Physiology, Psychology, and Genetics of Obesity

肥胖的生理学、心理学和遗传学

• 批准号: 10672078
• 负责人: JACK A. YANOVSKI
• 金额: $ 155.33万
• 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/10672078
• 关键词: Acute; Adipocytes; Adipose tissue; Adolescent; Adult; Agonist; Anxiety; Area; Autophagocytosis; Bardet-Biedl Syndrome; Behavior; Behavioral; Binge Eating; Body Composition; Body Weight; Body Weight decreased; Body fat; Body mass index; Bone Tissue; C-Peptide; C-reactive protein; Cells; Characteristics; Child; Childhood; Choline; Clinical; Colchicine; Communities; DNA Sequence Alteration; Data; Development; Diazoxide; Disease; Disease remission; Eating; Eating Behavior; Effectiveness; Energy Intake; Erythrocyte Sedimentation Rate; Etiology; Fasting; Fatty acid glycerol esters; Female Adolescents; Food; Froehlich' s Syndrome; Future; GCG gene; GLP-I receptor; Gastrectomy; Genes; Genetic; Genetic Polymorphism; Glucose; Goals; Growth; Health; Health education; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Human; Hyperphagia; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interruption; Intervention; Investigation; Knock-in Mouse; Knock-out; Lead; Leptin; Leptin receptor mutation; Leptin resistance; Link; Longitudinal cohort; LoxP-flanked allele; Measures; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; Metabolism; Modeling; Moods; Mus; Nutrient; OGTT; Obesity; Overweight; Palate; Patient Self-Report; Patients; Peripheral; Persons; Phenotype; Physiological; Physiology; Pilot Projects; Placebos; Population; Prader-Willi Syndrome; Predictive Factor; Prevalence; Prevention strategy; Protocols documentation; Psychological Factors; Psychology; Randomized; Randomized, Controlled Trials; Regulation; Reporting; Risk; Role; Series; Serum; Signal Pathway; Signal Transduction; Social Adjustment; Syndrome; Testing; Time; Tissues; Translational Research; Translational trial; Triglycerides; United States; United States Food and Drug Administration; Variant; WT1 gene; Walking; Weight; Weight Gain; White Blood Cell Count procedure; Youth; adult obesity; attentional bias; base; behavioral phenotyping; capsule; cardiometabolic risk; cognitive function; comorbidity; controlled release; efficacy evaluation; endophenotype; energy balance; expectation; experience; feeding; follow-up; food craving; gene function; genetic variant; girls; glucose tolerance; improved; inflammatory marker; interpersonal therapy; leptin receptor; loss of control over eating; metabolic phenotype; metabolomics; mutant; negative affect; neutrophil; novel; obese person; obesity development; obesity genetics; obesity in children; obesity risk; obesity treatment; peer; placebo group; precision medicine; prevent; programs; psychologic; randomized controlled study; receptor; sedentary; sedentary lifestyle; stem cell differentiation; therapy development; trait; treatment strategy

Obesity continues to be a major issue among children in the United States (1, 2). We continue to examine genes involved in the leptin signaling pathway to identify gene variants impacting body composition, with the expectation that improved understanding might help the development of precision medicine approaches for obesity. 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 and adults who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass and leptin compared with wild type or heterozygous children. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have successfully bred and studied novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice did not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiated into adipocytes that accumulated more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking to understand better the roles of MC3R in peripheral metabolism including studies of hepatic autophagy. We have obtained a floxed Mc3r mouse, which will allow us to study tissue-specific knockouts of Mc3r in hepatocytes, adipocytes, and other tissues. We have previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and leptin receptor mutations. We have also found hyperleptinemia out of proportion with body fat mass in children with psychological loss of control (LOC) over eating. 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 WAGR, Bardet-Biedl (3), PCSK1, Leptin Receptor deficiency, and other conditions (4). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (5-12), including humoral factors (5), alterations in energy balance (6-9), food cravings (10), cognitive function (11), negative affective states and disinhibited eating (12). For example, over a mean follow-up from baseline of 8.5 years, adjusting for covariates and repeated measures of BMI or fat mass, linear mixed models revealed that weight-based teasing was associated with greater gain of BMI and fat mass across the follow-up period (ps .007). Adjusting for covariates, youths reporting high weight-based teasing (two standard deviations above the mean) experienced a 33% greater gain per year in BMI and a 91% greater gain in fat mass per year compared with peers who reported no weight-based teasing. Another series of pilot studies has tested if short bouts of activity may improve glucose tolerance or alter mood in children. In children who have normal weight or overweight, we found that interrupting sitting resulted in a significantly lower insulin and C-peptide Area vs continuous sitting during oral glucose tolerance test. Interrupting sedentary time with brief moderate-intensity walking thus improved short-term metabolic function. A new, recently completed trial tested if these acute improvements are sustained over 1 week, finding similar results. These studies may help lead to community studies examining if interrupting sedentary behavior is a promising prevention strategy for reducing cardiometabolic risk in children. Investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children and predict future weight gain in children at-risk for overweight. Two completed protocols examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors versus a control health education (HE) program. Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p<.001) and fat mass (p<=.03). Thus, in obesity-prone adolescent girls, IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. Youth with remission of Loss of Control (LOC) eating at end-of-treatment had lower serum glucose, higher high-density lipoprotein cholesterol and lower triglycerides at 6-month follow-up when compared with youth with persistent LOC. Thus, reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome. A new study is underway to examine if retraining attentional biases away from palatable foods can help children avoid weight gain. Given the rapid increase in the prevalence of obesity (1,2), the development of treatments for obesity is urgently needed. We have conducted translational trials related to modulation of the leptin signaling pathway using the melanocortin agonist called setmelanotide. Our data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome is treatable with setmelanotide (3), which was recentl approved for use in this condition by the Food and Drug Administration. We have also completed a new randomized controlled study examining the use of diazoxide choline-controlled-release for the obesity of people with the Prader-Willi syndrome. Preliminary data suggest efficacy for those with significant hyperphagia. Finally, we have conducted studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (13). 