Thrifty energy phenotype predicts weight regain in postmenopausal women with overweight or obesity and is related to FGFR1 signaling.

BACKGROUND&AIMS: Long term improvement of body weight and metabolism is highly requested in obesity. The specific impact of weight loss associated temporary negative energy balance or modified body composition on metabolism and weight regain is unclear. METHODS: We randomly assigned 80 post-menopausal women (BMI 33.9 (32.2-36.8)kg/m2) to an intervention (IG) or control group (CG). IG underwent a dietary three month-weight loss intervention followed by a four week-weight maintenance period without negative energy balance. The CG was instructed to keep their weight stable. Phenotyping was performed at baseline (M0), after weight loss (M3), the maintenance period (M4) and 24-month follow-up (M24). Co-primary outcomes were changes of insulin sensitivity (ISIClamp) and lean body mass (LBM). Energy metabolism and adipose gene expression were secondary endpoints. RESULTS: Between March 2012 and July 2015, 479 subjects were screened for eligibility. 80 subjects were randomly assigned to IG (n = 40) or CG (n = 40). The total number of dropouts was 18 (IG: n = 13, CG: n = 5). LBM and ISIClamp were stable in the CG between M0 and M3, but were changed in the IG at M3 (LBM: -1.4 (95%CI -2.2-(-0.6)) kg and ISIClamp: +0.020 (95%CI 0.012-0.028) mg·kg-1·min-1/(mU·l-1)) (p < 0.01 and p < 0.05 for IG vs. CG, respectively). Effects on LBM, ISIClamp, FM and BMI were preserved until M4. Lower resting energy expenditure per LBM (REELBM) at M3 and stronger difference of REELBM between M3 and M4 (ΔREELBM-M3M4), which indicates a thrifty phenotype, were positively associated with FM regain at M24 (p = 0.022 and p = 0.044, respectively). Gene set enrichment analysis revealed a relationship of this phenotype to weight loss-induced adaption of adipose FGFR1 signaling. CONCLUSION: Negative energy balance had no additional effect on insulin sensitivity. FGFR1 signaling might be involved in the adaption of energy expenditure to temporary negative energy balance, which indicates a thrifty phenotype susceptible to weight regain. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01105143, https://clinicaltrials.gov/ct2/show/NCT01105143, date of registration: April 16th, 2010.

Caloric Restriction in Older Adults-Differential Effects of Weight Loss and Reduced Weight on Brain Structure and Function.

Dietary modifications such as caloric restriction (CR) have been suggested as a means to improve memory and prevent age-related decline. However, it is unclear whether those effects remain stable over time or are related specifically to negative energy balance during the weight loss phase of CR. Using a randomized interventional design, we investigated changes in recognition memory and neural correlates in postmenopausal obese women (n = 19): 1) after intense weight loss in the course of a 12-week low-caloric diet (reduced body weight and negative energy balance) and 2) after having sustained the reduced weight over 4 more weeks (reduced body weight, but energy balance equilibrium). Participants were contrasted to a control group (n = 18) instructed not to change dietary habits. In the CR group, we found improved recognition memory, paralleled by increased gray matter volume in inferior frontal gyrus and hippocampus, and augmented hippocampal resting-state functional connectivity to parietal areas. Moreover, effects were specific for transient negative energy balance and could not be detected after subsequent weight maintenance. Our data demonstrate for the first time in humans that beneficial effects of CR on brain structure and function are due to weight loss rather than an overall reduced weight.