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 negative energy homeostasis

• Applicant: Professor Dr. Heiko Krude
• Subject Area: Pediatric and Adolescent Medicine ; Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101434729

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”.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 218: Hormonal Regulation of Body Weight Maintenance
• Participating Persons: Professor Dr. Knut Mai; Professor Dr. Joachim Spranger; Dr. Susanna Wiegand