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Christian Vaisse

Publications and source records attributed to Christian Vaisse.

16 recordsLinked to original sources
PubMed2006

Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating.

CONTEXT: Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene are the most common monogenic form of severe obesity in children. There are conflicting reports regarding the prevalence, nature, and pathogenic effects of MC4R mutations in adults with severe late-onset obesity. OBJECTIVE: Our objective was to determine the prevalence of MC4R mutations in a cohort of severely obese adults and to determine the clinical phenotype and the phenotype-genotype relationship within adult MC4R mutation carriers. DESIGN AND SETTING: We conducted an observational study at a referral center. PATIENTS OR OTHER PARTICIPANTS: Participants included 769 adult patients with body mass index of at least 35 kg/m(2) and 444 nonobese control individuals. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: We assessed the prevalence of pathogenic MC4R mutations, functional characteristics of the detected mutations, phenotype, and phenotype-genotype relationship within mutation carriers. RESULTS: The global prevalence of obesity-specific MC4R mutations was 2.6%, and the 95% confidence interval (CI(95)) was 1.5-3.7. The prevalence of MC4R mutations was similar in patients developing obesity in childhood (2.83%; CI(95), 0.9-4.8) and in patients with a later onset of the disease (2.35%; CI(95), 0.9-3.8). Adult obese MC4R mutation carriers did not present with binge eating or with any specific clinical phenotype. The severity of the functional alterations of the mutated MC4Rs and in particular the intracellular retention of the receptor correlates both with the severity and the onset of the obesity in the mutation carriers. CONCLUSIONS: Obese adult carriers of functionally relevant MC4R mutations do not specifically present with binge-eating disorder or a history of early-onset obesity. The onset and severity of the obesity in the carriers is related to the functional severity of the MC4R mutations.

Adult↗
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↗
PubMed2005

High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes.

CONTEXT: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. OBJECTIVE: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in beta-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. DESIGN: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). RESULTS: The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation. CONCLUSIONS: This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

Africa, Western↗
PubMed2005

Leptin regulation of bone resorption by the sympathetic nervous system and CART.

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

Activating Transcription Factor 4↗
PubMed2005

A statistical approach for array CGH data analysis.

BACKGROUND: Microarray-CGH experiments are used to detect and map chromosomal imbalances, by hybridizing targets of genomic DNA from a test and a reference sample to sequences immobilized on a slide. These probes are genomic DNA sequences (BACs) that are mapped on the genome. The signal has a spatial coherence that can be handled by specific statistical tools. Segmentation methods seem to be a natural framework for this purpose. A CGH profile can be viewed as a succession of segments that represent homogeneous regions in the genome whose BACs share the same relative copy number on average. We model a CGH profile by a random Gaussian process whose distribution parameters are affected by abrupt changes at unknown coordinates. Two major problems arise: to determine which parameters are affected by the abrupt changes (the mean and the variance, or the mean only), and the selection of the number of segments in the profile. RESULTS: We demonstrate that existing methods for estimating the number of segments are not well adapted in the case of array CGH data, and we propose an adaptive criterion that detects previously mapped chromosomal aberrations. The performances of this method are discussed based on simulations and publicly available data sets. Then we discuss the choice of modeling for array CGH data and show that the model with a homogeneous variance is adapted to this context. CONCLUSIONS: Array CGH data analysis is an emerging field that needs appropriate statistical tools. Process segmentation and model selection provide a theoretical framework that allows precise biological interpretations. Adaptive methods for model selection give promising results concerning the estimation of the number of altered regions on the genome.

Algorithms↗
PubMed2005

Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function.

Mutations in the Melanocortin 4 receptor are implicated in 1-6% of early onset or severe adult obesity cases. Most of the patients carry heterozygous missense mutations. Arguments for the pathogenicity of these mutations are based on the frequency of rare functionally relevant non-synonymous mutations in severely obese children and adults versus non-obese controls, the segregation of mutations with obesity in the family of the probands (although with incomplete penetrance) and the relevant functional defects described for these mutations. We have developed new assays to study the functional characteristics of these obesity-associated MC4R mutations. Systematic and comparative functional study of over 50 different obesity-associated mutations suggests that multiple functional alterations contribute to their pathogenicity. These studies also lead to new insights into the structure-function relationship of MC4R, provide novel hypotheses for the genetic predisposition to common obesity in humans and allow the development of new molecular tools for studying the physiological role of GPCRs.

Animals↗
PubMed2004

PAX4 gene variations predispose to ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.

Africa, Western↗
PubMed2004

Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans.

