Protein Supplementation Intervention on Body Weight

The primary objective of this study is to determine whether adding dietary protein supplementation to GLP 1 receptor agonist (GLP-1RA, semaglutide) therapy enhances weight loss efficacy, improves energy and glucose-lipid metabolism, mitigates muscle loss, and prevents weight regain. Investigators will also explore key modifiers of treatment response-including obesity phenotype, gut microbiota composition, genetic background, and lifestyle factors-to provide an evidence base for personalized interventions. Investigators will enroll 120 adults with overweight or obesity (BMI ≥ 24 kg/m²) and randomly assign them (1 : 1 : 1) to one of three 3 month interventions: 1. CRD: calorie restricted balanced diet; 2. CRD + GLP-1RA: CRD plus semaglutide; 3. CRD + GLP-1RA + HP: CRD plus semaglutide and 30 g/day of dietary protein supplement. Baseline and post intervention assessments will include questionnaires; evaluations of diet, physical activity, and sleep patterns; physical examination (height, weight, waist and hip circumference, blood pressure, pulse); body composition analysis; hepatic fat and fibrosis imaging; facial skin phenotyping; 14 day continuous glucose monitoring; 14 day accelerometer based sleep and activity monitoring; stool and urine collection; and a mixed-macronutrient tolerance test (MMTT) performed in a metabolic chamber. During the MMTT, participants consume a standardized beverage containing 126.5 g glucose, 30.67 g fat, and 34.5 g protein. Blood samples are collected at 0, 0.5, 1, 2, 3, 4, and 5 hours to characterize post prandial dynamics of energy metabolism, routine clinical biomarkers, and metabolomic profiles. Throughout the intervention, dietary intake is recorded via a mobile application, and body weight changes are tracked with an application linked smart scale. Six months after the intervention, participants undergo follow up assessments (identical questionnaires, physical examination, fasting laboratory tests for glucose, insulin, HbA1c, lipids, and liver and renal function indices) and provide a stool sample. To provide a healthy reference, Investigators will additionally recruit 20 normal weight adults who will receive weight maintenance dietary counseling for 3 months and undergo pre and post intervention MMTTs in the metabolic chamber. These data will help determine whether the metabolic homeostasis of overweight/obese participants after the three interventions approaches that of healthy individuals and will aid in identifying determinants of inter individual variability. The study protocol has been approved by the Ethics Committee of Zhejiang Provincial Tongde Hospital.