Physiology, Psychology, and Genetics of Obesity

肥胖的生理学、心理学和遗传学

• 批准号: 7333905
• 负责人: JACK A. YANOVSKI
• 金额: --
• 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/7333905
• 关键词: Physiology; Psychology; Genetics; Obesity

The prevalence of overweight in children and adolescents has tripled during the past 30 years, and more than 60% of US adults are now overweight. The alarming rise in body weight in both children and adults has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this environment leads to obesity only in those individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorie/low activity environment, which suggests there are subgroups in the US with a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Indeed, certain ethnic and racial subgroups, such as Black and Hispanic Americans, do appear to have more difficulty matching energy intake and energy output in this environment, predisposing them to a greater incidence of overweight and obesity. During adolescence, African American and Hispanic boys and girls experience a steady rise in BMI such that twice as many African American and Hiispanic girls and boys have a BMI above the 95th percentile. These differences in prevalence are not fully accounted for by socioeconomic or cultural factors. The greater adiposity of African American and Hispanic children and adolescents confers risks for obesity's co-morbid conditions, such as Type 2 diabetes, hypertension, and atherosclerotic cardiovascular disease. These obesity-related comorbid conditions contribute to the greater mortality found in some minority groups in the US. However, data also suggest that the predictive risk factors related to body composition and the therapeutic approaches for these comorbid conditions that are derived from the study of Caucasians may be less applicable to those of differing ethnicity or race. Effective prevention and treatment of these obesity-related disorders requires a better understanding of the key elements for body weight regulation. The research of the Unit on Growth and Obesity is directed at increasing our understanding of the metabolic and behavioral factors involved in determining body weight regulation and body composition during childhood, with a special emphasis on minority populations. The ongoing research program prospectively evaluates risk factors for the development of obesity and its complications in children and adolescents, studies the effects of the new weight loss approaches on body weight and obesity-related comorbid conditions in children and adolescents, and seeks the genetic and environmental factors important for the markedly greater incidence of obesity and its comorbid conditions in some US minority populations. Using classical association studies, we have been studying polymorphisms in genes involved in the leptin signaling pathway, to attempt to identify gene variants impacting on body composition that have differing frequency in African American and Caucasian children. Genes currently under study include proopiomelanocortin, the melanocortin receptors 3, 4, and 5, neuropeptide Y and its receptors, brain derived neurotrophic factor (BDNF), and the BDNF receptor TrkB. We have found that polymorphisms in the melanocortin 3 receptor that affect its function by decreasing protein