ( n=711) and non-obese ( n=427) French Caucasian subjects were genotyped for a case-control study. RESULTS: Six SNPs were identified: two rare variants were located in 5'UTR (-109 C>T and -69 C>T), two in the intronic regions (IVS3+38 G>T and IVS5+3666delT) and two have been described previously (P303P in exon 8 and P387L in exon 9). A case-control study showed an association between the frequent IVS5+3666delT SNP and obesity ( p=0.02). In the obese group, associations between PTP 1B SNPs and features of dyslipidaemia were found. P303P was associated with lower apolipoprotein A1 levels ( p=0.05) whereas P387L was associated with higher triglyceride ( p=0.0003), apolipoprotein B ( p=0.09) and lipoprotein a concentrations ( p=0.006). CONCLUSIONS/INTERPRETATION: Our results support the hypothesis that the PTP 1B gene contributes to the polygenic basis of obesity. PTP 1B SNPs may interact with environmental factors to induce more severe phenotypes, e.g. atherogenic dyslipidaemia, in morbidly obese subjects.

[From obesity to obesities: from concepts to practices]. / De l'obésité aux obésités: des concepts aux pratiques.

In the singular, obesity is a symptom reflecting an excess of energy stores as fat mass, the only trait obese people are sharing. Long time ago we proposed to use the plural to account for the large diversity characterizing obese subjects that conceptual evolutions have put to the fore during the past three decades. Weight gain and obesity are resulting from a positive energy balance produced by the conjunction of a number of etiopathogenetic factors associated in various proportions according to patients and evolutive status. Decreasing physical activity, increasing sedentarity, quantitative and qualitative energy consumption unadapted to energy expenditure and to lipid oxidation capabilities, reinforced by psychological needs, are catching out the control of food intake, particularly since it is more efficient to defend against famine than to protect against plethora. These environmental factors, responsible for obesity pandemia, lead to obesity subjects predisposed by their genetic background, in itself extremely variable. The clinical heterogeneity of obesity is patent and a careful phenotypic analysis is a prerequisite to design the management strategy. Obesity is a chronic situation that needs a long-term treatment. The goals of treatment cannot be longer reduced to weight loss only, which in addition should be realistic, i.e. moderate. Management strategies must be conceived on a long-term basis, focused on prevention of weight regain, multifaceted and individually tailored. A number of tools are available and the state of the art is to use them appropriately to avoid being counter productive. Obesity may be viewed as an adaptive symptom in subjects poorly prepared to cope with recent environmental changes, but it is also a disease due to its prevalence, the number of weight dependent comorbidities and its socio economic costs. A specific medical approach of obesity has still to be developed.

Adipose tissue gene expression in patients with a loss of function mutation in the leptin receptor.

BACKGROUND: In order to maintain body weight regulation, leptin directly or indirectly signals nutritional changes to key organs, but little is known about its target genes in human adipose tissue. Leptin receptor loss of function is a unique way to explore the role of leptin in the regulation of adipose tissue. OBJECTIVE: We studied the consequences of the absence of leptin signaling on adipocyte gene expression in two girls with a mutation in the leptin receptor. The expression levels of the ob gene and adipocyte transcription factors (SREBP1c, C/EPBalpha, beta, PPARgamma1, gamma2) were quantified by RT-PCR in subcutaneous adipose tissue of these patients and of 10 morbidly obese women. RESULTS: Ob mRNA levels in subjects lacking the leptin receptor were not overexpressed but were in the range that could be expected from their BMI (58 and 26 amol/ micro g total mRNA, range in obese women: 26-69). Expression of the five transcription factors was also in the same range in the affected patients and in morbidly obese women (7.7 and 6.8 amol/ micro g total mRNA, range: 2.2-9.4 for SREBP1c, 159 and 51 range: 51-406 for C/EPBalpha, 6.1 and 3.3 range: 2.4-24.8 for C/EPBbeta, 16.7 and 27.4 range: 9.4-29.7 for PPARgamma1 and 1.7 and 5.4 amol/ micro g total mRNA range: 1.7-8.8 for PPARgamma2). Significant correlation was found between the mRNA levels of leptin and PPARgamma2 and leptin and C/EBPalpha whereas no correlation was observed between leptin and SREBP1c, PPARgamma1, or C/EBPbeta mRNA levels. CONCLUSION: In patients lacking leptin signaling, the fact that ob gene expression is adequately adapted to their body fat mass argues against a direct negative feedback loop in the regulation of leptin expression in humans. The normal expression of several transcription factors, known to be dependent of the nutritional status, suggests that leptin is not a major contributor of their in vivo transcriptional regulation in human adipose tissue.

Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.

A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

[Are diets fattening?]. / Les régimes font-ils grossir?

A diet always induces a weight loss in the short term. The loss does not depend on the diet composition but rather on the caloric deficit. However, a drastic diet often induces binge eating disorders and can lead to a weight gain in the long term. A cognitive-behavioural-nutritional approach allows a lasting weight loss. Results are much better in the long term with low fat diets. The benefits of a weight loss, even a little one, improves greatly morbidity and mortality at 10 years.

Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study.

BACKGROUND: Epidemiological studies suggest that obesity-induced atherosclerosis may start in childhood, but this process has never been demonstrated. We looked for arterial changes and investigated their relation to cardiovascular risk factors in obese children. METHODS: Non-invasive ultrasonographic measurements were made in 48 severely obese children and 27 controls to investigate arterial mechanics and endothelial function. Plasma lipid concentrations, indices of insulin resistance, and body composition were assessed in the obese children. FINDINGS: The obese children had significantly lower arterial compliance than the healthy controls (median 0.132 [0.022-0.273] vs 0.143 [0.112-0.237] mm(2).mm Hg; p=0.02) and lower distensibility (0.60 [0.10-1.00] vs 0.70 [0.50-1.10] mm Hg(-1).10(-2); p=0.0001). Conversely, the obese children had higher values than the controls for wall stress (3.36 [2.00-5.01] vs 2.65 [2.13-3.54] mm Hg.10(2); p=0.0001) and incremental elastic modulus (1.68 [0.72-10.8] vs 0.96 [0.64-1.47]; p=0.0001). Endothelium-dependent and independent function were also lower in the obese than in the control children. An android fat distribution was positively correlated with indices of insulin resistance and plasma triglyceride concentrations and was negatively correlated with plasma HDL-cholesterol concentration and arterial compliance. Endothelial dysfunction was correlated with low plasma apolipoprotein A-I and with insulin resistance indices. INTERPRETATION: Severe obesity in children is associated with arterial wall stiffness and endothelial dysfunction. Low plasma apolipoprotein A-I, insulin resistance, and android fat distribution may be the main risk factors for these arterial changes, which are of considerable concern as possible early events in the genesis of atheroma.

Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children.

OBJECTIVE: To search for mutations in melanocortin pathway elements, that is, the melanocortin-4 receptor (MC4R ), agouti-related protein (AGRP ), and (alpha-melanocyte-stimulating hormone (alpha MSH ) genes in children with severe obesity. STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children. Polymerase chain reaction (PCR) assays of restriction fragment length polymorphism were used to assess the frequency of each newly discovered mutation in 283 non-obese control subjects. RESULTS: Four dominantly inherited, heterozygous, missense MC4R mutations (Val50Met, Ser58Cys, Ile102Ser, and Ile170Val) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Clinical and laboratory features were similar in the obese children with and without an MC4R mutation. Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups. No mutations were found in the alpha MSH gene. CONCLUSIONS: MC4R mutations may be a non-negligible cause of severe obesity in children with variable expression and penetrance. Mutations in AGRP and alpha MSH genes were not among the causes of obesity in our population.

Use of 'light' foods and drinks in French adults: biological, anthropometric and nutritional correlates.

