BACKGROUND: Weight loss is a cornerstone of obesity treatment and diabetes mellitus type 2 (T2D) prevention, but its implementation in clinical practice is limited by its perceived burden and variability in response. Personalizing interventions to increase their success rate is an unmet clinical need. OBJECTIVE: Identification of predictive factors associated with successful weight loss after sequential exercise in women with obesity. METHODS: The study will consist of a 2-stage analytical approach, including a predictive validation study and a 2:1 randomized cross-over controlled trial. Women aged 25-45 years with obesity (BMI>30) will be included in the study. The intervention will consist of a progressive protocol of aerobic exercise on a treadmill and a bicycle ergometer. We will measure weight loss in terms of fat mass (FM) and fat-free mass (FFM), metabolic flexibility (MetFlex) as ΔRQ (change in respiratory quotient (VCO2/VO2) between basal and insulin-stimulated state during glucose clamp), insulin sensitivity, glucose tolerance, hemoglobin A1c, microbiome composition, and metabolomic signatures. RESULTS: Recruitment for the trial began in January 2024. A total of 12 participants were enrolled and randomized. Among them 6 participants have completed the first phase of the A-arm and 6 participants have completed the control period of the B-arm and their intervention is ongoing. Recruitment is ongoing. We expect the preliminary data from this study to be completed in 2026. CONCLUSIONS: This intervention will investigate whether whole body and gut MetFlex can be further explored and used as ex ante predictors of successful weight loss following exercise intervention, providing proof of concept and paving the way for personalized lifestyle interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT06329349; https://clinicaltrials.gov/study/NCT06329349. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/67570.

• Keywords
• diabetes, endocrinology, exercise, gut microbiota, metabolic flexibility, obesity, overweight, physical activity, protocol, randomized control trial, validation study, weight loss,
• MeSH
• Exercise physiology   MeSH
• Diabetes Mellitus, Type 2 prevention & control   MeSH
• Adult MeSH
• Weight Loss physiology   MeSH
• Insulin Resistance MeSH
• Cross-Over Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Obesity * therapy   metabolism   MeSH
• Randomized Controlled Trials as Topic MeSH
• Treatment Outcome MeSH
• Life Style * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH