Randomized controlled trial analyzing effects of a multimodal lifestyle intervention on weight maintenance in adults and children: comprehensive characterization of the variability and dynamics of mechanisms counter-balancing a period of negative energy h

生活方式干预显示，10%-20%的参与者体重持续下降；然而，大多数患者未能保持他们的体重下降。体重恢复的个体间差异很大，这表明对体重减轻或环境因素的内源性反应的差异可能会改变内源性体重的设定点。已经确定了各种内分泌回路，以向大脑发送关于身体能量储存的信息，而其他内分泌回路则作为效应器，将大脑活动整合到行为和新陈代谢反应中。减肥会导致这种内分泌网络的协调反应，有利于体重恢复。这些荷尔蒙循环的个体间变异性和动力学尚不清楚。具体地说，与成人相比，儿童保持体重的生理学在可塑性、与性成熟的关系以及生长方面可能不同。因此，我们将在儿童、青少年和成人中进行一项针对这些主题的随机对照临床试验，利用参与肥胖研究小组的长期临床专业知识，以及在不同机构的纵向护理中获得具有良好特征的不同年龄组肥胖患者的大量队列。将进一步分析POMC和MC4R基因突变导致的一组严重孟德尔肥胖症青少年的中枢神经系统回路的相关性。在最初12周的磨合减肥饮食之后，参与者将接受基于体力活动和营养咨询的为期12个月的随机多模式干预试验。只有在磨合期内体重下降至少8%(儿童体重指数分别为-0.2 BMI-SDS)的个体才会被招募参加随机体重维持试验。干预组在定期会议的基础上进行个别营养咨询，并进行适度运动；对照组将收到一份简短的建议传单，但不进行进一步的干预。参与者的详细代谢表型将在基线、12周磨合阶段和12个月体重维持期之后进行。表型分析将包括对多种荷尔蒙机制的分析，这些机制可能会平衡减肥。最后，干预的持续效果将在干预期结束后6个月进行跟踪调查，这将启动对参与者的定期召回，最长可达48个月的自由生活条件。这一随访期将帮助我们估计，无论短期干预是否能够至少在某些个体中诱导调节体重的设定值的持续修改。这项试验将提高对体重减轻结果的预测，并将为深入了解改变能量平衡的激素机制的可变性和动力学奠定基础。长期结果可能有助于启动有针对性的个体化治疗干预，旨在减肥后保持体重。这项研究将作为一个核心项目，将CRG的许多其他项目的结果转化为人类，因此被命名为“Z”项目。我们将把注意力集中在确定那些能够承受减重的人和那些不能承受减重的人之间的差异。

Life-style interventions show a sustained weight reduction in 10-20% of participants; however, most patients fail to maintain their weight loss. The considerable inter-individual variation of weight regain suggests that differences in the endogenous response to weight loss or environmental factors might shift the endogenous set point of body weight. Various endocrine circuits have been identified to signal information about the body energy stores to the brain, while others act as effectors integrating brain activity into behavioral and metabolic responses. Weight loss induces a coordinated response of this endocrine network favoring weight regain. The inter-individual variability and the dynamics of those hormonal circuits are unknown. Specifically, childhood physiology of maintaining body weight may be different in terms of plasticity, relationship to sexual maturation, and growth, compared to adults. We will therefore perform a randomized controlled clinical trial addressing these topics in children, adolescents, and adults taking advantage of the longstanding clinical expertise of the participating obesity research groups and the access to well characterized large cohorts of patients with obesity of different age groups with obesity in longitudinal care of the different institutions. The relevance of central-nervous system circuits will be further analyzed in a group of adolescents with severe Mendelian adiposity induced by POMC and MC4R gene mutations. After an initial 12-week run-in weight loss diet, participants will undergo a randomized 12-month, multimodal intervention trial based on physical activity and nutritional counseling. Only individuals who lose at least 8% of their initial body weight (-0.2 BMI-SDS in children, respectively) within the run-in period will be recruited to participate in the randomized weight maintenance trial. In the intervention group, an individual nutritive counseling based on regular meetings will be performed and moderate exercise will be offered; the control group will receive a brief advice leaflet, but no further intervention. Detailed metabolic phenotyping of the participants will be performed at baseline, after the 12- week run-in phase, and after the 12-month weight maintenance period. The phenotyping will include the analysis of numerous hormonal mechanisms potentially counter-balancing weight loss. Finally, the sustained effects of the intervention will be investigated by a follow-up 6 months after the end of the intervention period, which will initiate regular recalls of the participants up to 48 months under free-living conditions. This follow-up period will help us estimate, whether or not a short-term intervention is able to induce at least in some individuals, a sustained modification of the set point regulating body weight. This trial will improve the prediction of the outcome of a weight reduction and will set the basis for an indepth understanding of the variability and the dynamics of hormonal mechanisms modifying energy homeostasis. The long-term results may help to initiate targeted and individualized therapeutic interventions aiming for body weight maintenance after weight loss. The study will serve as a core project to translate findings of numerous other projects of the CRG to humans, hence, the designation “Z” project. We will focus our attention on determining the difference between the weight-reducers who can sustain weightloss, compared to those who cannot.