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%的参与者体重持续减轻；然而，大多数患者无法维持他们的体重减轻。体重恢复的个体间差异表明，对体重减轻或环境因素的内源性反应的差异可能会改变体重的内源性设定点。已经确定了各种内分泌回路向大脑发送有关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代谢反应中。体重减轻引起这个内分泌网络的协调反应，有利于体重恢复。个体间的差异和这些激素回路的动态是未知的。具体来说，与成人相比，儿童维持体重的生理可能在可塑性、与性成熟和生长的关系方面有所不同。因此，我们将在儿童、青少年和成人中开展一项随机对照临床试验，利用参与肥胖研究小组的长期临床专业知识，并在不同机构的纵向护理中获得不同年龄组肥胖患者的特征大队列。在一组由POMC和MC4R基因突变引起的严重孟德尔式肥胖青少年中，中枢神经系统回路的相关性将进一步分析。在最初的12周减肥饮食后，参与者将进行为期12个月的随机多模式干预试验，该试验基于身体活动和营养咨询。只有在磨合期内体重下降至少8%（儿童BMI-SDS分别为-0.2）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人营养咨询，并进行适度运动；对照组将收到一份简短的建议传单，但没有进一步的干预。参与者的详细代谢表型将在基线、12周的磨合期和12个月的体重维持期后进行。表型分析将包括许多可能抵消体重减轻的激素机制的分析。最后，干预的持续效果将在干预期结束后6个月的随访中进行调查，这将在自由生活条件下对参与者进行为期48个月的定期召回。这一随访期将帮助我们估计，短期干预是否能够至少在某些个体中诱导对调节体重的设定值的持续修改。这项试验将改善对减肥结果的预测，并将为深入了解调节能量稳态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针对减肥后体重维持的针对性和个体化治疗干预。该研究将成为将CRG众多其他项目的成果转化为人类的核心项目，因此被命名为“Z”项目。我们将把注意力集中在确定能够维持体重的减肥者与不能维持体重的减肥者之间的区别。

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.