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：
7734702
负责人：
JACK A. YANOVSKI
金额：
$ 130.53万
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/7734702
关键词：
11p Adolescent Adult Affect African American Age Aniridia BDNF gene Behavior Behavioral Binge Eating Blood Pressure Body Composition Body Weight Body Weight decreased Body fat Brain-Derived Neurotrophic Factor Caucasians Caucasoid Race Characteristics Child Childhood Cholesterol Chromosome inversion Clinical Clinical Protocols Code Collaborations Comorbidity Condition Consumption Coupled DNA Data Development Disease Eating Eating Behavior Energy Intake Etiology Exons Expenditure Fat-Soluble Vitamin Fatty acid glycerol esters Food Future Gene Mutation Genes Genetic Genetic Polymorphism Genetic Variation Genitourinary system Genomics Genotype Glucose Goals Growth Homeostasis Human Hyperinsulinism Hyperphagia In Vitro Individual Insulin Insulin Resistance Intervention Investigation Kidney Knock-in Mouse Lead Leptin Link Lymphocyte Measurement Measures Metabolic Metformin Morbid Obesity Mutation Nephroblastoma Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Parents Pathway interactions Patients Peripheral Phenotype Physiologic pulse Physiological Physiology Placebos Plasma Platelet Count measurement Play Population Predictive Factor Prevalence Prevention Prevention strategy Protocols documentation Psychology Pulse taking Questionnaires Randomized Range Regression Analysis Regulation Risk Role Satiation Score Serum Severities Signal Pathway Signal Transduction Syndrome Translational Research Variant Vitamin A Vitamin D Vitamin E Weight Weight Gain base chromosome 11p deletion syndrome cohort comparative genomic hybridization double-blind placebo controlled trial driving behavior endophenotype energy balance gene function genetic variant improved interpersonal therapy mutant obesity risk obesity treatment orlistat prevent programs psychologic randomized placebo controlled trial severe early onset obesity size therapy development

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 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. Ongoing studies attempt to understand the mechanisms by which these sequence alterations may impact body weight. "Knock-in" mice expressing the human wild type and human double-mutant MC3R are being developed in collaboration with Dr. Westphal, and will be studied during the next two years. We have also recently investigated the BDNF-TrkB pathway in regards to body mass in children. We measured serum BDNF in 328 children, in a group enriched for extreme obesity. BDNF was significantly lower in overweight children (p=0.03); in multiple regression analyses, BMI (p=0.03), BMI-Z (p=0.01), and body fat (ps<0.02), were all negatively associated with BDNF. We next explore if some obese individuals with low serum BDNF for age and platelet count have mutations that alter BDNF function. In collaboration with Drs. Farooqi and ORahilly, we studied a child with hyperphagia and severe obesity who had a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. The patients genomic DNA was heterozygous for a common coding polymorphism in BDNF but monoallelic expression was seen in peripheral lymphocytes. Serum BDNF was markedly reduced compared to age and BMI matched control subjects. Functional haploinsufficiency for BDNF was thus associated with increased ad libitum food intake and severe early onset obesity. A new initiative has 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. In 33 subjects with heterozygous 11p deletions ranging in size from 1.0-26.5 Mb, 19 had regions of deletion that involved the BDNF gene (BDNF+/-). Compared to those with intact BDNF (BDNF+/+), BDNF+/- had significantly greater body mass during childhood, starting at age 2y. 100% (95% CI: 76.8-100%) of BDNF+/- were overweight by age 10y vs. only 20% (95%CI: 2.5-55.6%) of BDNF+/+ (P<0.0001). Parent-completed hyperphagia questionnaires suggest significantly greater hyperphagic behavior, drive, and severity for BDNF+/- than BDNF+/+. Mean serum BDNF was approximately 50% lower among BDNF+/- (P=0.001). Analysis of the telomeric deletion boundaries indicated the presence of a critical region for pediatric-onset overweight within 80 kb of BDNF exon 1. These findings provide strong evidence for the role of BDNF in human energy homeostasis. A full characterization of the energy intake and expenditure of subjects with WAGR syndrome and other 11p deletion syndromes is planned in the coming year. Other studies are directed at understanding the 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. 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 in childhood is urgently needed. In three ongoing clinical protocols, we have studied pharmacotherapeutic approaches to the control of body weight, We recently completed a placebo-controlled randomized trial, studying whether the weight loss of African American and Caucasian children and adolescents who have obesity-related comorbidities was improved by the use of orlistat 120 mg TID. 200 adolescents, 61% African American, mean BMI 41.70.6 kg/m2 (range 27-87 kg/m2) were studied. 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). Orlistat treatment did not significantly alter pulse or blood pressure (all P>0.25). Fat soluble vitamins 25OH vitamin D, vitamin A, and vitamin E concentrations were not significantly altered by orlistat treatment (all P>0.46). We concluded that orlistat added to a behavioral program significantly improved weight loss over a 6-month interval, but had little impact on obesity-related co-morbid conditions in overweight adolescents. A second recently-completed study examined the mechanism by which metformin may affect the body weight of younger children who have hyperinsulinemia, and are therefore at risk for later development of type 2 diabetes. We conducted a single-center, 6-month, randomized, double-blind, placebo-controlled trial of the effects of metformin, 1000 mg BID administered with meals, 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.

