Bernard 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 ingenes encoding leptin or the leptin receptor cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism. 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.

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.

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.

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.

Indication for linkage of the human OB gene region with extreme obesity

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1–8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514–1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483–1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72–93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected–sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

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

OBJECTIVE: Peroxisome-proliferator-activated receptors γ (PPAR γ), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR γ gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPARγ2 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 γ2 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.

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.

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 normoglycaemic (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 (ρ=−0.24, P=0.0001) and particularly in NIDDM subjects (ρ=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 (ρ=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.

Menopause, fat and lean distribution in obese women.

OBJECTIVES Whether menopause per se influences fat distribution independently of the effect of aging remains controversial. The lack of consistency in the menopause related changes in body fat distribution may be the result of differences in the methods for measuring fat distribution or in the characteristics of the women studied. The aim of this cross sectional study in obese women was to compare total body composition and regional fat and lean distribution, in premenopausal, perimenopausal and postmenopausal women. METHODS Body composition was assessed by dual energy X-ray absorptiometry (DEXA) in premenopausal (n = 26), perimenopausal (n = 24) and postmenopausal (n = 73) obese women with no intercurrent diseases. RESULTS It was shown that postmenopausal obese (n = 73) women had a higher proportion of total fat mass in the trunk and a lower proportion of total fat and lean mass in the femoral and leg regions than premenopausal women after adjustment for age and total fat mass. In the same analysis, perimenopausal women had a lower proportion of total fat in the leg and femoral regions and of total lean in the femoral region than premenopausal women; they had a regional body composition similar to that of postmenopausal women. CONCLUSION The present data indicate that in obese women, post menopause and perimenopause are associated with differences in fat and lean distribution, independently of age and total fat.

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.