Translational Health Research Into Vascular and Neurocognitive Effects of Weight Loss

Registry record from ClinicalTrials.gov (NCT07592546). This is a study registration, not published results. Lead sponsor: Alain Dagher. Recruitment status: RECRUITING. Phase: PHASE4. Study type: INTERVENTIONAL. Enrollment: 240 participants (ESTIMATED). Conditions: Class I/II Obesity. Interventions: DRUG: semaglutide. Primary outcome measures: Serum C-reactive Protein (CRP) , Baseline & Change from Baseline; Serum Pro-inflammatory Cytokines (Interleukin-6, TNF-α, Interleukin-1β, and IL-1 Receptor Antagonist) , Baseline & Change from Baseline; Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) , Baseline & Change from Baseline; Fasting Plasma Glucose , Baseline & Change from Baseline; Glycated Hemoglobin A1c (HbA1c) , Baseline & Change from Baseline; Serum Leptin , Baseline & Change from Baseline; Serum Ghrelin , Baseline & Change from Baseline; Serum Adiponectin , Baseline & Change from Baseline; Fasting Serum Insulin , Baseline & Change from Baseline; Serum Glucagon-Like Peptide-1 (GLP-1) , Baseline & Change from Baseline; Serum C-peptide , Baseline & Change from Baseline; Serum Lipid Panel (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides, and Non-Esterified Fatty Acids [NEFA]) , Baseline & Change from Baseline; Serum Apolipoprotein B (ApoB) , Baseline & Change from Baseline; Red Blood Cell Phospholipid Fatty Acid Composition , Baseline & Change from Baseline; Cerebral Blood Flow as Measured by Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI , Baseline & Change from Baseline; Oxygen Extraction Fraction (OEF) as Measured by Quantitative Susceptibility Mapping (QSM) and T2* MRI , Baseline & Change from Baseline; Cerebral Metabolic Rate of Oxygen (CMRO₂) as Measured by QSM and T2* MRI , Baseline & Change from Baseline; Cortical Thickness as Measured by Structural MRI , Baseline & Change from Baseline; Grey Matter Volume as Measured by Structural MRI , Baseline & Change from Baseline; Grey Matter Surface Area as Measured by Structural MRI , Baseline & Change from Baseline; White Matter Fractional Anisotropy (FA) as Measured by Diffusion Tensor Imaging (DTI) , Baseline & Change from Baseline; White Matter Mean Diffusivity (MD) as Measured by Diffusion Tensor Imaging (DTI) , Baseline & Change from Baseline; White Matter Microstructure as Measured by NODDI (intracellular volume fraction [ICVF], isotropic volume fraction [ISOVF], and Orientation Dispersion Index [ODI]) , Baseline & Change from Baseline; White Matter Hyperintensity Volume as Measured by FLAIR MRI , Baseline & Change from Baseline; Cerebrovascular Reactivity (CVR) as Measured by BOLD fMRI with End-Tidal CO₂ (EtCO₂) Challenge , Baseline & Change from Baseline; Neuroinflammation proxy as Measured by T2* relaxation times , Baseline & Change from Baseline; Neuromelanin Contrast Ratio in the Substantia Nigra as Measured by Neuromelanin-Sensitive MRI , Baseline & Change from Baseline; Intracranial Artery Lumen Diameter as Measured by Time-of-Flight MRA , Baseline & Change from Baseline; Body Mass Index (BMI) , Baseline & Change from Baseline; Waist Circumference, Hip Circumference , Baseline & Change from Baseline; Waist-to-height ratio, Waist-to-hip ratio , Baseline & Change from Baseline; Visceral Adipose Tissue as Measured by MRI , Baseline & Change from Baseline; Subcutaneous Adipose Tissue as Measured by MRI , Baseline & Change from Baseline; Body Composition , Baseline & Change from Baseline. Brief summary: The goal of this clinical trial is to learn about the nature of brain abnormalities associated with excess body fat in healthy adults aged 35-55. The main questions it aims to answer are: * Will excessive fat be associated with brain abnormalities on MRI measures? * Will weight loss change brain health on MRI measures? Participants will: * Self-administer study drug, semaglutide, once a week for 80 weeks * Complete metabolic and basic body measurements * Complete cognitive, mood, and dietary assessments * Complete questionnaires * Undergo MRIs