Skip to content
Go back

Diet-induced Weight Loss and Phenotypic Flexibility Among Healthy Overweight Adults: A Randomized Trial

American Journal of Clinical Nutrtion – 2023


Milena Rundle, Jarlei Fiamoncini, E Louise Thomas, Suzan Wopereis, Lydia A. Afman,Lorraine Brennan, Christian A. Drevon, Thomas E. Gundersen, Hannelore Daniel, Isabel Garcia Perez , Joram M. Posma, Diana G. Ivanova, Jimmy D. Bell, Ben van Ommen, Gary Frost


American Journal of Clinical Nutrtion



Background: The capacity of an individual to respond to changes in food intake so that postprandial metabolic perturbations are resolved, and metabolism returns to its pre-prandial state, is called phenotypic flexibility. This ability may be a more important indicator of current health status than metabolic markers in a fasting state.

Aim: In this parallel randomized controlled trial study, an energy-restricted healthy diet and 2 dietary challenges were used to assess the effect of weight loss on phenotypic flexibility.

Methods: Seventy-two volunteers with overweight and obesity underwent a 12-wk dietary intervention. The participants were randomized to a weight loss group (WLG) with 20% less energy intake or a weight-maintenance group (WMG). At weeks 1 and 12, participants were assessed for body composition by MRI. Concurrently, markers of metabolism and insulin sensitivity were obtained from the analysis of plasma metabolome during 2 different dietary challenges—an oral glucose tolerance test (OGTT) and a mixed-meal tolerance test.

Results: Intended weight loss was achieved in the WLG (5.6 kg, P < 0.0001) and induced a significant reduction in total and regional adipose tissue as well as ectopic fat in the liver. Amino acid-based markers of insulin action and resistance such as leucine and glutamate were reduced in the postprandial phase of the OGTT in the WLG by 11.5% and 28%, respectively, after body weight reduction. Weight loss correlated with the magnitude of changes inmetabolic responses to dietary challenges. Large interindividual variation in metabolic responses to weight loss was observed. Conclusion: Application of dietary challenges increased sensitivity to detect metabolic response to weight loss intervention. Large interindividual variation was observed across a wide range of measurements allowing the identification of distinct responses to the weight loss intervention and mechanistic insight into the metabolic response to weight loss.

Keywords: phenotypic flexibility, weight loss, insulin sensitivity, meal challenges, metabolites