expression are associated with overweight in both African American and Caucasian children, and appear to be more prevalent in African American children. These findings suggest melanocortin 3 receptor variation may be one of the factors predisposing African Americans to high body adiposity. In addition, we have studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins, and studied other genes in the leptin signaling pathway. We have found that alterations in the POMC sequence are more prevalent in African American children, but are not associated with excess body weight in African American and Caucasian children. Recently, we have also studied BDNF serum concentrations in individuals with genetic mutations expected to alter BDNF and TrkB gene function. Because in Caucasians, amount of visceral fat is highly associated with the complications of obesity, we have studied the distribution of adipose tissue in African American and Caucasian children. We have found that there is less visceral abdominal adipose tissue in non-obese and obese African American children than Caucasian children, but considerably greater insulin resistance in African American children, assessed through hyperglycemic and euglycemic clamp studies. These results imply the relationship between visceral fat and the complications of obesity are different in African Americans and Caucasians. The susceptibility to weight gain in African American may also result from differences in metabolic efficiency: we have also found that resting energy expenditure is approximately 90 kcal/d less in African American than in Caucasian normal weight and overweight boys and girls. Our studies suggest that these differences are not explained by difference in the hormone leptin but may be due to differences in appendicular skeletal mass. In ongoing protocols, we are studying normal weight African American and Caucasian children and adolescents, African American and Caucasian children who are already obese, and the non-obese African American and Caucasian children of obese parents, in order to study how racial differences in body composition, metabolic rate, insulin sensitivity, glucose disposal, or genetic factors believed to regulate adiposity, such as the uncoupling proteins, leptin and its downstream effectors, and genes that affect energy expenditures such as the beta-3 adrenergic receptor, affect the growth of adipose tissue. Psychological and behavioral factors, such as propensity to engage in binge eating behavior, are also examined. We have found that 6-11 year old children endorsing binge eating behaviors have greater adiposity and a greater propensity for weight gain than those who never report binge eating behaviors. Children are being studied longitudinally into adulthood. We hypothesize that differences in these factors will predict the development of obesity in the populations studied, and may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse US population. