Physiology, Psychology, and Genetics of Obesity

肥胖的生理学、心理学和遗传学

基本信息

批准号：
8736823
负责人：
JACK A. YANOVSKI
金额：
$ 90.2万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/8736823
关键词：
Adolescent Adult African American Age Alstrom syndrome Aniridia 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 Functional disorder Future Gene Mutation Genes Genetic Genetic Polymorphism Genetic Variation Genitourinary system Genotype Glucose Goals Growth Human Hyperinsulinism Hyperphagia In Vitro Insulin Insulin Resistance Intervention Investigation Kidney Knock-in Mouse Latino Lead Leptin Leptin receptor mutation Leptin resistance Link Measurement Mental Depression Metabolic Metabolic syndrome Metformin Nephroblastoma Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Physiology Pilot Projects 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 Translational Research Variant WAGR Syndrome WT1 gene Weight Weight Gain base chromosome 11p deletion syndrome ciliopathy cohort comparative genomic hybridization depressive symptoms endophenotype energy balance gene function genetic variant glucose tolerance improved interpersonal therapy loss of control over eating mutant obesity in children obesity risk obesity treatment open label orlistat prevent programs prospective psychologic randomized placebo controlled trial therapy development treatment strategy

项目摘要

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 have initiated 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. 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 have found that leptin is an important predictor of weight gain in children: those with high leptin gain even more weight when followed longitudinally and identified children with hyperleptinemia and leptin receptor mutations (3). We have also found hyperleptinemia out of proportion with body fat mass in children with psychological loss of control over eating (6). Such data suggest the importance of leptin resistance as a factor stimulating weight gain and have led to recent explorations of other syndromes associated with obesity that may cause dysregulation of leptin signaling, including Bardet Biedl syndrome (in collaboration with Dr. Biesecker) and Alstrom Syndrome. Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. We have also recently found evidence for hyperphagia among patients with BBS (10). Other studies are directed at understanding additional genetic, physiological, psychological, and metabolic factors that place children at-risk for undue weight gain (5,8,14,15). 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. Two recent initiatives target insulin resistance. One trial 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 on insulin resistance of preventing depression in obese adolescents with a family history of type 2 diabetes is ongoing. Another pilot study initiated in 2013 examines how sedendary behaviors contribute to poor glucose tolerance. 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 (5,8), especially when coupled with decreased subsequent satiety, may play a role in the greater weight gain found in binge eating children. Using our longitudinal cohort, we have also found that the development of some aspects of metabolic syndrome in children is predicted by the presence of binge eating behaviors. These data also suggest that interventions targeting disordered eating behaviors may potentially be useful in preventing excessive fat gain in children prone to obesity. Two ongoing protocols examine efficacy of interpersonal therapy as a weight gain preventive strategy among children and adolescents who report binge eating behaviors. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity is urgently needed. We recently reported efficacy data in Latino children for low-fat and low glycemic load diets, finding both can be successful (7). In other clinical protocols, we have studied pharmacotherapeutic approaches to the control of body weight (11). Two placebo-controlled randomized trials studied the effects of medications 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. 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 near future related to modulation of the leptin signaling pathway.

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。我们已经开始了一项新的研究，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能量平衡。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。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：慢性瘦素较高的体重更大的人会增加体重，并鉴定出患有高瘦素血症和瘦素受体突变的儿童（3）。我们还发现，患有心理失去对饮食的心理丧失的儿童与体内脂肪量的成比例不合时宜（6）。这样的数据表明，瘦素耐药性作为刺激体重增加的因素的重要性，并导致了与肥胖相关的其他综合症的最新探索，这些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。 BBS患者的瘦素患者的肥胖程度高于预期，这与纤毛性诱导的瘦素信号传导功能障碍与瘦素耐药有关。我们最近还发现了BBS患者中的脾气的证据（10）。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，以增加体重不足（5,8,14,15）。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。最近的两项倡议针对胰岛素抵抗。一项试验研究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，研究对2型糖尿病家族史的肥胖青少年预防抑郁症的影响的影响。 2013年启动的另一项试点研究研究了镇静行为如何促进葡萄糖耐受性不佳。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（5,8），尤其是当随后的饱腹感降低时，可能会在进食儿童的暴饮暴食中发挥更大的体重增加。使用我们的纵向队列，我们还发现，由于存在暴饮暴食行为，可以预测儿童代谢综合征的某些方面的发展。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。两项正在进行的方案将人际疗法的功效视为报告暴饮暴食行为的儿童和青少年的预防策略。鉴于肥胖症患病率的迅速增加，迫切需要肥胖治疗的发展。我们最近报道了拉丁裔儿童对低脂和低血糖负荷饮食的有效数据，发现两者都可以成功（7）。在其他临床方案中，我们研究了控制体重的药物治疗方法（11）。两项安慰剂对照的随机试验研究了药物对体重减轻以及儿童和青少年与肥胖相关的合并症的影响。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。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。我们希望在不久的将来启动与瘦素信号通路的调节有关的其他翻译试验。