Randomized controlled trial analyzing long-term 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 negativ

随机对照试验分析多模式生活方式干预对成人和儿童体重维持的长期影响：平衡负面时期机制的变异性和动态性的综合特征

• 批准号: 225907405
• 负责人: Professor Dr. Heiko Krude
• 金额: --
• 依托单位: Institut für Experimentelle Endokrinologie (CVK)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225907405?language=en
• 关键词: Randomized; controlled; trial; analyzing; long

Life style interventions show a sustained body weight reduction in only 10-20% of the individuals. The considerable inter-individual variation of weight regain suggests that the endogenous response to weight loss as the integrated result of the various, counterregulatory endocrine, metabolic and other mechanisms is a major obstacle for long-term body weight maintenance. In this clinical trial we focused on the endocrine basis of body weight maintenance and the interaction of endocrine circuits with environmental determinants in long-term energy balance. We performed a large randomized controlled trial in children and adults analyzing the effects of a multimodal lifestyle intervention on body weight maintenance after a 12-week weight loss period, assuming that the lifestyle intervention might shift the endogenous set-point of body weight and consequently modify the long-term modification of the hormonal counter-regulation. We screened more than 400 individuals and included in total 153 children and 156 adults into the weight reduction program. 143 children and adults, respectively, finally met the inclusion criteria as defined by at least 8% (-0.2 BMI-SDS in children) weight reduction during the 3-months weight loss period and were randomized to the intervention or control group. We presented already within our primary application (first funding period) that a long-term follow-up of study participants will be mandatory to analyse whether the lifestyle intervention induces a shift of the long-term energy homeostasis (i.e. the set-point of body weight). In addition, the dynamics of weight regain are unclear. Some individuals may regain body weight later than others and the molecular basis of this dynamic variation is also unclear. Long-term data in patients with obesity after intervention programs are scarce and the proposed research questions have not yet been addressed. We will therefore aim to analyse our well characterized large cohort by follow-up investigations and regular recalls of the participants up to 48 months.At present the intervention was finished by the majority of participants at 12 months. Phenotyping at 18 months is expected to be completed in fall 2012 (adults) and spring 2013 (children), which is slightly faster than initially expected at application. The drop-out rate is within the expected range (below 20% in adults and below 5% in children) and the majority of participants completed the full set of phenotyping, including fat and muscle biopsies in 119 adults before and after weight reduction. Considering the ongoing study, we present within this interim report the preliminary data of metabolic and hormonal changes induced by weight loss, although this is not the primary endpoint of this trial. The analyses of weight regain (primary endpoint) and determining parameters will not be performed before all participants finished phenotyping at 18 months and are therefore not yet available. Details of the weight reduction period will be reported below, demonstrating considerable heterogeneity of the hormonal counter-regulation after weight loss in both, children and adults. Briefly, the reduction of BMI was accompanied by an improvement of several anthropometric and metabolic parameters, as expected. Weight loss also resulted in an expected reduction of total resting energy expenditure (REE), although we found within the rather large cohort no significant changes after adjustment for lean body mass. Considerable variation of hormonal changes was found, suggesting that the variability of these parameters may contribute to the heterogeneity of long-term body weight maintenance. Exemplarily, a reduction of sympathetic tone, a centrally driven down-regulation of thyroid hormones and an increase of insulin sensitivity was observed in both, adults and children. Within the next funding period we will address the central question whether the 12 months intervention study was able to shift to a reduced long-term body weight despite the hormonal counter-regulation or which parts of the endocrine counter-regulation correlate with weight regain in both groups in a period up to 36 months after intervention. The effects of the intervention will be investigated by regular recalls of the participants under standard care conditions. Appointments will be made every 3 months and detailed phenotyping investigating metabolic, anthropometric and endocrine characteristics will be performed every 12 months. This follow-up period will be essential to estimate, whether a 12 months intervention is able to induce a sustained modification of endocrine counter-regulation and whether this contributes to long-term body weight maintenance.We will also apply mRNA deep sequencing and analyse mRNA-expression profiles to identify novel links between peripheral tissue, CNS and energy balance. We recently established mRNA deep sequencing of muscle and fat biopsies and confirmed that this approach is feasible in our tissue specimen. mRNA-Sequencing of muscle tissue of all adult participants before and after weight loss is expected to be finished within the first funding period, while analysis of those data and sequencing of fat specimen will be a major issue of the second funding period. Although being a considerable effort, we anticipate that those data will offer a unique opportunity to identify novel fat or muscle molecules modifying body weight maintenance and whole body metabolism. Although being beyond the scope of this CRG, those novel targets will be functionally characterized in collaboration with the experimental partners of this CRG or within external collaborations.This trial will hopefully improve the prediction of the outcome of a weight reduction and a lifestyle intervention focussing on weight maintenance. Our data will set the basis for an indepth understanding of the variability and the dynamics of hormonal mechanisms modifying long-term weight maintenance. Finally the results may help to initiate targeted and individualized therapeutic interventions aiming for body weight maintenance after weight loss. The available data and biological specimen of this study will further serve as a core project to translate findings of numerous other projects of the CRG to humans, hence, the designation “Z-project”.

