RESUMO
Bone density, anthropometric data, and markers of bone turnover were collected on 21 subjects diagnosed with Prader-Willi syndrome (PWS) and compared with 9 subjects with obesity of unknown cause. In addition, urinary N-telopeptide levels were obtained in all subjects. N-telopeptides are the peptide fragments of type I collagen, the major bone matrix material. During periods of active bone degradation or high bone turnover, high levels of N-telopeptides are excreted in the urine. However, no significant difference was detected in the urinary N-telopeptide levels when corrected for creatinine excretion (raw or transformed data) between our subjects with obesity or PWS and the observed effect size of the between-group difference was small. Although N-telopeptide levels were higher but not significantly different in the subjects with PWS compared with obese controls, the subjects with PWS had significantly decreased total bone and spine mineral density and total bone mineral content (all P < 0.001). No differences in N-telopeptide levels or bone mineral density were observed between subjects with PWS and chromosome 15q deletion or maternal disomy. Thus, decreased bone mineral density in subjects with PWS may relate to the lack of depositing bone mineral during growth when bones are becoming more dense (e.g., during adolescence), possibly because of decreased production of sex or growth hormones and/or long-standing hypotonia. It may not be caused by loss, or active degradation, of bone matrix measurable by the methods described in this study further supporting the possible need for hormone therapy during adolescence.
Assuntos
Densidade Óssea , Obesidade/patologia , Síndrome de Prader-Willi/patologia , Adolescente , Adulto , Fatores Etários , Criança , Cromossomos Humanos Par 15/genética , Colágeno/urina , Colágeno Tipo I , Estrogênios/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/urina , Peptídeos/urina , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/urina , Fatores Sexuais , Estatística como Assunto , Testosterona/sangueRESUMO
The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the differentiation of several tissues and cell types. PPARgamma was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPARgamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPARgamma expression and found that PPARgamma is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPARgamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPARgamma activity, but has no effect on PPARgamma expression. We demonstrated that the PPARgamma ligand 15-deoxy-delta12,14-prostaglandin J2 (15deltaPGJ2) and the thiazolidinedione troglitazone stimulate PPARgamma activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15deltaPGJ2 diminishes trophoblast differentiation. Furthermore, 15deltaPGJ2, but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPARgamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPARgamma results in opposing effects on trophoblast differentiation. Our results suggest that PPARgamma plays an important role in placental differentiation during human pregnancy.
Assuntos
Receptores Citoplasmáticos e Nucleares/fisiologia , Tiazolidinedionas , Fatores de Transcrição/fisiologia , Trofoblastos/fisiologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Diferenciação Celular , Células Cultivadas , Gonadotropina Coriônica/metabolismo , Cromanos/farmacologia , Densitometria , Imunofluorescência , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Ligantes , Prostaglandina D2/farmacologia , Tiazóis/farmacologia , Transfecção , Troglitazona , Trofoblastos/citologiaRESUMO
BACKGROUND: Weight gain is a frequent consequence of smoking cessation. Leptin, the protein product of the obese gene, seems to regulate appetite and body fat stores. The purpose of this study was to assess changes in circulating leptin levels and lipid metabolism during nicotine abstinence (NA) and their role in postcessation weight gain. METHODS: Six sedentary, weight-stable, nonobese adult smokers were studied before and after 7 days of NA while following a weight-maintenance diet of standard composition. All subjects refrained from smoking overnight (as assessed by breath CO) and were instructed to chew nicotine polacrilex gum (4 mg) hourly from 7:00 AM to 8:00 PM [nicotine intake (NI) day]. Venous blood samples were collected at 7:00 AM (after an overnight fast) and 5:00 PM (pre-supper) on NI day and again after 7 days of NA. RESULTS: Body weight did not change after 7 days of NA (72.0 +/- 2.8 versus 71.8 +/- 2.7 kg). Serum cotinine levels declined from 207 +/- 40 ng/mL during NI to undetectable levels during NA (P < 0.01). Fasting plasma leptin was similar during NI and NA (5.7 +/- 1.4 versus 6.4 +/- 1.9 ng/mL; P = NS). Moreover, plasma concentrations of glucose, insulin, and free fatty acids were unaffected by 7 days of NA. Although plasma triglycerides, total cholesterol, and low-density lipoprotein cholesterol were similar during NI and NA, high-density lipoprotein cholesterol increased by 15% after 7 days of NA (P < 0.05). CONCLUSIONS: In this group of nonobese, adult smokers consuming an isocaloric diet, NA for 7 days did not affect body weight or circulating concentrations of leptin, glucose, insulin, or free fatty acids. In contrast, HDL cholesterol increased significantly after NA. These results indicate that under controlled dietary conditions, changes in leptin expression do not contribute to the weight gain that commonly accompanies smoking cessation.