BACKGROUND: A population of over 12,000 mature subjects participated in a longitudinal study (8 years) of nutrition and health (the Su.Vi.Max Study). In this context, a specific cross-sectional study was carried out in a randomly selected subpopulation. AIM: To identify anthropometric, nutritional and biochemical correlates of spontaneous use of 'light' foods and drinks in a free-living population. DESIGN: Men (n = 2299) and women (n = 1979), 45-60 years, reported their food intakes over six non-consecutive days. Consumers of low-fat and low-sugar foods and drinks, and artificial sweeteners, were compared with non-consumers. RESULTS: Users of low-sugar products were heavier than non-users; female consumers of low-fat products, but not males, had higher body weight and BMI than non-consumers. Users of low-sugar products had higher triacylglycerols and glycaemia than non-users while biochemical parameters were not different in users and non-users of low-fat products. Use of low-sugar products led to increased diet density of a few micronutrients, including cholesterol. Low-fat product selection was associated with increased intake of most micronutrients, both in absolute value and in density. CONCLUSIONS: In mature adults, selection of fat-reduced products was associated with improved quality of the diet, while anthropometric and biological parameters appeared less favourable in consumers of low-sugar products vs. non-consumers. The longitudinal follow-up of the cohort in future years will help determine cause-and-effect relationships among these parameters.

Dual x-ray absorptiometry, bioelectrical impedance, and near infrared interactance in obese women.

PURPOSE: Whether the evaluation of body composition in obese people using low-cost, simple bedside, two-compartment techniques reflects the data obtained by indirect methods such as dual x-ray absorptiometry (DEXA) remains controversial. The aim of this study was to compare the data obtained by three methods of assessment of body composition (DEXA; bioelectrical impedance, BIA; and near infrared interactance, NII). METHOD: Data on body composition obtained in 53 obese women by these three methods were compared, using the Bland and Altman procedure to test the relative validity. RESULTS: Although the correlation coefficients between DEXA and the two other methods were high, there were some major differences (limits of agreement) between data concerning fat and lean mass. CONCLUSIONS: The present study indicates that these methods cannot be considered as interchangeable and raises some questions on the use of BIA and NII as a single method of evaluation of body composition in clinical research and practice in obese populations.

High concentration of leptin stimulates myeloid differentiation from human bone marrow CD34+ progenitors: potential involvement in leukocytosis of obese subjects.

OBJECTIVE AND DESIGN: As well as its involvement in control of adipose mass and body energy balance, several reports suggest a link between leptin and hemopoiesis. To test its putative role in human hemopoiesis, we developed a homologous system, ie recombinant human leptin treatment of purified CD34+ progenitors from adult human bone marrow. RESULTS: Leptin (50-100 ng/ml) significantly stimulated the appearance of granulocyte-macrophage colonies in the presence or absence of erythropoietin. The concentration of leptin required for this effect was rather high but within the range of plasma leptin levels observed in obesity. Two results further support the hypothesis that leptin may be involved in the leukocytosis associated with obesity: (i) leptin concentrations in bone marrow and plasma of subjects studied were highly correlated; (ii) leptin and leukocyte count were correlated only in obese subjects. Paracrine effects of locally released leptin from bone marrow adipocytes could also be involved in the regulation of hemopoiesis, a hypothesis supported by marrow immunocytochemistry revealing the close association of CD34+ cells with adipocytes and by previous demonstration that leptin is secreted at a high level by these cells. CONCLUSION: These results indicate that leptin acts on human multilineage CD34+ cells and that high plasma leptin levels associated with obesity could participate in the differentiation of granulocytes from hemopoietic progenitors.

Soluble leptin receptor in serum of subjects with complete resistance to leptin: relation to fat mass.

