Dietary factors impact on the association between CTSS variants and obesity related traits.

Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology--this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors--increased by high protein, glycemic index and energy diets

Implication of genetic variability at the CTSS, CSTK, CTSL and CST3 loci in corpulence and related phenotypes

Les facteurs génétiques seraient responsables de 57 à 86% des variations interindividuelles de BMI. Notre équipe a identifié la Cathepsine S (CTSS) comme étant un nouveau biomarqueur d adiposité : son expression génique dans le tissu adipeux est très corrélée au BMI. Les taux circulants sériques ainsi que les taux d expression de ce gène dans le tissu adipeux étaient plus élevés chez des patients obèses que chez des témoins de poids normal. Plusieurs équipes ont montré que la Cathepsine K (CTSK) était surexprimé dans le tissu adipeux de patients obèses. Les souris CTSK -/- et CTSL -/- (invalidées pour la Cathepsine L) étaient protégés contre la prise de poids sous un régime riche en graisse et avaient également une amélioration des paramètres glycémiques. L inhibition de Cathepsine K chez la souris entraine une inhibition du stockage des lipides. L activité enzymatique des Cathepsines est régulée par des inhibiteurs endogènes, le plus puissant étant la Cystatine C (CST3). Des corrélations positives entres les taux sériques de Cystatine C et le BMI ont été trouvés dans différentes populations. Notre équipe a montré précédemment que la Cystatine C était exprimée et secrété par des préadipocytes humains différentiés in vitro. Notre groupe a finalement montré que des patients obèses avaient des taux circulants et des taux d expression de Cystatine C au niveau du tissu adipeux plus élevés que des témoins de poids normal. Nos hypothèses de travail étaient donc que la variabilité génétique aux loci CTSS, CTSK, CTSL et CST3 pourraient influencer les phénotypes liés à la corpulence ainsi que ceux liés aux paramètres lipidiques et glycémiques. Nous avons donc mené une étude génétique dans diverses populations de patients obèses ou de témoins de poids normal (enfants et adultes) dans le but de vérifier nos hypothèses. Nous avons trouvé une association entre le polymorphisme CST3 rs2424577 et l évolution de paramètres liés à la corpulence au cours de la vie dans 4 populations indépendantes. Nous avons aussi trouvé que les polymorphismes CST3 (rs2424577 et rs3827143) étaient associés à des paramètres liés au métabolisme du glucose, que ce soit à jeun ou pendant une HGPO, dans un groupe d individus obèses. Aucune association avec les variants situés dans les loci CTSS, CTSK et CTSL n a été trouvée. Ces résultats confirment la présence de variants fonctionnels au locus CST3 affectant sa fonctionnalité. Ces résultats montrent qu en dépit de leur fort rôle physiologique présumé, les loci CTSS, CTSK et CTSL n ont aucune contribution génétique aux phénotypes liés à la corpulence. En ce qui concerne le gène CST3, il semble jouer un rôle physiologique et génétique sur les phénotypes liés à la corpulence cependant ces contributions ont besoin d être explorés plus en détail.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Association between CST3 rs2424577 polymorphism and corpulence related phenotypes during lifetime in populations of European ancestry

Objective: Cystatin C, a protein coded by CST3 gene, is implicated in adipose tissue biology. Our hypothesis is that common variants in CST3 gene could play a role in the development of corpulence during lifetime. Methods: Two tag SNPs were selected to capture all SNPs in the CST3 region. We first investigated the association of the two tag SNPs individually and combined into haplotypes with corpulence related phenotypes in 4,288 French subjects (BMI = 24.31 +/- 3.74 kg/m(2)). Significant findings were replicated in five independent populations 790 Danish lean men (BMI = 24.63 +/- 2.30 kg/m(2)), 672 Danish obese men (BMI = 33.23 +/- 2.34 kg/m(2)), 763 Swedish women (BMI = 21.73 +/- 2.87 kg/m(2)), 1,848 Danish lean women (BMI = 22.66 +/- 2.85 kg/m(2)) and 2,061 Danish obese women (BMI = 37.01 +/- 3.59 kg/m(2)). Results: Rs2424577 was associated with BMI in three independent populations - G/G carriers were less corpulent than A/A carriers in the French individuals (p = 0.045) and in the Danish lean men (p = 0.021), and they were more corpulent in the group of Swedish women (p = 0.004). This phenomenon has been described as a flip-flop phenomenon, probably caused by a multi-locus effect. Conclusion: CST3 rs2424577 is associated with BMI in a complex fashion. This association is probably caused by the interaction between several functional variants

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

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Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Ppar expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPAR expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesit

Association between <i>CTSS</i> SNPs and weight change during the study.

<p>Overall Meta analysis estimates (β or odd ratios), p values, standard error and 95% confidence intervals for association between SNPs and weight change during the study, ED: energy density, GI: glycemic index. RSC: random subcohort.</p

Association between <i>CTSS</i> SNPs and body fat distribution change during the study.

<p>Overall Meta analysis estimates (β or odd ratios), p values, standard error and 95% confidence intervals for associations between SNPs and body fat distribution change during the study, ED: energy density, GI: glycemic index. RSC: random subcohort.</p

Description of <i>CTSS</i> variability in subcohort and cases.

<p>Genotype and allele counts, genotype and allele frequencies and Hardy Weinberg Equilibrium test p-values for each SNP in the subcohort and in the cases respectively.</p

Linkage disequilibrium (LD) plot of the <i>CTSS</i> locus in cases and random subcohort.

<p>This Figure shows LD (linkage disequilibrium) values (r²) between each tag SNP in (A) cases and (B) subcohort. Each diamond contains the LD value (r²) between the two SNPs that face each of the upper sides of the diamond, ex: the LD between rs10888390 (SNP N°3) and rs1136774 (SNP N°4) is r² = 0.62; the darker the diamond, the higher the LD value. There seems to be no difference in the LD pattern at the <i>CTSS</i> locus between the cases and the subcohort.</p

Characteristics of participants of cases, noncases and subcohort.

<p>Values presented are mean ± standard deviation or percentage (%) as indicated.</p>1<p><i>p-</i>values for the difference between cases and noncases, tested by Student t-test (for continuous variables) or Cochran-Armitage trend test (categorical variables).</p