Physiology And Genetics Of Obesity

肥胖的生理学和遗传学

• 批准号: 6541142
• 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/6541142
• 关键词: African American; adipose tissue; adolescence (12-20); basal metabolism; bioenergetics; body composition; caucasian American; child (0-11); clinical research; disease /disorder proneness /risk; epidemiology; glucose metabolism; glucose tolerance test; health behavior; human puberty; human subject; insulin sensitivity /resistance; leptin; lipid metabolism; noninsulin dependent diabetes mellitus; obesity; racial /ethnic difference

The prevalence of overweight in children, adolescents, and adults has doubled during the past 20 years. 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 do appear to have more difficulty matching caloric intake and energy output in this environment, predisposing them to a greater incidence of overweight and obesity. One such group are African Americans. During adolescence, African American boys and girls experience a steady rise in BMI such that 18.5% of African American girls (vs. 8.2% of Caucasian girls), and 10.2% of African American boys (vs. 5.7% of Caucasian boys) have a BMI > 95th percentile. These differences in prevalence are not fully accounted for by socioeconomic or cultural factors. The greater adiposity of African American 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 medications 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. A second research direction examines the pathophysiology of HIV-associated lipodystrophy in children and adults. Using classical association studies, we are 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, and neuropeptide Y and its receptors. In addition, we have studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins. We have found that a 45 base pair insertion polymorphism in the 8th exon of UCP-2, is associated with excess body weight in African American, Asian, and Caucasian children. Because in Caucasians, amount of visceral fat is highly associated with the complications of obeisty, 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. 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. In two ongoing protocols (83-CH-0169 and 96-CH-0101), 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 determine if racial differences in body composition, metabolic rate, insulin sensitivity, glucose disposal, or genetic factors believed to regulate metabolic rate, such as the uncoupling proteins, leptin and its receptor, and the beta-3 adrenergic receptor, exist prior to puberty. Psychological and behavioral factors, such as propensity to engage in binge eating behavior, are also examined. 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 (98-CH-0111 and 00-CH-0134), we are studying novel approaches to the control of body weight in children. We have completed a pilot study demonstrating that severely overweight adolescents can lose weight when enrolled in a comprehensive weight management program which includes the novel 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 placebo-controlled randomized trial will determine whether the weight loss of African American and Caucasian children and adolescents who have obesity-related comorbidities is improved by the use of orlistat. A second study examines the mechanism by which another novel weight loss agent, metformin, may affect the body weight of younger children who have hyperinsulinemia. The UGO also studies HIV-associated lipodystrophy. Since it was initially recognized in 1982, acquired immunodeficiency syndrome (AIDS) has been a leading cause of death among children and young adults in the United States for much of the last decade. Following the introduction of protease inhibitors as part of "highly active antiretroviral therapy" (HAART) for the treatment of HIV infected patients, AIDS-related morbidity and mortality decreased dramatically. HIV-infected children and adults, particularly those treated with protease inhibitors, often develop a lipodystrophy that includes significant changes in body shape, with fat loss in the face, arms and legs, and fat gain in the trunk. This lipodystrophy is often accompanied by hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Understanding the pathophysiology of lipodystrophy is therefore important for the long-term therapy of HIV infection. In addition, since certain types of body habitus are associated with increased risks of cardiovascular disease in non-HIV infected individuals, an enhanced understanding of the control of adipocyte physiology and fat distribution may have additional significance for the broader population. We have studied the etiology of HIV-associated lipodystrophy in clinical populations. We reported that visceral adipose tissu

在过去的20年中，儿童，青少年和成年人的超重患病率增加了一倍。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似乎确实在这种环境下的热量摄入量和能量输出匹配，使它们易于超重和肥胖的发生率更大。这样一个群体是非裔美国人。在青春期，非洲裔美国男孩和女孩的BMI稳定增长，因此18.5％的非洲裔美国女孩（占高加索女孩的8.2％）和10.2％的非洲裔美国男孩（占高加索男孩的5.7％）的BMI> 95％。这些患病率的差异并未完全由社会经济或文化因素解释。非洲裔美国儿童和青少年的肥胖更大，赋予了肥胖症的风险，例如2型糖尿病，高血压和动脉粥样硬化心血管疾病。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，研究了新的减肥药物对儿童和青少年在儿童和青少年中与肥胖相关的合并症的影响，并寻求对肥胖症及其在某些少量疾病中更大的遗传和环境因素的遗传和环境因素重要的。第二个研究方向研究了儿童和成人中与HIV相关的脂质营养不良的病理生理学。 使用经典关联研究，我们正在研究涉及瘦素信号通路基因的多态性，以尝试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，以及神经肽Y及其受体。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。我们发现，UCP-2第8外显子中的45个基对插入多态性与非裔美国人，亚洲和高加索儿童的体重过剩有关。 因为在高加索人中，大量的内脏脂肪与服从的并发症高度相关，所以我们研究了在非裔美国人和高加索儿童中脂肪组织的分布。我们发现，与白种人儿童相比，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，但在非裔美国儿童中的胰岛素抵抗更大。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，这些差异不能通过激素瘦素的差异来解释。 在两项正在进行的协议（83-CH-0169和96-CH-0101）中，我们正在研究非洲人和白种人的儿童和青少年，非洲裔美国人和高加索儿童的正常体重据信调节代谢率的因素，例如在青春期之前就存在于β-3肾上腺素能受体。还检查了心理和行为因素，例如参与暴饮暴食行为的倾向。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（98-CH-0111和00-CH-0134）中，我们正在研究儿童控制体重的新方法。我们已经完成了一项试点研究，该研究表明，当参加一项全面的体重管理计划时，严重超重的青少年可以减肥，该计划包括新型的胃肠道脂肪酶抑制剂Orlistat，作为行为修改程序的辅助手段。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。安慰剂对照的随机试验将确定与肥胖相关合并症的非裔美国人和白人儿童和青少年的体重减轻是否可以通过使用Orlistat改善。第二项研究研究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。 UGO还研究与HIV相关的脂肪营养不良。自1982年最初认可的免疫缺陷综合征（AIDS）一直是美国和年轻人在过去十年中的大部分时间里的主要死亡原因。在引入蛋白酶抑制剂作为“高度活性抗逆转录病毒疗法”（HAART）的一部分之后，用于治疗艾滋病毒感染患者，与艾滋病相关的发病率和死亡率急剧下降。感染HIV的儿童和成人，尤其是接受蛋白酶抑制剂治疗的儿童，通常会发展出一种脂肪营养不良，其中包括体形的重大变化，面部，手臂和腿部脂肪减少，并且树干中的脂肪增加。这种脂肪营养不良通常伴有高甘油三酯血症，高胆固醇血症和高胰岛素血症。因此，了解脂肪营养不良的病理生理学对于HIV感染的长期治疗很重要。此外，由于某些类型的身体习惯与非HIV感染个体的心血管疾病风险增加有关，因此对脂肪细胞生理和脂肪分布的控制的了解增强了对更广泛的人群的额外意义。我们研究了临床人群中与HIV相关的脂肪营养不良的病因。我们报道了内脏脂肪组织