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

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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.