Physiology, Psychology, and Genetics of Obesity

肥胖的生理学、心理学和遗传学

• 批准号: 8351114
• 负责人: JACK A. YANOVSKI
• 金额: $ 138.73万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8351114
• 关键词: Adolescent; Adult; African American; Age; Alstrom syndrome; Aniridia; BDNF gene; Bardet-Biedl Syndrome; Behavior; Behavioral; Binge Eating; Body Composition; Body Weight; Body Weight decreased; Body fat; Brain-Derived Neurotrophic Factor; Breeding; Characteristics; Child; Childhood; Cholesterol; Clinical; Clinical Protocols; Collaborations; Comorbidity; Consumption; Coupled; Data; Development; Diet; Disease; Eating; Eating Behavior; Energy Intake; Energy Metabolism; Etiology; Family history of; Fatty acid glycerol esters; Food; Future; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genitourinary system; Genotype; Glucose; Goals; Growth; Heating; Human; Hyperinsulinism; In Vitro; Individual; Insulin; Insulin Resistance; Intervention; Investigation; Kidney; Knock-in Mouse; Lead; Leptin; Link; Measurement; Mental Depression; Metabolic; Metformin; Nephroblastoma; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Other Genetics; Overweight; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Placebos; Plasma; Play; Population; Predictive Factor; Prevalence; Prevention strategy; Protocols documentation; Psychology; Randomized; Randomized Clinical Trials; Regulation; Reporting; Risk; Role; Satiation; Serum; Signal Pathway; Signal Transduction; Syndrome; Testing; Translational Research; Variant; WAGR Syndrome; WT1 gene; Weight; Weight Gain; base; chromosome 11p deletion syndrome; cohort; comparative genomic hybridization; depressive symptoms; endophenotype; energy balance; gene function; genetic variant; improved; interpersonal therapy; loss of control over eating; mouse model; mutant; obesity in children; obesity risk; obesity treatment; open label; orlistat; prevent; programs; prospective; psychologic; randomized placebo controlled trial; receptor; therapy development; treatment strategy

We have been examining polymorphisms in genes involved in the leptin signaling pathway, to identify gene variants impacting on body composition. We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction. Children who were homozygous variant for both the polymorphisms (Thr6Lys and Val81Ile) had significantly greater BMI-SD score, fat mass, body circumference measurements, and higher plasma levels of insulin and leptin compared with wild type or heterozygous children. In vitro studies subsequently found that expression was significantly lower for the double mutant MC3R and suggest degradation of the double mutant MC3R is increased. We have found energy intake is increased but energy expenditures are not altered in children having these polymorphisms. Ongoing studies attempt to understand the mechanisms by which these sequence alterations may impact body weight. We are initiating a new study comparing energy balance during adaptation to a high-fat diet in humans with double mutant and wild type MC3R this year. We have also successfully bred knock-in mice expressing the human wild type and human double-mutant MC3R that were developed in collaboration with Dr. Westphal, and will be studied during the next few years. We have also recently investigated the BDNF-TrkB pathway in regards to body mass in children. We found serum BDNF was significantly lower in overweight children (p=0.03) and have assessed the role of BDNF haploinsufficiency as a cause of obesity in patients with syndromes that are due to deletions in the vicinity of 11p14.1, where the human BDNF gene is found. Using a comparative genomic