The melanocortin-4 receptor (MC4R), a centrally expressed G protein-coupled receptor (GPCR), is essential for the maintenance of long-term energy balance in humans. Mutations in MC4R are the most common genetic cause of obesity. Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity. Control of MC4R activity in vivo is modulated by the opposing effects of the anorexigenic agonist alpha-melanocyte-stimulating hormone (alpha-MSH) and the orexigenic antagonist agouti-related protein (AGRP). In addition, experiments in vitro have demonstrated that the human MC4R has an intrinsic constitutive activity on which AGRP also acts as an inverse agonist. The physiological role of this constitutive activity in the control of energy balance as well as the domain of the protein implicated in its maintenance are unknown. By systematically studying functional defects in naturally occurring MC4R mutations from obese patients, we defined a cluster of N-terminal mutations that selectively impair the constitutive activity of the receptor. Further characterization of this domain demonstrated that it functions as a tethered intramolecular ligand that maintains the constitutive activity of MC4R and may provide novel avenues for the design of drugs targeting this receptor. Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans.

Agouti-Related Protein↗
PubMed2004

A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans.

As a mediator of the effects of leptin, the melanocortin-4 receptor (MC4R) is an essential component of the central regulation of long-term energy homeostasis. Heterozygous mutations in this receptor are the most frequent genetic cause of severe obesity in children. The very rare described carriers of homozygous MC4R mutations for whom clinical data were available had a residual receptor activity thus not allowing for the description of the full extent of the role of MC4R in humans. Here, we present the clinical and biological features of a patient with complete absence of MC4R activity and compare the clinical and endocrine characteristics of this patient with those previously observed in leptin receptor-deficient patients. Our data suggest that in humans, the MC4R mediates most of the anorectic effects of leptin in early childhood. In contrast, MC4R does not mediate the effect of leptin on linear growth and other endocrine axes. In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations.

Body Weight↗
PubMed2004

Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance.

Nonautoimmune ketosis-prone diabetic syndromes are increasingly frequent in nonwhite populations. We have characterized a cohort of patients of sub-Saharan African origin who had ketosis-prone type 2 diabetes (n = 111), type 1 diabetes (n = 21), and type 2 diabetes (n = 88) and were admitted to a hospital for management of uncontrolled diabetes. We compared epidemiological, clinical, and metabolic features at diabetes onset and measured insulin secretion (glucagon-stimulated C-peptide) and insulin action (short intravenous insulin tolerance test) during a 10-year follow-up. Ketosis-prone type 2 diabetes shows a strong male predominance, stronger family history, higher age and BMI, and more severe metabolic decompensation than type 1 diabetes. In ketosis-prone type 2 diabetes, discontinuation of insulin therapy with development of remission of insulin dependence is achieved in 76% of patients (non-insulin dependent), whereas only 24% of patients remain insulin dependent. During evolution, ketosis-prone type 2 diabetes exhibit specific beta-cell dysfunction features that distinguish it from type 1 and type 2 diabetes. The clinical course of non-insulin-dependent ketosis-prone type 2 diabetes is characterized by ketotic relapses followed or not by a new remission. Progressive hyperglycemia precedes and is a strong risk factor for ketotic relapses (hazard ratio 38). The probability for non-insulin-dependent ketosis-prone type 2 diabetes to relapse is 90% within 10 years, of whom approximately 50% will become definitively insulin dependent. Insulin sensitivity is decreased in equal proportion in both ketosis-prone type 2 diabetes and type 2 diabetes, but improves significantly in non-insulin-dependent ketosis-prone type 2 diabetes, only after correction of hyperglycemia. In conclusion, ketosis-prone type 2 diabetes can be distinguished from type 1 diabetes and classical type 2 diabetes by specific features of clinical pathophysiology and also by the natural history of beta-cell dysfunction and insulin resistance reflecting a propensity to glucose toxicity.

Adult↗
PubMed2003

Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations.

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.

Amino Acid Sequence↗
PubMed2003

Emerging trends in the search for genetic variants predisposing to human obesity.

