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Karine Clément

Publications and source records attributed to Karine Clément.

At least 19 recordsLinked to original sources
PubMed2006

Unraveling the genetics of human obesity.

The use of modern molecular biology tools in deciphering the perturbed biochemistry and physiology underlying the obese state has proven invaluable. Identifying the hypothalamic leptin/melanocortin pathway as critical in many cases of monogenic obesity has permitted targeted, hypothesis-driven experiments to be performed, and has implicated new candidates as causative for previously uncharacterized clinical cases of obesity. Meanwhile, the effects of mutations in the melanocortin-4 receptor gene, for which the obese phenotype varies in the degree of severity among individuals, are now thought to be influenced by one's environmental surroundings. Molecular approaches have revealed that syndromes (Prader-Willi and Bardet-Biedl) previously assumed to be controlled by a single gene are, conversely, regulated by multiple elements. Finally, the application of comprehensive profiling technologies coupled with creative statistical analyses has revealed that interactions between genetic and environmental factors are responsible for the common obesity currently challenging many Westernized societies. As such, an improved understanding of the different "types" of obesity not only permits the development of potential therapies, but also proposes novel and often unexpected directions in deciphering the dysfunctional state of obesity.

Animals↗
PubMed2006

Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation.

We previously showed that the cysteine protease cathepsin S (CTSS), known to degrade several components of the extracellular matrix (ECM), is produced by human adipose cells and increased in obesity. Because ECM remodeling is a key process associated with adipogenesis, this prompted us to assess the potential role of CTSS to promote preadipocyte differentiation. Kinetic studies in primary human preadipocytes revealed a modest increase in CTSS gene expression and secretion at the end of differentiation. CTSS activity was maximal in preadipocyte culture medium but decreased thereafter, fitting with increased release of the CTSS endogenous inhibitor, cystatin C, during differentiation. Inhibition of CTSS activity by an exogenous-specific inhibitor added along the differentiation, resulted in a 2-fold reduction of lipid content and expression of adipocyte markers in differentiated cells. Conversely, the treatment of preadipocytes with human recombinant CTSS increased adipogenesis. Moreover, CTSS supplementation in preadipocyte media markedly reduced the fibronectin network, a key preadipocyte-ECM component, the decrease of which is required for adipogenesis. Using immunohistochemistry on serial sections of adipose tissue of obese subjects, we showed that adipose cells staining positive for CTSS are mainly located in the vicinity of fibrosis regions containing fibronectin. Herein we propose that CTSS may promote human adipogenesis, at least in part, by degrading fibronectin in the early steps of differentiation. Taken together, these results indicate that CTSS released locally by preadipocytes promotes adipogenesis, suggesting a possible contribution of this protease to fat mass expansion in obesity.

Adipocytes↗
PubMed2006

Genetic polymorphisms and weight loss in obesity: a randomised trial of hypo-energetic high- versus low-fat diets.

OBJECTIVES: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. DESIGN: Randomised, parallel, two-arm, open-label multi-centre trial. SETTING: Eight clinical centres in seven European countries. PARTICIPANTS: 771 obese adult individuals. INTERVENTIONS: 10-wk dietary intervention to hypo-energetic (-600 kcal/d) diets with a targeted fat energy of 20%-25% or 40%-45%, completed in 648 participants. OUTCOME MEASURES: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. RESULTS: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from -0.6 to 0.8 kg, and homozygotes, from -0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to -1.6 kg in heterozygotes, and from 3.8 kg to -2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. CONCLUSIONS: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet.

Journal Article↗
PubMed2006

Genetics of human obesity.

We present the knowledge acquired in the field of the genetics of human obesity. The molecular approach proved to be powerful to define new syndromes associated to obesity. The pivotal role of leptin and melanocortin pathways were recognized but in rare obesity cases. In the commoner form of obesities, a multitude of polymorphisms located in genes and candidate regions participate in an individual susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify the domain.

Animals↗
PubMed2006

Genetics of human obesity.

This chapter presents the current state of knowledge in the field of the genetics of human obesity. The molecular approach has proved to be powerful in defining new syndromes associated with obesity. The pivotal role of leptin and melanocortin pathways has been recognized, but only in rare cases of obesity. In the more common form of obesity a multitude of polymorphisms located in genes and candidate regions throughout the genome regulate an individual's susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. Combining these single nucleotide polymorphisms and defining the associated risks for obesity will be a real challenge in the future. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify this field.

Body Mass Index↗
PubMed2006

Serum amyloid A: a marker of adiposity-induced low-grade inflammation but not of metabolic status.

