Weight Regain Reverses Caloric Restriction–Induced Benefits on the Insulin–IGF-1 Nutrient-Sensing Pathway: Post Hoc Analysis From the CALERIE-2 Randomized Controlled Trial

OBJECTIVE To investigate the long-term metabolic and hormonal consequences of sustained weight loss versus weight regain after 1 year of caloric restriction (CR), with attention to insulin resistance and type 2 diabetes risk. RESEARCH DESIGN AND METHODS In the 2-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy 2 (CALERIE-2) trial (n = 220), participants were randomized to 25% CR or control diet. The intervention targeted weight loss over the first 6–12 months, followed by a 12-month maintenance phase. To assess weight-regain consequences, participants were stratified by weight trajectory regardless of randomization, and group differences were balanced by propensity score weighting. Cardiometabolic and hormonal markers of available participants (n = 190), as well as a biomarker-based estimate of biological age, were compared across weight trajectory groups. RESULTS At 12 months, weight loss ranged from 5.0 to 5.8 kg between groups. Between months 12 and 24, most participants either maintained weight (n = 112) or continued to lose weight (n = 58), whereas a smaller group regained >5% of baseline weight (n = 20). This group had the largest initial caloric reductions. Weight regain reversed improvements in insulin area under the curve and the ratio of insulin-like growth factor 1 (IGF-1) to insulin-like growth factor-binding protein 1, and sustained weight loss maintained metabolic benefits and was associated with greater reductions in biological age. CONCLUSIONS Substantial weight loss followed by weight regain can attenuate or reverse CR-induced benefits on key regulators of the insulin–IGF-1 nutrient-sensing pathway and markers of biological aging. Sustained, moderate weight loss more effectively improves insulin resistance and maintains favorable hormonal profiles linked to type 2 diabetes risk and aging biology.