PURPOSE OF REVIEW: The models currently proposed for the genetic architecture of obesity are critically reviewed in the light of recent developments in the search for genetic causes of this condition. RECENT FINDINGS: As for many other 'complex' diseases, most of the genetic variants predisposing to human obesity have not yet been identified. To date, investigation of the genetic contribution to obesity has been conducted according to two main hypotheses. The common disease/common variant hypothesis proposes that the genetic architecture of complex diseases (including obesity) is likely to consist of a limited number of alleles, each conferring a small increase in risk to the individual. Alternatively, it has also been proposed that complex diseases such as obesity may instead result from the effects of a large number of rare variants, with substantial allelic heterogeneity at disease-causing loci. These two hypotheses have shaped strategies for the identification of disease genes, including the use of linkage analysis, association studies and the systematic sequencing of candidate genes. Linkage studies have recently been very successful in identifying new genes in which mutations cause rare monogenic syndromes of obesity. In common obesity, numerous linkage and association studies have suggested that an increasing number of genetic loci could be involved. Overall, however, these studies have failed to identify the causal genetic variants. In contrast, the direct sequencing of well-chosen candidate genes has led to the identification of numerous rare alleles causing both syndromic and common obesity, which are less severe forms of the condition in humans. SUMMARY: The genetic architecture of obesity is still a matter of debate. The previously accepted hypothesis of a small number of common variants has been undermined by the low reproducibility of association studies and inconsistencies among genome scans for obesity. While high-throughput association mapping of candidate regions holds some promise for the identification of common susceptibility alleles, it must also be considered that the genetic predisposition to obesity may instead result from multiple rare variants in a large number of genes.

Alleles↗
PubMed2003

Molecular genetics of human obesity-associated MC4R mutations.

Heterozygous coding mutations in the melanocortin 4 receptor (MC4R) are implicated in 1 to 6% of early onset or severe adult obesity cases. To better address the problem of the genotype:phenotype relationship within this specific form of obesity, we systematically studied the functional characteristics of 50 different obesity-associated MC4R mutations. Structure modeling of MC4R indicates that obesity-associated MC4R mutations are not localized in a single domain of the protein. We developed a flow cytometry-based assay to compare cell membrane expression of obesity-associated MC4R mutants. Using this assay, we demonstrate that over 54% of the obesity-associated MC4R mutations impair the membrane expression of MC4R. All other mutations impair the basal constitutive activity and/or the EC(50) for the physiological agonist alpha-MSH as measured in a cAMP- dependent luciferase assay. The extent of the alterations in receptor activity ranges from a total suppression of MC4R activation in response to alpha-MSH to a mild alteration of the basal constitutive activity of the receptor. Since most patients are heterozygous for MC4R mutations, these data indicate that a small decrease in overall MC4R activity can cause obesity, strongly supporting the hypothesis that the MC4R is a critical component of the adipostat in humans.

Amino Acid Sequence↗
PubMed2003

Engineering the melanocortin-4 receptor to control G(s) signaling in vivo.

G-protein-coupled receptors (GPCRs) are the largest known family of cell surface receptors, and they control many important physiological events, including sensory perception, chemotaxis, neurotransmission, and energy homeostasis. However, GPCR signaling can be difficult to study in vivo because of the multitude of GPCRs, the lack of specific synthetic agonists, and the fact that some GPCRs activate multiple signaling pathways. One method to circumvent these problems is to develop an engineered receptor that is unresponsive to its endogenous agonist, yet can be fully activated by synthetic, small-molecule drugs. Such a receptor, called a receptor activated solely by a synthetic ligand (RASSL), can be rapidly and reversibly activated by a small-molecule drug and would be a powerful tool to control G-protein signaling in vivo. Here we present the development of a G(s)-coupled RASSL based on the melanocortin-4 receptor (MC4R). MC4R couples exclusively to G(s) at physiologically relevant concentrations of its endogenous ligand, alpha-melanocyte-stimulating hormone (alpha-MSH). Data from human patients and structure-activity studies have shown that several mutations in MC4R cause a decreased affinity for alpha-MSH and can be exploited for RASSL development. Synthetic, small-molecule agonists of MC4R are now available and can be used to activate mutated receptors in vivo. We are engineering a series of mutations in MC4R to remove the peptide-binding site while retaining small-molecule binding and activation. The MC4R G(s) RASSL could be used to control many physiological responses associated with G(s) signaling such as heart rate, energy homeostasis, and cell proliferation.

Amino Acid Sequence↗
PubMed2003

The human MC4R promoter: characterization and role in obesity.

Heterozygous mutations in the coding sequence of the serpentine melanocortin 4 receptor (MC4R) are the most frequent genetic cause of severe human obesity. Since haploinsufficiency has been proposed as a causal mechanism of obesity associated with these mutations, reduction in gene transcription caused by mutations in the transcriptionally essential regions of the MC4R promoter may also be a cause of severe obesity in humans. To test this hypothesis we defined the minimal promoter region of the human MC4R and evaluated the extent of genetic variation in this region compared with the coding region in two cohorts of severely obese subjects. 5'RACE followed by functional promoter analysis in multiple cell lines indicates that an 80-bp region is essential for the transcriptional activity of the MC4R promoter. Systematic screening of 431 obese children and adults for mutations in the coding sequence and the minimal core promoter of MC4R reveals that genetic variation in the transcriptionally essential region of the MC4R promoter is not a significant cause of severe obesity in humans.

Adult↗