hybridization approach, we examined genotype-phenotype relationships in patients with the WAGR (Wilms Tumor, Aniridia, Genitourinary, and Renal abnormalities) syndrome. Compared to those with intact BDNF (BDNF+/+), BDNF+/- had significantly greater body mass during childhood, starting at age 2y. 100% of BDNF+/- were overweight by age 10y vs. only 20% of BDNF+/+ (P<0.0001). A full characterization of the energy intake and expenditure of subjects with WAGR syndrome and other 11p deletion syndromes is underway. We are also exploring other syndromes associated with obesity that may cause dysregulation of leptin signaling, including Bardet Biedl syndrome (in collaboration with Dr. Biesecker) and Alstrom Syndrome. Other studies are directed at understanding other genetic, physiological, psychological, and metabolic factors that place children at-risk for undue weight gain. We have found that leptin is an important predictor of weight gain in children: those with high leptin gain even more weight when followed longitudinally. We have validated prior associations between body weight and variation in the FTO gene and found SNPs in FTO to be associated with behavioral loss of control over eating. We are actively studying SNPs in FTO and histaminergic receptors for their associations with body weight regulation and particularly with energy intake and intentional weight loss. We have also investigated the impact of modulation of histaminergic tone on human energy intake. A new initiative studies the role of depressive symptoms in childrens insulin resistance. We have found both cross-sectional and prospective longitudinal associations between depressive symptoms and the development of insulin resistance. A randomized clinical trial to study the effects of preventing depression in obese adolescents with a family history of type 2 diabetes will begin in 2011. Other investigations have examined how heat is dissipated in obese individuals and tested the hypothesis that alterations in heat management may contribute to the development of obesity. Recent investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children, predict future weight gain in children at-risk for overweight, and predict both greater energy consumption during meals and decreased satiety after eating. The ability to consume large quantities of palatable foods, especially when coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge eating children. These data also suggest that interventions targeting disordered eating behaviors may potentially be useful in preventing excessive fat gain in children prone to obesity. An ongoing protocol examines efficacy of interpersonal therapy as a weight gain preventive strategy. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity is urgently needed. In clinical protocols, we have studied pharmacotherapeutic approaches to the control of body weight. Two placebo-controlled randomized trials studied the effects on weight loss and on obesity-related comorbidities in children and adolescents. Orlistat 120 mg TID was studied in 200 adolescents, 61% African American, mean BMI 41.70.6 kg/m2. Adolescents treated with orlistat lost more weight (orlistat -2.90.7 vs. placebo -0.60.7 kg, P=0.011), BMI units (-1.720.24 vs. -0.700.24 kg/m2, P=0.002), and fat mass (-3.90.8 vs. -1.40.8 kg, P=0.029), but had little impact on obesity-related co-morbid conditions in overweight adolescents. Metformin 1000 mg BID was studied in 100 severely overweight children (6-12y) who manifested hyperinsulinemia and insulin resistance. Subjects participated in a monthly weight reduction program. Compared to