[Prevalence of melanocortin 4 receptor (MC4R) mutations and polymorphismsin consecutively ascertained obese children and adolescents from a pediatric health care utilization population]. / Prävalenz von Melanocortin-4-Rezeptor(MC4R)-Mutationen und Polymorphismen bei adipösen Kindern und Jugendlichen in einer konsekutiven pädiatrischen Inanspruchnahmepopulation.

BACKGROUND: The prevalence of childhood obesity is steadily increasing. Weight regulation and food intake are subject to complex regulatory mechanisms. The leptinergic-melanocortinergic system is known to be of major importance. AIM OF THE STUDY: Identification of mutations in the melanocortin 4 receptor gene (MC4R) and of phenotypic effects of detected mutations in German obese children and adolescents. Family specific and cardiovascular risk factors were also analysed. PATIENTS: Consecutive ascertainment of 90 obese children and adolescents with a medium BMI SDS of + 2.6, age range 3 to 16 years. METHODS: Mutation screen within the MC4R was carried out by denaturing high performance liquid chromatography (dHPLC) and re-sequencing of samples with aberrant dHPLC patterns. Eating behaviour and obesity-associated diseases within the families were evaluated by semi-structured interviews. Metabolic evaluation included: oral glucose tolerance test (OGTT, WHO criteria) for calculation of insulin resistance (Homeostasis Model Assessment, HOMA) and insulin sensitivity index (ISI), lipid panel for lipid status, blood pressure measurement and abdominal ultrasound. RESULTS: Three patients were heterozygous MC4R mutation carriers (Thr112Met, Ala175Thr and Gly181Asp). Gly181Asp leads to a complete loss of function; whereas Thr112Met and Ala175Thr lead to a reduced receptor function. The patients with heterozygous MC4R mutations had BMIs, cholesterol levels and waist to hip ratios (W/H) that did not differ from the rest of our study group. The overall occurrence of hypertriglyceridemia (34 %) and hypercholesterinemia (22 %) was correlated with the W/H-ratio. The overall incidence of impaired glucose tolerance was 12 %. In those with a normal glucose tolerance 68 % already had an increased HOMA (mean 3.12; reference value < 1.9) and decreased ISI (mean 4.3; reference value > 7.2). The patients with MC4R mutations had a normal glucose tolerance with similar HOMA and ISI values compared to the rest of the patients. Hypertension was found in 24 % of all cases and blood pressure was correlated with BMI (r+ 0.8). None of the patients with MC4R mutations were hypertensive. Leptin levels did not discriminate between patients with MC4R mutations and the other patients. Five patients harboured one of the MC4R polymorphisms (Val103Ile, Ile251Leu). These were phenotypically indistinguishable from the individuals without MC4R variants. CONCLUSION: We detected MC4R mutations (Thr112Met, Ala175Thr and Gly181Asp) in 3.3 % and MC4R polymorphisms (Val103Ile, Ile251Leu) in 5.5 % of the analysed obese children and adolescents, respectively. The patients with MC4R mutations did not show a higher metabolic risk compared to obese children and adolescents without mutations. However the total study group is prone to an increased risk for developing metabolic and cardiovascular diseases.

Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives.

The association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke. We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-kappaB and its inhibitor molecule IkappaBalpha. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-kappaB. Experiments on cultured monocytes/macrophages demonstrated enhanced IkappaBalpha degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression. This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.