40 Adults with obesity were randomized to colchicine 0.6 mg or placebo capsules twice daily for 3 months. Compared with placebo, colchicine significantly reduced C-reactive protein (P <0.005), erythrocyte sedimentation rate (P <0.01), white blood cell count (P <0.005), and absolute neutrophil count (P <0.001). Changes in homeostatic model assessment of insulin resistance (P = 0.0499), fasting insulin (P = 0.07) and glucose effectiveness (P = 0.08), suggested metabolic improvements in the colchicine versus placebo group. This pilot study found colchicine significantly improved obesity-associated inflammatory variables among adults with obesity using a metabolomics approach (13). These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals. A trial for this purpose is underway. Additional collaborative studies (14-17), include a randomized controlled trial of a glucagon-like peptide-1 receptor agonist in people with hypothalamic obesity that suggests some individuals with this condition can be successfully treated with a GLP1 receptor agonist. We recently initiated a pilot study of a GLP1 receptor agonist in adolescents who have undergone sleeve gastrectomy but have insufficient weight loss.

在美国儿童中，肥胖仍然是一个主要问题（1，2）。我们继续检查涉及瘦素信号传导途径的基因，以鉴定影响人体组成的基因变异，并期望得到改善的理解可能有助于开发精确医学方法的肥胖方法。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。与野生型或杂合儿童相比，对两种罕见的多态性（Thr6lys和val81ile）的纯合儿童和成人的脂肪质量和瘦素明显更高。正在进行的研究试图了解这些序列改变会影响身体体重的机制。我们已经成功地育种并研究了表达人类野生型MC3R（HWT/HWT）和人双突变MC3R（HDM/HDM）的小鼠。 MC3R（HDM/HDM）的重量和脂肪质量更大，能量摄入量提高和进食效率，但与MC3R（HWT/HWT）相比，无脂肪质量降低。 MC3R（HDM/HDM）小鼠尽管脂肪组织浸润量更大，但脂肪组织炎症细胞浸润或更大的表达增加。 MC3R（HDM/HDM）骨和脂肪组织衍生的间充质干细胞（MSC）分化为脂肪细胞，这些脂肪细胞积累了比MC3R（HWT/HWT）MSC更多的甘油三酸酯。 MC3R（HDM/HDM）影响了营养分配，从而产生了增加代谢健康的脂肪组织。这些数据证实了MC3R信号在人类代谢中的重要性，并提出了MC3R在脂肪组织发育中的先前未认可的作用。当前的研究试图更好地了解MC3R在外周代谢中的作用，包括肝自噬的研究。我们已经获得了一只flox的MC3R小鼠，这将使我们能够研究肝细胞，脂肪细胞和其他组织中MC3R的组织特异性敲除。 我们以前已经发现，瘦素是儿童体重增加的重要预测指标，并确定患有高血治和瘦素受体突变的儿童。我们还发现，在饮食中心理丧失控制（LOC）的儿童中，与体内脂肪量的比例不合时宜。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征的最新探索，这些综合症可能导致瘦素信号传导失调，包括WAGR，包括Bardet-Biedl（3），PCSK1，PCSK1，瘦素受体缺乏症和其他条件（4）。当前的研究旨在理解其他遗传，生理和心理因素，这些因素使儿童处于危险中，以增加体重增加（5-12），包括体液因素（5），能量平衡的改变（6-9），食物渴望（10），认知功能（11），负面情感状态和不抑制饮食（12）。例如，在基线为8。5年的平均随访中，调整协变量和BMI或脂肪质量的重复测量，线性混合模型表明，基于重量的戏弄与整个随访期间BMI和脂肪质量的增加有关（PS .007）。调整协变量，与没有报告基于体重戏弄的同龄人相比，BMI每年的增长戏弄高茶（两个标准偏差）每年增加33％的增益，每年增加91％的脂肪质量增长。 另一系列试点研究已经测试了短暂的活动是否可以提高葡萄糖耐受性或改变儿童的情绪。在体重正常或超重的儿童中，我们发现坐姿中断导致胰岛素和C肽面积明显降低，而在口服葡萄糖耐受性测试期间的连续坐着。短暂的中强度步行中断久坐时间，因此改善了短期代谢功能。如果这些急性改善在1周内持续了一周，则进行了新的，最近完成的试验测试，发现相似的结果。这些研究可能有助于导致社区研究检查是否中断久坐行为是降低儿童心脏代谢风险的有前途的预防策略。 研究重点是儿童暴饮暴食行为的调查表明，这种行为也与儿童肥胖有关，并预测儿童在危险中的未来体重超重。两个完整的方案检查了人际关系疗法（IPT）的疗效，作为报告暴饮暴食行为与对照健康教育（HE）计划的儿童和青少年的预防策略。在自我报告的基线社会调整问题或焦虑症的女孩中，与他相比，IPT与BMIZ（p <.001）和脂肪质量的急剧下降有关（p <=。03）。因此，在肥胖的青春期女孩中，IPT与患有高度社会调整问题或特质焦虑的青年中BMIZ的改善有关。与持续性LOC的青年相比，在治疗结束时饮食丧失（LOC）饮食损失（LOC）进食（LOC）的饮食率较低，高密度脂蛋白胆固醇和较低的甘油三酸酯。因此，减少青春期女孩的LOC饮食可能对代谢综合征的某些成分产生有益的影响。正在进行一项新的研究，以检查是否从可口的食物中脱离注意力偏见可以帮助儿童避免体重增加。 鉴于肥胖症患病率的迅速增加（1,2），迫切需要肥胖治疗的发展。我们已经使用了称为set -Melanotide的黑素皮质素激动剂进行了与瘦素信号通路调节有关的翻译试验。我们的数据表明，罕见的引起肥胖症的患者Bardet Biedl综合征的瘦素耐药性可以用set-Melanotide（3）治疗，set-Melanotide（3）被食品药物和药物管理批准在这种情况下批准用于这种情况。我们还完成了一项新的随机对照研究，研究了二氮氧化胆碱控制释放的释放，以使Prader-Willi综合征的肥胖症的肥胖症。初步数据表明对患有明显的心脏的人有疗效。最后，我们进行了研究，以研究秋水仙碱可以减少NLRP3激活的炎症并改善与肥胖相关的代谢失调的假设（13）。 40名肥胖的成年人被随机分配给秋水仙碱0.6 mg或安慰剂胶囊，每天两次，持续3个月。与安慰剂相比，秋水仙碱显着降低了C反应性蛋白（P <0.005），红细胞沉降率（P <0.01），白细胞计数（P <0.005）和绝对嗜中性粒细胞计数（P <0.001）。胰岛素耐药性（P = 0.0499），禁食胰岛素（P = 0.07）和葡萄糖有效性（P = 0.08）的体内平衡模型评估的变化，表明秋水仙碱与安慰剂组的代谢改善。这项试点研究发现，秋水仙碱使用代谢组学方法显着改善了肥胖的成年人中与肥胖相关的炎症变量（13）。这些结果表明，应该进行更大的，充分的动力研究，以确定秋水仙碱是否改善了处于危险中的胰岛素抵抗和其他代谢健康的措施。为此目的进行试验。 其他协作研究（14-17）包括在下丘脑肥胖者中对胰高血糖素样肽-1受体激动剂的随机对照试验，这表明某些患有这种疾病的人可以通过GLP1受体激动剂成功治疗。最近，我们在接受袖子切除术但体重减轻不足的青少年中对GLP1受体激动剂进行了试点研究。