Leptin resistance and obesity have been related to mutations of the leptin receptor gene in rodents and, recently, in a consanguineous family. The latter mutation results in a receptor lacking transmembrane and intracellular domains. Homozygous and heterozygous individuals with this mutation had serum leptin levels higher than expected, given their BMIs: 600, 670, and 526 ng/ml and 145, 362, 294, 240, and 212 ng/ml, respectively. Their serum leptin was fractionated by gel filtration: >80% was present as a high-molecular size complex vs. 7.5% in the nonmutated sister. Western blot analysis showed a band at 146 kDa reacting specifically with an antibody directed against the leptin receptor ectodomain. In 10 obese control subjects, as in the mutated patients, free leptin levels correlated with BMI (r = 0.70, P = 0.0011) and reflected fat mass, regardless of leptin receptor functioning. In the patients, bound leptin levels correlated with BMI (r = 0.99, P = 0.0002) and were related to the number of mutated alleles. These data demonstrate that the truncated receptor is secreted into blood and binds the majority of serum leptin, markedly increasing bound and total leptin. Free serum leptin was similarly correlated with BMI in the mutated and nonmutated obese individuals, providing evidence that the relationship between BMI and circulating free leptin is preserved in this family. This finding suggests that the leptin receptor itself may not be specifically involved in the control of leptin secretion, and it supports the concept of relative resistance to leptin in common obesity.

Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.

By integrating an agonist satiety signal, provided by alpha-melanocyte-stimulating hormone (alpha-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein-coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R-associated obesity is not due to variations in genes for alpha-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.

Sweet taste of aspartame and sucrose: effects on diet-induced thermogenesis.

UNLABELLED: Among factors that affect diet-induced thermogenesis (DIT) are the sensory characteristics of food. The aim of this study was to test whether the sweet flavour obtained with a low-energy sweetener (aspartame) or with sucrose have a different effect on DIT. Following a standardized breakfast, 24 healthy male subjects were served three test lunches in a randomized fashion. Lunch contained soft white cheese added with maltodextrins and aspartame, or sucrose, or maltodextrins only (non-sweetened control) (each 900 kcal). Energy expenditure (indirect calorimetry) was monitored during the five postprandial hours. For the first two periods of measurement (30-60 and 90-120 min after meal ingestion), postprandial energy expenditure was significantly increased with sucrose compared to maltodextrins and maltodextrins plus aspartame, whereas no significant difference was found between maltodextrins and maltodextrins plus aspartame. No significant difference between lunches was observed for DIT expressed as incremental area above premeal baseline energy expenditure. Plasma glucose area under the curve was significantly lower for sucrose compared to maltodextrins plus aspartame. Plasma insulin area under the curve was significantly lower for sucrose compared to the other tests foods. IN CONCLUSION: (1) variation in sweet-taste induced by aspartame or by sucrose does not seem to have a major effect on DIT in healthy humans; (2) differences in energy expenditure observed in the early postprandial period suggest a substrate effect.

Genetics of obesity: towards the understanding of a complex syndrome. / Génétique de l'obésité: vers la compréhension d'un syndrome complexe.

GENETICS AND ENVIRONMENT: Obesity is a multifactorial disease combining the effects of genetic predisposition with very powerful environmental risk factors. Recent genetic studies have demonstrated that there is a continuum between different forms of human obesity. SINGLE GENE FACTORS: In certain cases, mainly cases of very severe obesity with childhood onset, a single gene would play a permissive role allowing environmental factors to have major impact. Rare mutations of the leptin gene and its receptor, proopiomelanocortin, or more frequently, melanocortin receptor 4 mutations, are evidence of the existence of an obesity gene. Inactivity of this gene would be sufficient to produce early onset anomalous eating habits. COMMON OBESITY: The more common forms of obesity are however polygenic. The strong environmental pressure exceeds the capacity for homeostatic adaptation of genetically predisposed persons, leading to an energy imbalance favoring fat storage. WHICH GENES? Certain candidate genes, such as decoupling genes, beta-3 adrenergic receptor genes, or regulator regions of the leptin gene, play a minor role in the constitution or aggravation of overweight. Recently, "whole genome" explorations in obese families have localized major obesity genes on chromosomes 2, 5, 10, 11, and 20. Identification of these genes with positional cloning and functional genomic techniques will be helpful in better understanding the molecular determinants of obesity and better defining targets for new therapies.

The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes.

OBJECTIVE: Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPAR gamma2 isoform of the receptor and to be associated with obesity or diabetes-related phenotypes in different populations. SUBJECTS: We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians. RESULTS: The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical parameters tested. CONCLUSIONS: We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.