placebo-treated children, those randomized to metformin decreased BMI (metformin -0.910.3 vs. placebo +0.230.3 kg/m2, P=0.006), BMI-Z score (-0.110.02 vs. -0.040.02, P=0.02), and body fat mass (-1.40.7 vs. +2.10.7 kg, P<0.001) to a significantly greater extent. Serum glucose (-2.40.9 vs. +1.61.2 mg/dL, P=0.018), HOMA-IR (-0.190.4 vs. +0.950.4, P=0.05), and total cholesterol (-9.92.7 vs. +1.14.8, P=0.04) also decreased more in metformin-treated compared to placebo-treated children. We concluded that metformin, added to a monthly behavioral program, significantly improved weight loss, insulin resistance, and cholesterol over a 6-month interval in severely overweight, insulin-resistant children. In 2012, we will report on a 3-year open-label extension protocol to examine the long-term impact of metformin therapy on weight. We expect to initiate additional translational trials in the coming year related to modulation of the leptin signaling pathway. A new protocol to study how to treat the obesity of patients with Bardet Biedl syndrome based on the proposed mechanism for obesity in mouse models of Bardet Biedl syndrome will be initiated this year.

我们一直在研究参与瘦素信号通路的基因中的多态性，以鉴定影响人体组成的基因变异。我们目前正在深入研究与儿童肥胖相关的变体MC3R，并且似乎对MC3R信号转导具有功能意义。与野生型或杂合子儿童相比，多态性变体的儿童（THR6LYS和VAL81IL）都具有更高的BMI-SD评分，脂肪质量，体圆度测量值，胰岛素和瘦素的血浆水平更高的儿童。体外研究随后发现，双突变体MC3R的表达显着降低，并表明增加了双突变体MC3R的降解。我们发现能量摄入量增加了，但能量消耗没有改变这些多态性的儿童。正在进行的研究试图了解这些序列改变可能影响体重的机制。我们正在启动一项新的研究，比较了今年具有双重突变体和野生型MC3R的人类中能量平衡与高脂饮食的比较。我们还成功地繁殖了表达人类野生型和人类双线MC3R的敲门型小鼠，这些小鼠与Westphal博士合作开发，并将在未来几年内进行研究。我们最近还研究了关于儿童体重的BDNF-TRKB途径。我们发现，超重儿童的血清BDNF显着降低（p = 0.03），并评估了BDNF单倍耐药性作为肥胖症的原因在综合症患者中是由于11p14.1缺失所致的综合症，在那里发现了人类BDNF基因。使用比较基因组杂交方法，我们检查了WAGR（WILMS肿瘤，Aniridia，Genitiorinary和肾异常）综合征患者中的基因型 - 表型关系。与完整的BDNF（BDNF+/+）的人相比，BDNF +/-在童年时期的体重明显更大，从2岁开始。 BDNF +/-的100％按年龄超重，仅为BDNF+/+的20％（p <0.0001）。 WAGR综合征和其他11p缺失综合症的能量摄入和支出的全面表征正在进行中。我们还正在探索与肥胖相关的其他综合症，可能导致瘦素信号传导失调，包括Bardet Bardet Biedl综合征（与Biesecker博士合作）和Alstrom综合征。其他研究旨在理解其他遗传，生理，心理和代谢因素，这些因素使儿童处于危险中，以增加体重增加。我们发现，瘦素是儿童体重增加的重要预测指标：慢性瘦素较高的人会增加体重更大。我们已经验证了FTO基因体重与变异之间的先前关联，并发现FTO中的SNP与行为失去对饮食的控制丧失有关。我们正在积极研究FTO和组蛋白能受体中的SNP，以与体重调节有关，尤其是能量摄入和故意体重减轻。我们还研究了组胺能张力张力对人类能量摄入的调节的影响。一项新计划研究了抑郁症状在儿童胰岛素抵抗中的作用。我们发现抑郁症状和胰岛素抵抗的发展之间横断面和前瞻性纵向关联。一项随机临床试验，研究了2型糖尿病家族史的肥胖青少年预防抑郁症的影响。其他研究已经研究了肥胖个体中的热量如何耗散热量，并检验了热量管理的改变可能有助于肥胖的发展。最近的调查集中在儿童的暴饮暴食行为上表明，这种行为也与儿童肥胖有关，预测儿童在危险中的未来体重超重，并且可以预测进餐期间的能源消耗和饮食后的饱腹感。消耗大量可口食品的能力，尤其是当随后的饱腹感下降时，可能会在吃暴饮暴食的儿童中发挥更大的体重增加。这些数据还表明，针对无序饮食行为的干预措施可能有可能有助于防止容易发生肥胖的儿童过度增加脂肪。正在进行的协议将人际疗法的功效视为一种体重增加的预防策略。鉴于肥胖症患病率的迅速增加，迫切需要肥胖治疗的发展。在临床方案中，我们研究了控制体重的药物治疗方法。两项安慰剂对照的随机试验研究了对体重减轻和儿童和青少年肥胖相关合并症的影响。在200名青少年，61％的非裔美国人，平均BMI 41.70.6 kg/m2中研究了Orlistat 120 mg TID。接受Orlistat治疗的青少年减轻体重更大（Orlistat -2.90.7 vs.安慰剂-0.60.7 kg，p = 0.011），BMI单位（-1.720.24 vs. -0.700.24 vs. -0.24 kg/m2，m2，p = 0.002），litter thick and fat litter Intight（-3.90.8 vs. -1.8 vs. -1.8 vs. -1.8 vs. -1.8 vs. -1.8 vs.-1.8 vs. -1.8 vs.40 ppse but p = 0.8 vs. -1.8 kg，40.40 p = 0.8 vs. -140 by kg kg，40.8 vs.40 pre超重青少年中与肥胖相关的合并状况。在表现出高胰岛素血症和胰岛素抵抗的100个严重超重儿童（6-12y）中，研究了二甲双胍1000 mg的出价。受试者参加了每月减肥计划。 Compared to placebo-treated children, those randomized to metformin decreased BMI (metformin -0.910.3 vs. placebo +0.230.3 kg/m2, P=0.006), BMI-Z score (-0.110.02 vs. -0.040.02, P=0.02), and body fat mass (-1.40.7 vs. +2.10.7 kg, P<0.001)在很大程度上。血清葡萄糖（-2.40.9 vs. +1.61.2 mg/dl，p = 0.018），homa-ir（-0.190.4 vs. +0.950.4，p = 0.05）和总胆固醇和总胆固醇（-9.92.7 vs. +1.14.8，p = 0.04），还降低了更多的儿童。我们得出的结论是，二甲双胍增加了一个每月的行为计划，在6个月的时间间隔内显着改善了体重减轻，胰岛素抵抗和胆固醇，严重超重，耐胰岛素耐药的儿童。 2012年，我们将报告一项为期3年的开放标签扩展方案，以检查二甲双胍治疗对体重的长期影响。我们希望在来年与瘦素信号通路的调节有关的其他翻译试验。一项新的方案，用于研究如何根据Bardet Biedl综合征小鼠模型中提出的肥胖机制来治疗Bardet Biedl综合征患者的肥胖症。