Dissertação de Mestrado Nutrição Humana e Metabolismo 2023 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

Introduction: The prevalence of obesity and type 2 diabetes continues to increase worldwide. Although efficiency in weight loss and improvement of comorbidities is showed by several nutritional intervention studies, they don’t clarify the underlying mechanism of the metabolic changes that occur. Thus, it becomes important to identify the metabolites that can serve as biomarkers of weight loss success to improve the efficiency of future weight loss interventions. Objectives: To characterize the variation in the serum metabolite profile of overweight or obese women with intermediate hyperglycemia who consumed a low-calorie diet (LCD) for 8 weeks, correlating it with the variation of clinical and biochemical parameters and to identify the metabolites that predict the success of the weight loss. Methodology: A convenience sample (n=28) from the clinical trial PREVIEW was used and a non-targeted metabolomics analysis was performed using nuclear magnetic resonance (NMR) spectrometry to identify serum metabolites from participants at baseline and after diet. To compare the concentrations of metabolites in the serum before and after LCD, the t test was used for dependent samples and multivariate analysis methods were used. To correlate the variation of clinical and biochemical parameters with the variation of metabolite concentrations, multiple linear regression were used. Finally, robust logistic regression were employed to identify the metabolites that at baseline could predict a better response to weight loss (≥10%). Results: Participants lost an average of 11.16 ± 2.58 kg after 8 weeks of LCD and had statistically significant reductions in most clinical and biochemical parameters. Through the metabolomic analysis, there was an increase in metabolites associated with lipid and fatty acids (FA) metabolism - 2-hydroxybutyrate, 3-hydroxybutyrate and acetylcarnitine, as well as mannose and metabolites that reflected dietary intake with LCD - isobutyrate and dimethyl-sulfone. Choline and the amino acids creatine and tyrosine decreased their concentration after LCD. The variation of BMI and HDL cholesterol had no statistically significant association with the evaluated metabolites. However, the variation in the fat mass (%) was found to be negatively associated with the variation in 2-hydroxybutyrate, 3-hydroxybutyrate, acetylcarnitine and mannose; variation in triglycerides was negatively associated with variation in 2-hydroxybutyrate, acetylcarnitine and choline, and variation in fasting serum insulin was negatively associated with variation in 3- hydroxybutyrate. No metabolites were found that could predict a better response to weight loss. Conclusion: The results suggest that the caloric restriction induced by LCD resulted in a greater dependence on FA metabolism, by increasing lipolysis, for energy production, which presupposes a metabolic shift in substrate oxidation. Further studies will be needed in the future to identify biomarkers that predict successful weight loss for a personalized nutritional intervention.