生活方式干预显示，只有10-20%的人体重持续减轻。体重恢复的个体间差异很大，这表明体重减轻的内源性反应是多种内分泌、代谢等反调节机制综合作用的结果，是长期维持体重的主要障碍。在这项临床试验中，我们关注体重维持的内分泌基础，以及内分泌回路与长期能量平衡中环境决定因素的相互作用。我们在儿童和成人中进行了一项大型随机对照试验，分析了在12周减重期后，多模式生活方式干预对体重维持的影响，假设生活方式干预可能会改变体重的内源性设定点，从而改变激素反调节的长期变化。我们筛选了400多人，并将153名儿童和156名成年人纳入了减肥计划。143名儿童和成人在3个月的减肥期间体重减轻至少8%（儿童BMI-SDS为-0.2），分别达到纳入标准，随机分为干预组和对照组。我们已经在我们的主要申请（第一个资助期）中提出，必须对研究参与者进行长期随访，以分析生活方式干预是否会导致长期能量稳态（即体重设定点）的改变。此外，体重反弹的动态还不清楚。有些人可能比其他人更晚恢复体重，这种动态变化的分子基础也不清楚。干预方案后肥胖患者的长期数据很少，提出的研究问题尚未得到解决。因此，我们的目标是通过随访调查和参与者长达48个月的定期召回来分析我们具有良好特征的大型队列。目前，大多数参与者在12个月时完成了干预。18个月的表型分析预计将于2012年秋季（成人）和2013年春季（儿童）完成，这比最初申请时预计的要快一些。退出率在预期范围内（成人低于20%，儿童低于5%），大多数参与者完成了全套表型，包括119名成人减肥前后的脂肪和肌肉活检。考虑到正在进行的研究，我们在这篇中期报告中提出了体重减轻引起的代谢和激素变化的初步数据，尽管这不是本试验的主要终点。体重恢复的分析（主要终点）和确定参数将在所有参与者完成18个月的表型分析之前进行，因此尚未可用。减肥期的细节将在下面报道，显示出在儿童和成人减肥后激素反调节的相当大的异质性。简而言之，正如预期的那样，BMI的降低伴随着一些人体测量和代谢参数的改善。体重减轻也导致预期的总静息能量消耗（REE）减少，尽管我们发现在相当大的队列中，调整瘦体重后没有显著变化。研究发现，激素变化有相当大的差异，表明这些参数的可变性可能导致长期体重维持的异质性。例如，在成人和儿童中都观察到交感神经张力的减少，甲状腺激素的中枢驱动下调和胰岛素敏感性的增加。在下一个资助期内，我们将解决一个核心问题，即12个月的干预研究是否能够在激素反调节的情况下转变为长期体重减轻，或者在干预后长达36个月的两组中，内分泌反调节的哪些部分与体重恢复相关。干预的效果将通过定期召回标准护理条件下的参与者来调查。每3个月进行一次预约，每12个月进行一次详细的表型分析，调查代谢、人体测量和内分泌特征。这一随访期对于估计12个月的干预是否能够诱导内分泌反调节的持续改变以及这是否有助于长期体重维持至关重要。我们还将应用mRNA深度测序和分析mRNA表达谱，以确定外周组织，中枢神经系统和能量平衡之间的新联系。我们最近建立了肌肉和脂肪活检的mRNA深度测序，并证实了这种方法在我们的组织标本中是可行的。所有成年参与者减肥前后肌肉组织的mrna测序预计将在第一个资助期内完成，而这些数据的分析和脂肪标本的测序将是第二个资助期的主要问题。虽然是相当大的努力，我们预计这些数据将提供一个独特的机会，以确定新的脂肪或肌肉分子改变体重维持和全身代谢。尽管这些新靶点超出了本研究小组的范围，但将与该研究小组的实验伙伴合作或在外部合作中对其进行功能表征。这项试验有望改善对减肥结果的预测，以及以维持体重为重点的生活方式干预。我们的数据将为深入了解改变长期体重维持的激素机制的可变性和动力学奠定基础。最后，该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。该研究的现有数据和生物标本将进一步作为核心项目，将CRG众多其他项目的发现转化为人类，因此命名为“z项目”。