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。在体外研究随后发现双突变体MC3R的表达显着降低。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。表达人类野生型和人类双线MC3R的“敲门”小鼠正在与Westphal博士合作开发，并将在未来两年进行研究。我们最近还研究了关于儿童体重的BDNF-TRKB途径。我们测量了328名儿童的血清BDNF，这是一个富含极端肥胖症的组。超重儿童的BDNF明显降低（p = 0.03）；在多元回归分析中，BMI（P = 0.03），BMI-Z（P = 0.01）和体内脂肪（PS <0.02）都与BDNF负相关。接下来，我们探讨了一些年龄和血小板计数低血清BDNF的肥胖个体是否具有改变BDNF功能的突变。与Drs合作。 Farooqi和Orahilly，我们研究了一个患有从头染色体反转的儿童和严重的肥胖症，46，XX，INV（11）（P13P15.3），该区域包括BDNF基因。患者的基因组DNA对于BDNF中的常见编码多态性是杂合的，但在外周淋巴细胞中观察到单相表达。与年龄相比，血清BDNF显着降低，而BMI匹配的对照组受试者。因此，BDNF的功能性单倍不足与自发食物摄入量增加和严重的早期发作肥胖有关。一项新的倡议评估了BDNF单倍性作为肥胖症在综合症患者中的作用，这些综合症是由于发现了人类BDNF基因的11p14.1的缺失。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。在33名杂合11P缺失的受试者中，大小为1.0-26.5 MB，有19个含量涉及BDNF基因（BDNF +/-）的缺失区域。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％（95％CI：76.8-100％）在10Y年龄的BDNF+/+（p <0.0001）中超重，而仅为10y（95％CI：2.5-55.6％）。与BDNF+/+相比，父母完成的食性噬菌体问卷表明，BDNF +/-的倍率行为，驱动和严重程度要大得多。在BDNF +/-中，平均血清BDNF降低了约50％（p = 0.001）。对端粒缺失边界的分析表明，在BDNF外显子1的80 kb内，小儿发作超重的关键区域存在。这些发现为BDNF在人类能量稳态中的作用提供了有力的证据。计划在来年计划对WAGR综合征和其他11P缺失综合症的受试者的能量摄入和支出的全面表征。其他研究旨在理解使儿童处于危险中，以增加体重增加的生理，心理和代谢因素。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。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，迫切需要幼儿期肥胖治疗的发展。在三种正在进行的临床方案中，我们研究了用于控制体重的药物治疗方法，我们最近完成了一项安慰剂对照的随机试验，研究了通过使用Orllistat 120 mg Tid的Orllistat 120 mg Tid而改善了与肥胖相关的合并症的非洲裔美国人和白种儿童和青少年的体重损失。研究了200名青少年，61％的非裔美国人，平均BMI 41.70.6 kg/m2（范围27-87 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). Orlistat治疗并未显着改变脉搏或血压（所有P> 0.25）。脂溶性维生素25OH维生素D，维生素A和维生素E浓度没有通过Orlistat处理显着改变（所有P> 0.46）。我们得出的结论是，在6个月的时间间隔内，Orlistat添加了行为计划可显着改善体重减轻，但对超重青少年的肥胖相关合并状况几乎没有影响。最近完成的第二项研究研究了二甲双胍可能影响患有高胰岛素血症的幼儿体重的机制，因此有后来患有2型糖尿病的风险。我们进行了一次单中心，6个月，随机，双盲的，安慰剂对照的试验，对二甲双胍的作用，用餐食给药的1000 mg竞标，在100个表现出高胰岛素血症和胰岛素抵抗的100个严重超重的儿童（6-12岁）中。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。

项目成果

期刊论文数量（79）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Treatment of pediatric and adolescent obesity.

治疗儿童和青少年肥胖。

DOI：
10.1001/jama.289.14.1851
发表时间：
2003
期刊：
JAMA
影响因子：
0
作者：
Yanovski,JackA;Yanovski,SusanZ
通讯作者：
Yanovski,SusanZ

Eating disorders, race, and mythology.

饮食失调、种族和神话。

DOI：
10.1001/archfami.9.1.88
发表时间：
2000
期刊：
Archives of family medicine
影响因子：
0
作者：
Yanovski,SZ
通讯作者：
Yanovski,SZ

Rapid weight gain during infancy as a predictor of adult obesity.

DOI：
10.1093/ajcn/77.6.1350
发表时间：
2003-06
期刊：
The American journal of clinical nutrition
影响因子：
0
作者：
J. Yanovski
通讯作者：
J. Yanovski

Weight and its relationship to adolescent perceptions of their providers (WRAP): a qualitative and quantitative assessment of teen weight-related preferences and concerns.

DOI：
10.1016/j.jadohealth.2004.08.025
发表时间：
2005-08-01
期刊：
The Journal of adolescent health : official publication of the Society for Adolescent Medicine
影响因子：
0
作者：
Cohen, Marc L;Tanofsky-Kraff, Marian;Yanovski, Jack A
通讯作者：
Yanovski, Jack A

Intensive therapies for pediatric obesity.

小儿肥胖症的强化治疗。