Physiology, Psychology, and Genetics of Obesity

肥胖的生理学、心理学和遗传学

• 批准号: 10266462
• 负责人: JACK A. YANOVSKI
• 金额: $ 142.55万
• 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/10266462
• 关键词: Acute; Adipocytes; Adipose tissue; Adolescent; Adult; Agonist; Alexithymias; Antibiotics; Anxiety; Area; Autophagocytosis; Bacitracin; Bardet-Biedl Syndrome; Behavior; Behavioral; Binge Eating; Body Composition; Body Weight; Body fat; Bone Tissue; C-Peptide; C-reactive protein; Cells; Characteristics; Child; Childhood; Choline; Clinical; Colchicine; Communities; DNA Sequence Alteration; Data; Development; Diabetes Mellitus; Diazoxide; Disease; Disease remission; Eating Behavior; Effectiveness; Energy Intake; Erythrocyte Sedimentation Rate; Etiology; Family history of; Fasting; Fatty acid glycerol esters; Female Adolescents; Food; Future; Genes; Genetic; Genetic Polymorphism; Glucose; Goals; Growth; Health; Health education; Hemolysis; Hepatic; High Density Lipoprotein Cholesterol; Human; Hyperphagia; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Institution; Insulin; Insulin Resistance; Insulinase; Interruption; Intervention; Investigation; Knock-in Mouse; Knock-out; Lead; Leptin; Leptin receptor mutation; Leptin resistance; Link; Longitudinal cohort; LoxP-flanked allele; Measures; Mental Depression; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; Metabolism; Modeling; Moods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; OGTT; Obesity; Overweight; PF4 Gene; Palate; Patient Self-Report; Patients; Peripheral; Phenotype; Physiological; Physiology; Pilot Projects; Placebos; Plasma; Population; Prader-Willi Syndrome; Prediabetes syndrome; Predictive Factor; Prevalence; Prevention strategy; Protocols documentation; Psychological Factors; Psychology; Randomized; Regulation; Reporting; Research Personnel; Risk; Role; Sampling Studies; Series; Serum; Signal Pathway; Signal Transduction; Sleep; Social Adjustment; Syndrome; Testing; Time; Tissues; Translational Research; Translational trial; Triglycerides; Variant; WT1 gene; Walking; Weight; Weight Gain; White Blood Cell Count procedure; Youth; adult obesity; attentional bias; base; behavioral phenotyping; capsule; cardiometabolic risk; comorbidity; controlled release; endophenotype; energy balance; executive function; expectation; feeding; follow-up; gene function; genetic variant; girls; glucose monitor; glucose tolerance; high risk; improved; inflammatory marker; interest; interpersonal therapy; loss of control over eating; metabolic phenotype; metabolomics; mutant; negative affect; neutrophil; novel; obesity development; obesity genetics; obesity in children; obesity risk; obesity treatment; placebo group; precision medicine; prevent; programs; psychologic; randomized controlled study; sedentary; sedentary lifestyle; stem cell differentiation; trait; treatment strategy

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 (1) 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. 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 (2), Bardet-Biedl (3) and Alstrm syndromes. Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (6-14), including humoral factors (4) sleep (5-6), negative affective states like depression and anxiety (7-11), weight-based teasing (12), alexithymia (13), executive functioning (14) and LOC eating (15-17). Some recent initiatives have targeted insulin resistance in girls at high risk for type 2 diabetes because of obesity and a family history of diabetes (18). Further studies are required to determine if adolescents with moderate depression show metabolic benefits after CBT. Another series of pilot studies has tested if short bouts of activity may improve glucose tolerance or alter mood (19) 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, the development of treatments for obesity is urgently needed. We have recently initiated additional translational trials related to modulation of the leptin signaling pathway using a melanocortin agonist called setmelanotide. Our data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome may be treatable with setmelanotide (3). Additional studies in other disorders that may be responsive to melanocortin agonists are underway. 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 (20). 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 (22). We identified GDF-15 as a molecule of interest changed by colchicine. All of 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. We are initiating such a trial this year. Additional studies have examined: 1). avoiding hemolysis of insulin during frequent sampling studies (repurposing the antibiotic bacitracin because of its abilities to inhibit insulin-degrading enzymes (23), 2) predicting prediabetes using oral glucose tolerance testing (24), 3). Determining if free fatty acid (FFA) concentrations may be a good indicator for the fasted versus the non-fasted state in children (25), 4) Studying how well continuous glucose monitoring reflects actual plasma glucose in children with obesity (26). We have also collaborated with investigators at other institutions on additional studies (27-29).

