Biomedical subjects

Jean-Marc Lacorte

Publications and source records attributed to Jean-Marc Lacorte.

8 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

Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats.

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD (n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.

Adiponectin↗

PubMed2005

Relationship between single nucleotide polymorphisms in leptin, IL6 and adiponectin genes and their circulating product in morbidly obese subjects before and after gastric banding surgery.

BACKGROUND: Certain adipose-produced signals are secreted in proportion to body fat mass and are involved in regulation of the energy metabolism of the whole body. Leptin, IL6 and adiponectin can be considered as adiposity signals. Several Single Nucleotide Polymorphisms (SNPs) in genes encoding for these molecules are known to influence their concentration in situations of stable weight. We hypothesized that polymorphism effects could be better detected in a situation of negative energy balance and that modified concentrations of adiposity signal genes could change the dynamics of weight gain in obese subjects. METHODS: 65 obese patients undergoing gastric banding surgery were genotyped for LEP+19A-->G, LEP-2548G-->C, IL6-174G-->C, APM1-11377C-->G and PM1-11391G-->A common SNPs. BMI and concentrations of leptin, IL6 and adiponectin were measured before surgery and after 1 year. RESULTS: All SNPs except IL6-174G-->C SNP were associated with modifications of the circulating concentrations of signals produced by adipose tissue at baseline. During weight loss, variant genotype carriers of LEP -2548 and +19 SNPs were characterized by a trend towards less decrease in circulating leptin. Weight loss was associated with an increase in IL6 concentration (16.9%+/-12.2) in the IL6-174 C/C genotype carriers, whereas the C/G or G/G genotypes carriers showed a decrease in IL6 (19.9%+/-5.2, P=0.001). CONCLUSION: We observed that the SNPs studied could modulate the concentration of adiposity signals not only at baseline but also during weight loss. Such variations may be sensed by the homeostatic feedback system that controls energy balance and may in turn contribute to some disturbances in weight regulation.

Adiponectin↗

PubMed2004

Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes.

Decrease of plasma lipid levels by polyphenols was linked to impairment of hepatic lipoprotein secretion. However, the intestine is the first epithelium that faces dietary compounds, and it contributes to lipid homeostasis by secreting triglyceride-rich lipoproteins during the postprandial state. The purpose of this study was to examine the effect of apple and wine polyphenol extracts on lipoprotein synthesis and secretion in human Caco-2/TC7 enterocytes apically supplied with complex lipid micelles. Our results clearly demonstrate that apple, but not wine, polyphenol extract dose-dependently decreases the esterification of cholesterol and the enterocyte secretion of lipoproteins. Apple polyphenols decrease apolipoprotein B (apoB) secretion by inhibiting apoB synthesis without increasing the degradation of the newly synthesized protein. Under our conditions, cholesterol uptake, apoB mRNA, and microsomal triglyceride protein activity were not modified by apple polyphenols. The main monomers present in our mixture did not interfere with the intestinal lipid metabolism. By contrast, apple procyanidins reproduced the inhibition of both cholesteryl ester synthesis and lipoprotein secretion. Overall, our results are compatible with a mechanism of action of polyphenols resulting in impaired lipid availability that could induce the inhibition of intestinal lipoprotein secretion and contribute to the hypolipidemic effect of these compounds in vivo.

Apolipoproteins B↗

PubMed2003

Reg IV, a new member of the regenerating gene family, is overexpressed in colorectal carcinomas.

A better understanding of the mechanisms by which colon tumor cells are able to survive exposure to drugs would be valuable for the development of new therapeutic strategies. We used differential display-PCR to compare gene expression in the drug-sensitive HT-29 colon cancer cell line and 3 drug-resistant subpopulations derived from this parental cell line. One of the genes identified is a new gene, Regenerating IV gene (Reg IV), and was strongly overexpressed in HT-29 drug-resistant cells. Other drug-resistant cell lines expressed Reg IV at a high level, whereas a low expression was noted in sensitive cell lines. Northern blot and real-time PCR analysis showed that Reg IV is more strongly expressed in 71% of colorectal tumors (in particular in mucinous carcinomas) than in normal colon tissues. The comparison of Reg IV expression with that of other REG genes, Regenerating Ialpha or (Reg Ialpha), Regenerating Ibeta (Reg Ibeta) and Pancreatitis-associated protein (PAP), highlights its predominant expression in colorectal tumors. Reg IV mRNA-positive tumor cells display different phenotypes: mucus-secreting, enterocyte-like or undifferentiated. Interestingly, whereas Reg IV expression is low in normal colon, its level in normal small intestine is similar to that in some colorectal tumors. In normal tissue, Reg IV mRNA-positive cells are mostly enteroendocrine cells and goblet cells. Our results point out the potential role of Reg IV in colorectal tumors and its subsequent interest as a pronostic indicator of tumor survival.