Assuntos
Lipídeos/sangue , Nicotina/sangue , Obesidade/sangue , Proteínas/metabolismo , Abandono do Hábito de Fumar , Aumento de Peso , HDL-Colesterol/sangue , Cotinina/sangue , Ingestão de Energia , Feminino , Humanos , Leptina , Masculino , Nicotina/administração & dosagem , Obesidade/etiologia , Estudos ProspectivosRESUMO
OBJECTIVE: Our goal was to determine the expression and activity of 15-hydroxy-prostaglandin dehydrogenase, a prostaglandin-metabolizing enzyme, in differentiating trophoblasts in vitro. STUDY DESIGN: Cytotrophoblasts from placentas of term healthy women were cultured in either Ham's-Waymouth medium, which hinders the process of cytotrophoblast differentiation, or medium 199, which facilitates differentiation into syncytiotrophoblasts. 15-Hydroxy-prostaglandin dehydrogenase expression was determined with Western immunoblotting, and activity was measured by a specific enzyme immunoassay of 13, 14-dihydro-15-keto prostaglandin F2 alpha, an inactive product of 15-hydroxy-prostaglandin dehydrogenase activity. RESULTS: The expression and activity of 15-hydroxy-prostaglandin dehydrogenase were enhanced during trophoblast differentiation and were higher in cells grown in medium 199 than in those grown in Ham's-Waymouth medium. 8-Bromo-cyclic adenosine monophosphate, which stimulates prostaglandin H synthase-2 expression, diminished the expression and activity of 15-hydroxy-prostaglandin dehydrogenase in concentration- and time-dependent manners. CONCLUSIONS: 15-Hydroxy-prostaglandin dehydrogenase expression and activity are regulated during trophoblast differentiation and by cyclic adenosine monophosphate. Coordinated expression of l5-hydroxy-prostaglandin dehydrogenase and prostaglandin H synthase-2 contributes to the regulation of prostaglandin release from trophoblasts.
Assuntos
Hidroxiprostaglandina Desidrogenases/biossíntese , Trofoblastos/enzimologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Western Blotting , Diferenciação Celular , Células Cultivadas , Meios de Cultura , AMP Cíclico/fisiologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Gravidez , Trofoblastos/citologiaRESUMO
INTRODUCTION: Adenosine triphosphate (ATP)-sensitive potassium (K+) channels are modulated by drugs, so that they are opened by vasodilators such as minoxidil but are closed by hypoglycemic agents such as glyburide (glibenclamide). Animal studies and in vitro evidence suggests that the coadministration of drugs with opposing effects on K+ channels attenuates their pharmacodynamic effects. METHODS: To investigate whether this important pharmacodynamic interaction occurs in humans, we administered 5 mg minoxidil, 2.5 mg glyburide or both in a double-blind fashion to nine healthy subjects. Glucose and insulin responses during an intravenous glucose tolerance test (0.3 gm/kg) were measured and blood pressure was recorded for 8 hours. In an additional four subjects the effect of 5 mg glyburide on the hypotensive effect of 5 mg minoxidil was examined. RESULTS: None of the parameters of glucose metabolism differed significantly when subjects received glyburide alone, minoxidil alone, or glyburide with minoxidil. Minoxidil or minoxidil in combination with 2.5 mg glyburide resulted in a similar significant decrease in blood pressure compared with the response to glyburide alone. The hypotensive effect of minoxidil was smaller in the four subjects who received the higher dose of glyburide, but significant hypoglycemia (blood glucose concentration < 60 mg/dl) occurred in three of the four subjects. CONCLUSION: We conclude that, in healthy volunteers, the coadministration of 2.5 mg glyburide and 5 mg minoxidil does not result in attenuation of the blood pressure-lowering effect of minoxidil. The smaller hypotensive response in four subjects who received 5 mg glyburide and 5 mg minoxidil suggests the possibility of a dose-related drug interaction. Studies with strict clamping of blood glucose concentrations will be required to address this possibility.
Assuntos
Anti-Hipertensivos/farmacologia , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Minoxidil/farmacologia , Canais de Potássio/efeitos dos fármacos , Adulto , Anti-Hipertensivos/administração & dosagem , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Antagonismo de Drogas , Teste de Tolerância a Glucose , Glibureto/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Masculino , Minoxidil/administração & dosagem , Norepinefrina/sangue , Valores de Referência , Renina/sangueRESUMO
The combined effects of exercise and energy restriction on changes in body fat and fat-free mass (FFM) are controversial. This study was conducted to determine whether muscle hypertrophy is possible during weight loss. Fourteen obese females received a 3360-kJ/d liquid diet for 90 d. Seven subjects received a weight training (WT) regimen and seven subjects remained sedentary (C). Biopsy samples were obtained from the vastus lateralis muscle at baseline and after 90 d of treatment. The average weight loss over the 90-d period was 16 kg with approximately 24% of the weight loss from FFM and 76% from fat. The amount and composition of the weight loss did not differ between WT and C groups. The cross-sectional area of slow twitch and fast twitch fibers was unchanged by treatment in C subjects but significantly increased in WT subjects. It appears that weight training can produce hypertrophy in skeletal muscle during severe energy restriction and large-scale weight loss.