Thrifty energy phenotype predicts weight regain - results of a randomized controlled trial

Abstract Background & Aims Weight loss is associated with an improvement of insulin sensitivity. Both, a negative energy balance and changes of body composition are integrative components of weight loss interventions. However, the individual impact of these two components on insulin sensitivity and energy metabolism is unclear. Methods We performed a randomized controlled trial including 80 overweight or obese post-menopausal women. Participants randomly assigned to the intervention group underwent an 800 kcal/d liquid diet for 2 months followed by four weeks in which the formula diet was substituted by a calorie reduced healthy diet to facilitate further weight loss. This weight loss phase was followed by a 4-week weight maintenance phase, where weight stability was achieved by individualized daily caloric intake without negative energy balance. Volunteers of the control group were instructed to keep their weight stable during the entire period of 4 months. Metabolic phenotyping was performed in both groups at baseline (M0), after weight loss (M3) and after the maintenance period (M4). Additional phenotyping was performed during follow-up at 12 (M12) and 24 months (M24). Primary outcomes were changes of lean body mass (LBM) and changes of insulin sensitivity (ISIClamp) between baseline and M3 and M4. Estimates of energy metabolism were secondary endpoints. Results No significant changes of body weight or LBM were found in the control group between any time points. A significant reduction of body weight, fat mass (FM) and LBM was found in the intervention group between M0 and M3, while no further change was seen between M3 and M4. Only subjects of the intervention group were characterized by an improvement of the second primary outcome ISIClamp at M3, which was preserved until M4. Notably, a lower resting energy expenditure per LBM (REELBM) at M3 as well as the individual difference of REELBM between M3 and M4 significantly predicted a stronger regain of fat mass during follow-up. Conclusions In summary, our data demonstrate that modulation of LBM and insulin sensitivity during weight loss is predominantly driven by changes in body weight and body composition, rather than an individual effect of negative energy balance. However, the variance in energy expenditure during negative and steady energy balance indicates a thrifty phenotype, which is highly susceptible to future regain of fat mass.