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in childhood is urgently needed. In two ongoing clinical protocols, we are studying approaches to the control of body weight in children. We have completed a pilot study demonstrating that severely overweight African American and Caucasian adolescents can lose weight when enrolled in a comprehensive weight management program that includes the gastrointestinal lipase inhibitor, orlistat as an adjunct to a behavioral modification program. We have also found evidence that one mechanism through which orlistat may affect body weight is by changing the hedonic value of dietary fat. A randomized controlled trial (RCT) using orlistat is currently underway in 200 severely overweight African American and Caucasian adolescents who have one or more comorbid condition associated with obesity. A second RCT examines the mechanism by which another novel weight loss agent, metformin, may affect the body weight of younger children who have hyperinsulinemia. Because younger children undergo substantial linear growth, agents that promote weight stability such as metformin may be of greater benefit in improving body mass index for children aged 6-12y. A third RCT examines the role of supplemental dietary calcium for body weight regulation. Pilot investigations to study the effects of interpersonal therapy, and to evaluate the impact of increasing non-exercise activity thermogenesis in overweight children are also underway.

在过去的30年中，儿童和青少年超重的患病率增加了两倍，而美国60％以上的成年人现在超重。儿童和成人的体重令人震惊，因为当前的环境可容易获得卡路里密集的食物，并且需要减少自愿的能源消耗。但是，这种环境仅在那些体重调节系统无法在我们的高热量/低活动环境中以足够精度控制体重调节系统的个体才会导致肥胖，这表明在美国，在美国的体重易受易于体重增加的情况下，体重群体在预期的环境条件下具有唯一的体重增加。的确，某些种族和种族亚组，例如黑人和西班牙裔美国人，似乎在这种环境中的能量摄入和能量输出匹配时似乎更加困难，使它们易于超重和肥胖的发生率更大。在青春期，非裔美国人和西班牙裔男孩和女孩的BMI稳步上升，因此许多非裔美国人和Hiispanic Girls and Boys的BMI超过了第95个百分位的BMI。这些患病率的差异并未完全由社会经济或文化因素解释。非洲裔美国人和西班牙裔儿童和青少年的肥胖更大，赋予了肥胖症的合并状况的风险，例如2型糖尿病，高血压和动脉粥样硬化性心血管疾病。这些与肥胖相关的合并症条件有助于美国一些少数群体中发现的更大的死亡率。但是，数据还表明，与人体组成有关的预测危险因素以及这些合并症条件的治疗方法可能不太适用于不同种族或种族的人。这些与肥胖相关疾病的有效预防和治疗需要更好地了解体重调节的关键要素。对生长和肥胖单位的研究是针对我们对确定体重调节体重调节和身体成分涉及的代谢和行为因素的理解，并特别强调了少数人群。正在进行的研究计划前瞻性地评估了肥胖发展及其在儿童和青少年中的并发症的风险因素，研究了新的体重减轻方法对儿童和青少年的体重和与肥胖相关的合并症的影响，并寻求遗传和环境因素对肥胖症及其在某些少数疾病中的更大疾病的遗传和环境因素很重要。使用经典关联研究，我们一直在研究参与瘦素信号通路的基因中的多态性，以试图鉴定影响非裔美国人和高加索儿童频率不同的人体组成的基因变异。目前正在研究的基因包括促蛋白酶皮质素，黑色皮质素受体3、4和5，神经肽Y及其受体，脑衍生的神经营养因子（BDNF）和BDNF受体TRKB。我们发现，通过降低蛋白质表达来影响其功能的黑色素皮质3受体中的多态性与非裔美国人和高加索儿童的超重有关，并且在非裔美国人儿童中似乎更为普遍。这些发现表明，黑色皮质素3受体变异可能是使非洲裔美国人高度肥胖的因素之一。此外，我们研究了对能量消耗很重要的基因，例如线粒体解偶联蛋白，并研究了瘦素信号通路中的其他基因。我们发现，在非洲裔美国儿童中，POMC序列的改变更为普遍，但与非洲裔美国人和高加索儿童的体重过高无关。最近，我们还研究了预计将改变BDNF和TRKB基因功能的基因突变个体中的BDNF血清浓度。因为在高加索人中，大量的内脏脂肪与肥胖的并发症高度相关，所以我们研究了非裔美国人和高加索儿童中脂肪组织的分布。我们发现，通过高加索儿童，非肥胖和肥胖的非洲裔美国儿童的内脏腹部脂肪组织较少，但在非洲裔美国儿童中的胰岛素抵抗性较大，通过高血糖和尤基血糖夹的研究来评估。这些结果暗示着内脏脂肪与肥胖并发症之间的关系在非裔美国人和高加索人中不同。非裔美国人体重增加的敏感性也可能是由于代谢效率的差异而引起的：我们还发现，在非洲裔美国人的静息能量消耗大约比白种人的正常体重和超重男孩和女孩少约90 kcal/d。我们的研究表明，这些差异不是由激素瘦素的差异来解释，而是由于阑尾骨骼质量的差异所致。在正在进行的协议中，我们正在研究已经正常体重的非洲裔美国人和白种人儿童和青少年，已经是肥胖的非洲裔美国人和高加索儿童，以及肥胖父母的非肥胖非裔美国人和高加索儿童，以研究种族差异，以研究身体成分，胰岛素敏感性，属于属性的属性，属于属性，属于属性，属于属性，以下瘦素及其下游效应子以及影响能量消耗的基因，例如β-3肾上腺素能受体，会影响脂肪组织的生长。还检查了心理和行为因素，例如参与暴饮暴食行为的倾向。我们发现，与从未报告暴饮暴食行为的人相比，认可暴饮暴食行为的6-11岁儿童具有更大的肥胖和体重增加的倾向。儿童正在纵向研究到成年。我们假设这些因素的差异将预测所研究人群中肥胖的发展，并且在开发有理方法的方法中可能非常重要，以预防和治疗美国多样化的人群肥胖。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。在两个正在进行的临床方案中，我们正在研究控制儿童体重的方法。我们已经完成了一项试点研究，该研究表明，当参加包括胃肠道脂肪酶抑制剂的全面体重管理计划时，严重超重的非裔美国人和高加索青少年可以减肥，作为行为修改计划的辅助手段。我们还发现证据表明，Orlistat可能影响体重的一种机制是通过改变饮食脂肪的享乐值。目前，使用Orlistat进行的随机对照试验（RCT）目前正在200个严重超重的非裔美国人和高加索青少年中，他们患有一种或多种与肥胖有关的合并症。第二个RCT检查了另一种新型减肥剂二甲双胍可能影响患有高胰岛素血症的年幼儿童的体重的机制。由于幼儿经历了实质性的线性生长，因此促进体重稳定性（例如二甲双胍）的药物在改善6-12岁儿童的体重指数方面可能具有更大的好处。第三个RCT检查了补充饮食钙在体重调节中的作用。试点研究以研究人际疗法的影响，并评估增强超重儿童非运动活性生热的影响。