我们继续检查瘦素信号通路中涉及的基因，以确定影响身体成分的基因变异，期望加深了解可能有助于开发针对肥胖的精准医学方法。我们目前正在深入研究一种与儿童肥胖相关的 MC3R 变体，该变体似乎对 MC3R 信号转导具有功能意义。与野生型或杂合子儿童相比，两种罕见多态性（Thr6Lys 和 Val81Ile）纯合的儿童和成人 (1) 具有显着更高的脂肪量和瘦素。正在进行的研究试图了解这些序列改变影响体重的机制。我们已经成功培育和研究了表达人类野生型MC3R（hWT/hWT）和人类双突变体MC3R（hDM/hDM）的新型敲入小鼠。与MC3R(hWT/hWT)相比，MC3R(hDM/hDM)具有更大的体重和脂肪量，增加的能量摄入和饲喂效率，但减少了去脂量。 MC3R(hDM/hDM)小鼠尽管脂肪量较大，但脂肪组织炎症细胞浸润并未增加，炎症标记物的表达也没有增加。 MC3R(hDM/hDM) 骨和脂肪组织来源的间充质干细胞 (MSC) 分化为比 MC3R(hWT/hWT) MSC 积累更多甘油三酯的脂肪细胞。 MC3R(hDM/hDM) 影响营养分配，产生代谢健康的脂肪组织。这些数据证实了 MC3R 信号传导在人类新陈代谢中的重要性，并表明 MC3R 在脂肪组织发育中具有以前未被认识的作用。目前的研究正在寻求更好地了解 MC3R 在外周代谢中的作用，包括肝自噬的研究。我们获得了一只 floxed Mc3r 小鼠，这将使我们能够研究 Mc3r 的组织特异性敲除。 我们之前发现瘦素是儿童体重增加的重要预测因子，并发现了患有高瘦素血症和瘦素受体突变的儿童。我们还发现，在饮食心理失控（LOC）的儿童中，高瘦血症与体脂量不成比例。这些数据表明瘦素抵抗作为刺激体重增加的因素的重要性，并导致最近对可能导致瘦素信号失调的其他与肥胖相关的综合征的探索，包括 WAGR (2)、Bardet-Biedl (3) 和 Alstrm 综合征。目前的研究旨在了解导致儿童体重过度增加风险的其他遗传、生理和心理因素 (6-14)，包括体液因素 (4) 睡眠 (5-6)、抑郁和焦虑等负面情感状态(7-11)、基于体重的戏弄 (12)、述情障碍 (13)、执行功能 (14) 和 LOC 饮食 (15-17)。最近的一些举措针对的是因肥胖和糖尿病家族史而患有 2 型糖尿病高风险女孩的胰岛素抵抗 (18)。需要进一步的研究来确定患有中度抑郁症的青少年在 CBT 后是否表现出代谢益处。 另一系列试点研究测试了短暂的活动是否可以改善儿童的葡萄糖耐量或改变情绪 (19)。在体重正常或超重的儿童中，我们发现在口服葡萄糖耐量测试期间，与持续坐着相比，中断坐着会导致胰岛素和 C 肽面积显着降低。通过短暂的中等强度步行来中断久坐时间，从而改善短期代谢功能。最近完成的一项新试验测试了这些急剧改善是否能持续超过一周，并发现了类似的结果。这些研究可能有助于开展社区研究，检查中断久坐行为是否是降低儿童心脏代谢风险的一种有前途的预防策略。 针对儿童暴食行为的调查表明，此类行为也与儿童肥胖有关，并预测有超重风险的儿童未来体重增加。两项已完成的方案对比了控制健康教育（HE）计划，对报告暴食行为的儿童和青少年中人际疗法（IPT）作为体重增加预防策略的效果进行了检验。在自我报告的基线社会适应问题或焦虑程度较高的女孩中，与 HE 相比，IPT 与 BMIz (p<.001) 和脂肪量 (p<=.03) 的急剧下降相关。因此，在易肥胖的青春期女孩中，IPT 与存在高度社会适应问题或特质焦虑的青少年 3 年内 BMIz 的改善相关。与持续性饮食失控 (LOC) 的青少年相比，治疗结束时饮食失控 (LOC) 得到缓解的青少年在 6 个月的随访中血糖较低，高密度脂蛋白胆固醇较高，甘油三酯较低。因此，减少青春期女孩的LOC饮食可能对代谢综合征的某些组成部分产生有益的影响。一项新的研究正在进行中，旨在检验重新训练注意力偏向远离美味食物是否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，迫切需要开发肥胖症的治疗方法。我们最近启动了与使用称为 setmelanotide 的黑皮质素激动剂调节瘦素信号通路相关的额外转化试验。我们的数据表明，患有罕见的导致肥胖的疾病 Bardet Biedl 综合征的患者的瘦素抵抗可以用 setmelanotide 来治疗 (3)。对可能对黑皮质素激动剂有反应的其他疾病的更多研究正在进行中。我们还完成了一项新的随机对照研究，检查二氮嗪胆碱控释药物在治疗普瑞德-威利综合征患者肥胖症中的应用。初步数据表明，对于那些患有明显食欲过盛的人来说是有效的。最后，我们进行了研究来验证以下假设：服用秋水仙碱可以减少 NLRP3 激活的炎症并改善与肥胖相关的代谢失调 (20)。 40 名肥胖成人被随机服用秋水仙碱 0.6 毫克或安慰剂胶囊，每天两次，持续 3 个月。与安慰剂相比，秋水仙碱显着降低C反应蛋白（P <0.005）、红细胞沉降率（P <0.01）、白细胞计数（P <0.005）和绝对中性粒细胞计数（P <0.001）。胰岛素抵抗（P = 0.0499）、空腹胰岛素（P = 0.07）和葡萄糖有效性（P = 0.08）的稳态模型评估的变化表明，与安慰剂组相比，秋水仙碱组的代谢有所改善。这项初步研究发现，利用代谢组学方法，秋水仙碱可显着改善肥胖成人中与肥胖相关的炎症变量 (22)。我们将 GDF-15 确定为秋水仙碱改变的目标分子。所有这些结果表明，应该进行更大规模、更有力的研究，以确定秋水仙碱是否可以改善高危个体的胰岛素抵抗和代谢健康的其他指标。我们今年正在启动这样的试验。 其他研究已经检查：1）。在频繁采样研究中避免胰岛素溶血（重新利用抗生素杆菌肽，因为它能够抑制胰岛素降解酶 (23), 2) 使用口服葡萄糖耐量测试预测糖尿病前期 (24), 3）。确定游离脂肪酸 (FFA) 浓度是否可以作为儿童禁食与非禁食状态的良好指标 (25)，4) 研究连续血糖监测如何反映肥胖儿童的实际血糖 (26)。我们还与其他机构的研究人员合作开展更多研究 (27-29)。