OBJECTIVE: Adipocytes secrete a series of acute phase proteins including serum amyloid A (SAA); the link with metabolic status is unknown. We studied the variations of expression of the SAA gene in adipose and liver tissues and of SAA serum levels, as well as their relationships with metabolic features during weight loss. RESEARCH METHODS AND PROCEDURES: Plasmatic variations of SAA, inflammatory markers (high sensitivity C-reactive protein, interleukin-6, fibrinogen, and orosomucoid), and adipokines (adiponectin, leptin) were studied in 60 morbidly obese patients before and after gastric surgery. For 10 subjects, SAA mRNA expression was measured at baseline in subcutaneous white adipose tissue (scWAT) and visceral white adipose tissue (vWAT) and in the liver. The evolution of SAA mRNA expression was also studied after surgery in scWAT. RESULTS: SAA serum concentration displayed a significant reduction 3 months after surgery and remained stable beyond 6 months. mRNA expression of inducible SAA isoforms (SAA 1 and 2) in scWAT was higher than in vWAT (p = 0.01) and the liver (p < 0.01) and correlated significantly with BMI, SAA, and high sensitivity C-reactive protein serum concentrations but not with metabolic markers (glucose, insulin, lipid parameters, adiponectin). SAA serum level and its variation during weight loss significantly correlated with adiposity markers (BMI and adipocyte volume, p < 0.01) and inflammatory markers but not with variations of metabolic parameters. The variations of SAA expression in scWAT after surgery correlated with changes in BMI and SAA protein serum levels (p < 0.05). DISCUSSION: SAA can be considered as a marker of adiposity-induced low-grade inflammation but not of the metabolic status of obese subjects.

Adipose Tissue↗
PubMed2006

[Human obesity: toward functional genomics].

Genetic and environmental aspects are recognized in the obesity field and attempts to elucidate multiple genes and gene/environment interactions are necessary. In rare cases of monogenic obesities, genetic tools have proved extremely powerful for identifying the genes responsible and for defining new syndromes. Abnormalities of genes involved in the leptin/melanocortin axis have been described. In common obesity, most studies include the search for genotype/phenotype associations without taking into account the influence of environment (diet, sedentary lifestyle) in the relationship. Many genes and candidate regions have been proposed to be involved in the determinism of human obesity. Among the limitations to this integrated approach, one can cite the difficulty of having large enough samples as well as biocomputing tools that are still in their infancy for accessing the question of multiple interactions with no "a priori hypotheses". This picture will probably change rapidly in the future. The purpose of this paper is to present some examples of the knowledge acquired in the field of obesity genetics and the new ongoing tools and developments that aim at studying the contribution of genes to obesity and their response to environmental changes. The capacity for studying multiple genes at once at the DNA or RNA levels is rapidly growing. Finally, tremendous progress in biocomputing will allow the integration of information from different sources (i.e. environment, phenotype, genotype, gene expression) and thus improve our ability to deal with complexity. Examples of these approaches exist in humans and in animal models.

Chromosome Aberrations↗
PubMed2006

Clustering biological annotations and gene expression data to identify putatively co-regulated biological processes.

MOTIVATION: Functional profiling is a key step of microarray gene expression data analysis. Identifying co-regulated biological processes could help for better understanding of underlying biological interactions within the studied biological frame. RESULTS: We present herein an original approach designed to search for putatively co-regulated biological processes sharing a significant number of co-expressed genes. An R language implementation named "FunCluster" was built and tested on two gene expression data sets. A discriminatory functional analysis of the first data set, related to experiments performed on separated adipocytes and stroma vascular fraction cells of human white adipose tissue, highlighted the prevalent role of nonadipose cells in the synthesis of inflammatory and immunity molecules in human adiposity. On the second data set, resulting from a model investigating insulin coordinated regulation of gene expression in human skeletal muscle, FunCluster analysis spotlighted novel functional classes of putatively co-regulated biological processes related to protein metabolism and the regulation of muscular contraction. AVAILABILITY: Supplementary information about the FunCluster tool is available on-line at http://corneliu.henegar.info/FunCluster.htm.

Algorithms↗
PubMed2006

Serum amyloid A and obstructive sleep apnea syndrome before and after surgically-induced weight loss in morbidly obese subjects.

