Metabolic adaptation characterizes short-term resistance to weight loss induced by a low-calorie diet in overweight/obese individuals

Background: Low-calorie diet (LCD)-induced weight loss demonstrates response heterogeneity. Physiologically, a decrease in energy expenditure lower than what is predicted based on body composition (metabolic adaptation) and/or an impaired capacity to increase fat oxidation may hinder weight loss. Understanding the metabolic components that characterize weight loss success is important for optimizing weight loss strategies. Objectives: We tested the hypothesis that overweight/obese individuals who had lower than expected weight loss in response to a 28-d LCD would be characterized by 1) impaired fat oxidation and 2) whole-body metabolic adaptation. We also characterized the molecular mechanisms associated with weight loss success/failure. Methods: This was a retrospective comparison of participants who met their predicted weight loss targets [overweight/obese diet sensitive (ODS), n = 23, females = 21, males = 2] and those that did not [overweigh/obese diet resistant (ODR), n = 14, females = 12, males = 2] after a 28-d LCD (900-1000 kcal/d). We used whole-body (energy expenditure and fat oxidation) and tissue-specific measurements (metabolic proteins in skeletal muscle, gene expression in adipose tissue, and metabolites in serum) to detect metabolic properties and biomarkers associated with weight loss success. Results: The ODR group had greater mean +/- SD metabolic adaptation (-175 +/- 149 kcal/d; +119%) than the ODS group (-80 +/- 108 kcal/d) after the LCD (P = 0.030). Mean +/- SD fat oxidation increased similarly for both groups from baseline (0.0701 +/- 0.0206 g/min) to day 28 (0.0869 +/- 0.0269 g/min; P < 0.001). A principal component analysis factor comprised of scrum 3-hydroxybutyric acid, citrate, leucine/isoleucine, acetylcarnitine, and 3-hydroxylbutyrIcarnitine was associated with weight loss success at day 28 (std. beta = 0.674. R-2 = 0.479. P < 0.001). Conclusions: Individuals who achieved predicted weight loss targets after a 28-d LCD were characterized by reduced metabolic adaptation. Accumulation of metabolites associated with acetyl-CoA excess and enhanced ketogenesis was identified in the ODS group.