Adenocarcinoma↗

PubMed2003

Adiponectin gene expression in subcutaneous adipose tissue of obese women in response to short-term very low calorie diet and refeeding.

Adiponectin is an adipocyte-derived protein suggested to be involved in energy homeostasis and in lipid and glucose metabolism. Little is known regarding the consequence of acute changes in energy balance on adiponectin mRNA expression in human adipose tissue. Using a real-time RT-PCR assay, we investigated the effects of 2-d very low calorie diet (VLCD) and subsequent refeeding on adiponectin mRNA expression in sc adipose tissue of morbidly obese women. Basal adiponectin mRNA abundance of the obese women showed a wide distribution (2.6-14.3 mRNA/18S rRNA; coefficient of variation, 51.2%) and was significantly lower than that of lean controls (P < 0.001). In the obese group, the VLCD caused a 33% rise (P < 0.01) in the average level of mRNA, whereas refeeding caused a 32.8% fall (P < 0.05). In contrast, the change in leptin mRNA expression with either VLCD or refeeding was not statistically significant. The obese subjects who showed an acute adiponectin mRNA response to the changes in energy intake had a higher basal level of adiponectin mRNA (P = 0.02) and a borderline-significantly lower body mass index compared with the subjects who showed no or weak adiponectin mRNA response. Insulin sensitivity of the responder subgroup significantly increased by 89% (P = 0.008) after the VLCD, whereas insulin sensitivity of the nonresponder subgroup only increased by 24% (P = 1.56). This study indicates that adiponectin mRNA in sc adipose tissue can acutely respond to short-term energy changes in some obese subjects. Both the levels of adiposity and insulin sensitivity may contribute to the variation in adiponectin gene expression in response to acute energy changes.

Adiponectin↗

PubMed2002

Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status.

Defects in apoptosis have been implicated in chemoresistance of colon cancer cells. We report here the ability to resist to 5-fluorouracil-induced apoptosis of 8 colon cancer cell lines differing in p53 and bax status: p53(-/0)bax(+/+) for TC7, SW480, HT-29; p53(+/+)bax(-/-) for LS174T, LoVo; p53(+/+) bax(+/-) for HCT116; p53(+/+) or p53(+/0)bax(+/+) for LS513 or HCT-EB, respectively. To approximate to the in vivo therapy, the cell lines were exposed to a long-term treatment of 5-FU. The analysis of proteins implicated in the apoptotic pathway has shown that the independent analysis of p53 or bax status was not sufficient to predict the extent of drug-resistance of all cell lines. In p53(+/+) cell lines but not in p53(-/0) cell lines, a low level of the pro-apoptotic Bax protein was correlated with a greater resistance of cells to 5-FU. In addition, we found that high levels of anti-apoptotic Bcl-2 and Bcl-x(L) proteins combined with a low level of Bax were correlated to high 5-FU resistance of wild-type p53 cell lines. The same correlation was obtained for 2 out of 3 mutated p53 cell lines. In conclusion, the relative levels of Bcl-2, Bcl-x(L) and Bax may altogether contribute to determine the resistance of a majority of colon tumor cells to long-term 5-FU treatment, whatever their p53 status.

Antimetabolites, Antineoplastic↗

PubMed2002

Two initiator-like elements are required for the combined activation of the human apolipoprotein C-III promoter by upstream stimulatory factor and hepatic nuclear factor-4.

Human apoC-III (-890/+24) promoter activity is strongly activated by hepatic nuclear factor (HNF)-4 through its binding to the proximal (-87/-72) element B. This site overlaps the binding site for an activity that we identified as the ubiquitously expressed upstream stimulatory factor (USF) (Ribeiro, A., Pastier, D., Kardassis, D., Chambaz, J., and Cardot, P. (1999) J. Biol. Chem. 274, 1216-1225). In the present study, we characterized the relationship between USF and HNF-4 in the activation of human apoC-III transcription. Although USF and HNF-4 binding to element B is mutually exclusive, co-transfection experiments in HepG2 cells surprisingly showed a combined effect of USF and HNF-4 in the transactivation of the (-890/+24) apoC-III promoter. This effect only requires the proximal region (-99/+24) of the apoC-III promoter and depends neither on USF binding to its cognate site in element B nor on a USF-dependent facilitation of HNF-4 binding to its site. By contrast, we found by electrophoretic mobility shift assay and footprinting analysis two USF low affinity binding sites, located within the proximal promoter at positions -58/-31 (element II) and -19/-4 (element I), which are homologous to initiator-like element sequence. Co-transfection experiments in HepG2 cells show that a mutation in element II reduces 2-fold the USF transactivation effect on the proximal promoter of apoC-III and that a mutation in element I inhibits the combined effect of USF and HNF-4. In conclusion, these initiator-like elements are directly involved in the transactivation of the apoC-III promoter by USF and are necessary to the combined effect between USF and HNF-4 for the apoC-III transcription.

Apolipoprotein C-III↗