Food Intake-Related Brain and Metabolic Responses in Obesity

This study is a prospective, single-center, randomized, controlled, crossover intervention trial enrolling 60 participants, including 30 obese patients and 30 healthy control volunteers. Each participant will be randomly assigned to one of the six possible sequences of three macronutrient interventions (A: glucose, B: fat, C: protein)-namely ABC, ACB, BAC, BCA, CAB, or CBA-to ensure balanced allocation across intervention orders. Each participant will undergo one nutrient challenge on each of three separate experimental days, with at least a 7-day washout period between visits to minimize carryover effects from prior interventions. During the washout periods, participants are required to maintain stable habitual dietary patterns and avoid extreme diets, high-intensity exercise, irregular sleep schedules, and intake of additional nutritional supplements; adherence will be monitored via brief diet and activity logs.

The intervention consists of isocaloric (200 kcal) and isovolumetric (300 mL) liquid meals, specifically formulated as follows: Glucose arm: 50 g glucose powder dissolved in water to a final volume of 300 mL; Fat arm: 100 mL intralipid emulsion diluted with water to a final volume of 300 mL; Protein arm: 54 g whey protein powder dissolved in water to a final volume of 300 mL. On each experimental day, participants must arrive in a fasting state. Prior to nutrient administration, they will complete clinical laboratory tests, body composition assessment, hepatic fat quantification, and eating behavior questionnaires. During and after the intervention, participants will provide dynamic postprandial satiety ratings, multi-timepoint blood and stool samples (for untargeted metabolomic analysis), and undergo functional magnetic resonance imaging (fMRI) within a predefined postprandial time window. Finally, neuroimaging metrics, peripheral metabolomic profiles, and subjective satiety scores will be integrated through multidimensional correlation analyses to explore the neuro-metabolic coupling responses to different macronutrient challenges in obesity, thereby providing theoretical insights and potential targets for precision nutrition interventions.

Inclusion criteria

Obese participants:

• BMI ≥ 28 kg/m²;
• Age 18-40 years;
• Any gender;
• Right-handed.

Healthy control participants:

• BMI 18.5-23.9 kg/m²;
• Age 18-40 years;
• Any gender;
• Right-handed.

Exclusion criteria

• Diabetes mellitus;
• Contraindications or allergies to any ingredient in the standardized meal or macronutrient challenges used in this study;
• Central nervous system disorders (e.g., traumatic brain injury, acute cerebral infarction, epilepsy) or psychiatric disorders (e.g., depression, schizophrenia); use of medications acting on the central nervous system within the past 3 months or long-term use;
• Severe impairment of liver, kidney, heart, or gastrointestinal function, including alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >2 times the upper limit of normal; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m² calculated by the CKD-EPI equation; history of unstable angina or myocardial infarction within the past 3 months, or heart failure classified as New York Heart Association (NYHA) class II or higher; history of gastrointestinal stoma, bowel resection, intestinal obstruction, or peptic ulcer disease;
• Contraindications to MRI, such as implanted metallic devices or claustrophobia;
• Pregnancy or lactation;
• Participation in another clinical trial currently or within the past 3 months; use of nutritional supplements within the past 3 months or long-term use;
• History of prior metabolic/bariatric surgery;
• Use of antibiotics or probiotics within the past 1 month;
• Use of medications affecting metabolism or causing weight loss within the past 1 month; body weight fluctuation exceeding 3 kg during the month prior to screening;
• Unusual dietary habits; daily alcohol intake >40 grams, smoking >10 cigarettes per day, or coffee consumption ≥2 cups per day.