The goal of this observational study is to investigate metabolic changes in individuals undergoing bariatric surgery, specifically focusing on those with obesity and varying metabolic health statuses. The main questions it aims to answer are:

• Can metabolic markers predict the transition from metabolically unhealthy obesity to metabolically healthy obesity after bariatric surgery?
• How do metabolic profiles change in individuals with metabolically healthy obesity after bariatric surgery?
• What are the metabolic differences between individuals with metabolically healthy and unhealthy obesity before and after bariatric surgery?

Participants will undergo routine evaluations and blood tests before and after bariatric surgery. These tests will include assessments of metabolic health markers and sampling of blood plasma for metabolomic analysis. The study will study changes in metabolic profiles between individuals who transition to metabolically healthy obesity and those who remain metabolically unhealthy after surgery.

In January 2025, a new definition of clinical obesity was proposed by the Lancet Commission, focusing on organ/system dysfunction induced by excess adiposity. In response, this study has expanded its objectives to assess the prevalence, predictors, and metabolomic correlates of clinical obesity and its remission after bariatric surgery.

This is a prospective observational study conducted at the bariatric surgery unit. Patients undergo routine assessments and preoperative evaluations by a multidisciplinary team including surgeons, endocrinologists, nutritionists, psychologists, psychiatrists, and anesthesiologists. Clinical evaluations include physical examinations and laboratory tests to detect cardiometabolic comorbidities before surgery. The two bariatric surgery techniques performed in this center are gastric bypass and vertical gastrectomy. The choice of technique is based on clinical criteria and consensus of the multidisciplinary team. After surgery, patients are evaluated at 3, 6, and 12 months through anthropometry, blood pressure measurements, smoking habits assessment, and routine blood analysis. Patients are invited to participate in the OBEMAR registry during the preoperative period. With informed consent, patients authorize the collection of serum and plasma samples at each visit for scientific purposes. Participation in the study does not entail additional visits or procedures beyond standard clinical practice and participation in the OBEMAR registry.

Metabolically Health Status Criteria:

Health status will be defined according to the criteria used by Wildman et al. in the NHANES 1999-2004 study, excluding C-reactive protein measurement. Patients will be classified as metabolically healthy obese (OMS) if they have only one or none of the cardiometabolic factors. Patients with two or more risk factors will be categorized as metabolically unhealthy obese (OME). This classification will be performed before and one year after surgery.

Metabolomics The study will analyze various metabolites related to amino acid metabolism, energy metabolism, and lipid profile. These metabolites will provide insights into metabolic changes before and after bariatric surgery. Specifically, the study will focus on branched-chain amino acids (BCAA), aromatic amino acids (AAA), energy metabolites, and lipid species.

Sample size and origin To ensure statistical power, a sample size calculation was performed based on the anticipated distribution of patients transitioning to metabolically healthy obesity (OMS) or maintaining metabolically unhealthy obesity (OME) status after surgery. It is estimated that 84.4% of patients will transition to OMS, while the remaining 15.6% will remain OME after surgery. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-tailed test, a minimum of 19 subjects in the OME group and 102 in the OMS group are required to detect a difference of 25% or more in the selected metabolites. Assuming a common standard deviation of 35% for these metabolites, a total of 145 patients need to be included to ensure that 121 meet OME criteria before surgery.

Patients for this study will be sourced from the OBEMAR registry, which comprises individuals who have undergone bariatric surgery at the Hospital del Mar. A portion of the patients included in this registry already have sufficient clinical information to classify them as OMS or OME, and their biological samples are stored in a biobank. As of February 2023, complete clinical data and pre- and post-operative samples are available for 70 patients. With approximately 100 surgeries performed annually in our unit, it is anticipated that the desired sample size will be attained by July 2025.

In January 2025, an international expert commission published a new definition of clinical obesity in The Lancet Diabetes & Endocrinology, shifting the paradigm from traditional risk-based classifications (such as the metabolically healthy/unhealthy obesity concept) to a functional definition based on organ and system-level dysfunctions attributable to excess adiposity. This new definition aims to set a precedent in public health policies, pharmacological treatment indications, and the clinical organization of obesity care. However, it has sparked considerable debate among experts and scientific societies regarding its impact, applicability, and clinical validity.

Given this context, it is essential to generate new knowledge around this concept. Although this study was initially designed to explore a specific metabolic phenotype (metabolically healthy obesity), it now represents a unique opportunity to evaluate the prevalence, predictors, and mechanisms associated with clinical obesity and its remission after bariatric surgery. This adaptation aligns with the research priorities outlined by the expert commission, which emphasize the need to:

Identify biomarkers and/or anthropometric criteria to improve the diagnosis and prognostic stratification of clinical obesity.

Evaluate the efficacy of current anti-obesity interventions in terms of remission or improvement of clinical obesity-not just weight loss or reduced risk of comorbidities.

Understand the degree of weight loss necessary to induce meaningful clinical improvement.

Advance the prevention and treatment of clinical and pre-clinical obesity using a precision medicine approach.

Incorporating these goals, this study will provide valuable insights into how bariatric surgery and metabolomic profiles relate to the new framework of clinical obesity, potentially influencing future therapeutic strategies and clinical trial design.

Inclusion Criteria:

Patients undergoing bariatric surgery at the Hospital del Mar in Barcelona. Criteria for bariatric surgery are:

• Ages between 18 and 60 years.
• Body Mass Index (BMI) equal to or greater than 40, or equal to or greater than 35 kg/m2 with at least one obesity-related comorbidity (type 2 diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea syndrome).
• Previous failure with conventional treatment involving diet and exercise.

Exclusion Criteria:

• History of previous bariatric surgery.
• Presence of severe psychiatric disorders, severe eating disorders, alcohol or drug abuse.
• Contraindications for major abdominal surgery, active gastric ulcer, severe liver disease.

Pregnancy or lactation.

The study population will consist of patients who have undergone bariatric surgery at the Hospital del Mar in Barcelona and meet the aforementioned inclusion criteria. These patients will be consecutively selected and must agree to participate in the study.