BACKGROUND: Serum amyloid A (SAA) is an inflammatory marker associated with cardiovascular disease (CVD) and found to be increased in obesity. Obstructive sleep apnea (OSA) syndrome, a frequent complication of obesity also associated with CVD risk, is improved after surgically-induced weight loss. To explore the potential role of SAA in the relation between OSA and CVD, we investigated relationships between changes in SAA concentrations and nocturnal respiratory events in obese subjects undergoing bariatric surgery. METHODS: We measured plasma SAA and used nocturnal respiratory polygraphy to assess the apneahypopnea index (AHI), the oxygen desaturation index (ODI) and the mean and lowest O(2) saturation (SaO(2) ) in 61 morbidly obese patients before either adjustable gastric banding or gastric bypass. For 35 subjects with OSA, the same data were obtained 1 year after the surgery. RESULTS: Before surgery, SAA concentrations were significantly higher in patients with severe OSA (56.2+/-6.4 microg/ml) compared to subjects with moderate OSA (22.9+/-3.2 microg/ml) or without OSA (16.2+/-2.2 microg/ml). Plasma SAA correlated positively with AHI and ODI, and negatively with mean and lowest SaO(2). After surgery, plasma SAA decreased significantly by 41.7%, and changes in plasma SAA correlated with variations in OSA parameters. In multivariate analyses, AHI was a predictor of plasma SAA, independent of BMI, both at baseline and during weight loss. CONCLUSION: The improvement of OSA after bariatric surgery is associated with a decrease in SAA, independent of the change in BMI. SAA may represent a marker of the improvement in CVD risk profile after surgically-induced weight loss in patients with OSA.

Adult↗
PubMed2006

Adiponutrin gene is regulated by insulin and glucose in human adipose tissue.

OBJECTIVE: Adiponutrin is a new transmembrane protein specifically expressed in adipose tissue. In obese subjects, short- or long-term calorie restriction diets were associated with a reduction in adiponutrin gene expression. Adiponut.rin mRNA level was previously shown to be negatively correlated with fasting glucose plasma levels and associated with insulin sensitivity of non-diabetic obese and non-obese subjects. The purpose of the present work was to get more insight into the regulation of adiponutrin gene expression by insulin and/or glucose using clamp studies and to examine its potential dysregulation in subjects with a deterioration of glucose homeostasis. METHODS: Adiponutrin gene expression was quantified by reverse transcriptase-quantitative PCR in s.c. adipose tissue of healthy lean subjects after an euglycemic hyperinsulinemic clamp (EGHI), a hyperglycemic euinsulinemic clamp, and a hyperglycemic hyperinsulinemic (HGHI) clamp. Adiponutrin gene expression was also analyzed in patients with different levels of insulin resistance. RESULTS: During EGHI, insulin infusion induced adiponutrin gene expression 8.4-fold (P = 0.008). Its expression was also induced by glucose infusion, although to a lesser extend (2.2-fold, P = 0.03). Infusion of both insulin and glucose (HGHI) had an additive effect on the adiponutrin expression (tenfold, P = 0.008). In a pathological context, adiponutrin gene was highly expressed in the adipose tissue of type-1 diabetic patients with chronic hyperglycemia compared with healthy subjects. Conversely, adiponutrin gene expression was significantly reduced in type-2 diabetics (P = 0.01), but remained moderately regulated in these patients after the EGHI clamp (2.5-fold increased). CONCLUSION: These results suggest a strong relationship between adiponutrin expression, insulin sensitivity, and glucose metabolism in human adipose tissue.

Adipose Tissue↗
PubMed2006

Insulin regulation of gene expression and concentrations of white adipose tissue-derived proteins in vivo in healthy men: relation to adiponutrin.

Adiponutrin is a newly described white adipose tissue (WAT)-derived protein whose function and regulation remain widely unclear in humans though it is suggested to be related to insulin sensitivity. Recently, we found that adiponutrin expression is reduced in type 2 diabetic subjects in basal and insulin-stimulated states. To examine adiponutrin regulation by the insulin pathway in relation to other WAT-related proteins with well-known relation to insulin signaling and action, we examined in healthy young men (1) the association of adiponutrin with p85alpha PI3K and HKII, leptin, adiponectin, and acylation-stimulating protein (ASP) and (2) the regulation of adiponutrin and WAT-derived proteins by 3-h hyperinsulinemic euglycemic clamp (HIEG). At baseline (N = 20), adiponutrin expressions were positively correlated with those of p85alpha PI3K (R = 0.54, P = 0.017), HKII (R = 0.58, P = 0.010), and serum leptin (R = 0.51, P = 0.036), but not with any other parameter measured including insulin sensitivity. Hyperinsulinemia (N = 10, +2365% above baseline) significantly increased the expression of adiponutrin (+770%, P = 0.002), p85alpha PI3K (+150%, P = 0.033), HKII (+147%, P = 0.007), and serum leptin (+11%, P = 0.031), while it decreased serum adiponectin (-15%, P = 0.001). In the insulin-stimulated state, adiponutrin mRNA expression levels correlated with basal p85alpha PI3K (R = 0.76, P = 0.018) and HKII (R = 0.86, P = 0.003) expression levels, with percentage increase in insulin (R = 0.73, P = 0.040), and with insulin-stimulated state HKII (R = 0.82, P = 0.007), leptin (R = 0.84, P = 0.005), and adiponectin (R = 0.85, P = 0.004) mRNA levels. In healthy young men, adiponutrin expression is upregulated [corrected] by hyperinsulinemia and is related to basal and/or insulin-stimulated p85alpha PI3K, HKII, adiponectin, and leptin expression levels. We hypothesize that insulin-mediated regulation of adiponutrin expression is under the PI3K pathway. The relevance of the present findings to reduced adiponutrin expression in type 2 diabetes is discussed.

Adiponectin↗
PubMed2006

Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity.

In human obesity, white adipose tissue (WAT) is enriched in macrophages. How macrophage infiltration in WAT contributes to the complications of obesity is unknown. This study tested the hypothesis that recruitment of macrophages in omental WAT is associated with hepatic damage in obese patients. Paired biopsies of subcutaneous and omental WAT and a liver biopsy were collected during gastric surgery in 46 obese women and 9 obese men (BMI 47.9 +/- 0.93 kg/m(2)). The number of HAM56+ macrophages in WAT was quantified microscopically, and correlations with clinical and biological parameters and histological liver pathology were investigated. There were twice as many macrophages in omental as in subcutaneous WAT (P<0.0001). After adjustment for age, omental WAT macrophage infiltration was correlated to fasting glucose and insulin, quantitative insulin sensitivity check index, triglycerides, aspartate aminotransferase (AST), and gamma-glutamyltranspeptidase. We propose an easy equation to estimate the amount of macrophages in omental WAT. Increased macrophage accumulation specifically in omental WAT was associated with hepatic fibroinflammatory lesions (P=0.01). The best predictive model for the severity of hepatic damage includes adiponectinemia, AST, and omental WAT macrophages. These data suggest that the presence of macrophages in omental WAT participates in the cellular mechanisms favoring hepatic fibroinflammatory lesions in obese patients.

Adipocytes↗
PubMed2005

Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes.

We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.

Adult↗
PubMed2005

Analysis of sequence variability in the CART gene in relation to obesity in a Caucasian population.

BACKGROUND: Cocaine and amphetamine regulated transcript (CART) is an anorectic neuropeptide located principally in hypothalamus. CART has been shown to be involved in control of feeding behavior, but a direct relationship with obesity has not been established. The aim of this study was to evaluate the effect of polymorphisms within the CART gene with regards to a possible association with obesity in a Caucasian population. RESULTS: Screening of the entire gene as well as a 3.7 kb region of 5' upstream sequence revealed 31 SNPs and 3 rare variants; 14 of which were subsequently genotyped in 292 French morbidly obese subjects and 368 controls. Haplotype analysis suggested an association with obesity which was found to be mainly due to SNP-3608T>C (rs7379701) (p = 0.009). Genotyping additional cases and controls also of European Caucasian origin supported further this possible association between the CART SNP -3608T>C T allele and obesity (global p-value = 0.0005). Functional studies also suggested that the SNP -3608T>C could modulate nuclear protein binding. CONCLUSION: CART SNP -3608T>C may possibly contribute to the genetic risk for obesity in the Caucasian population. However confirmation of the importance of the role of the CART gene in energy homeostasis and obesity will require investigation and replication in further populations.

Base Sequence↗
PubMed2005

Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population.

BACKGROUND: The Pro12Ala Single Nucleotide Polymorphism (SNP) of the Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-gamma 2) has been associated with insulin resistance and type 2 diabetes (T2D) and also inconsistently with obesity. The aim of this study was to evaluate the impact of this SNP with regards to T2D and childhood and adult obesity in the French Caucasian population. METHODS: We conducted three independent case/control studies encompassing 2126 cases and 1124 controls. RESULTS: We found a significant association between PPAR-gamma 2 Pro12Ala SNP and T2D (p = 0.04, OR = 1.37), which was stronger when the T2D cohort was stratified according to the obesity status (p = 0.03, OR = 1.81 in obese T2D subjects). In contrast, there was no association between the Pro12Ala SNP and childhood and adulthood obesity. In normal glucose tolerant obese adults (but not in lean subjects), the Pro12 allele was associated with a significant increase in fasting insulin levels (p = 0.01), and in insulin resistance estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (p = 0.003), after adjustment for age, gender and BMI. We didn't detect evidence for an interaction effect between the Pro12Ala SNP and the obesity status with respect to the HOMA-IR index in normal glucose tolerant children, but we found a borderline interaction (p = 0.06) in normal glucose tolerant adults. CONCLUSION: Our results showed that the Pro12Ala polymorphism is not associated with childhood or adult obesity in the French Caucasian population. In contrast, we confirm a contribution of the PPAR-gamma 2 Pro12 allele in the genetic risk forT2D, especially in obese subjects, where this allele worsens insulin resistanceand increases fasting insulin levels.

Adolescent↗
PubMed2005

Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function.

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.

Apoptosis Regulatory Proteins↗
PubMed2005

The case for strategic international alliances to harness nutritional genomics for public and personal health.

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.

Animals↗