Diet-induced Fasting Ghrelin Elevation Reflects the Recovery of Insulin Sensitivity and Visceral Adiposity Regression

Context: Lower fasting ghrelin levels (FGL) are associated with obesity and metabolic syndrome. Objective: We aimed to explore the dynamics of FGL during weight loss and its metabolic and adiposity-related manifestations beyond weight loss. Methods: This was a secondary analysis of a clinical trial that randomized participants with abdominal obesity/dyslipidemia to 1 of 3 diets: healthy dietary guidelines (HDG), Mediterranean diet (MED), or green-MED diet, all combined with physical activity (PA). Both MED diets were similarly hypocaloric and included 28 g/day walnuts. The green-MED group further consumed green tea (3-4 cups/day) and a Wolffia globosa (Mankai) plant green shake. We measured FGL and quantified body fat depots by magnetic resonance imaging at baseline and after 18 months. Results: Among 294 participants (body mass index = 31.3 kg/m2; FGL = 504 ± 208 pg/mL; retention rate = 89.8%), lower FGL was associated with unfavorable cardiometabolic parameters such as higher visceral adipose tissue (VAT), intrahepatic fat, leptin, and blood pressure (P < 0.05 for all; multivariate models). The ΔFGL18-month differed between men (+7.3 ± 26.6%) and women (-9.2% ± 21.3%; P = 0.001). After 18 months of moderate and similar weight loss among the MED groups, FGL increased by 1.3%, 5.4%, and 10.5% in HDG, MED, and green-MED groups, respectively (P = 0.03 for green-MED vs HDG); sex-stratified analysis revealed similar changes in men only. Among men, FGL18-month elevation was associated with favorable changes in insulin resistance profile and VAT regression, after adjusting for relative weight loss (HbA1c: r = -0.216; homeostatic model of insulin resistance: r = -0.154; HDL-c: r = 0.147; VAT: r = -0.221; P < 0.05 for all). Insulin resistance and VAT remained inversely related with FGL elevation beyond that explained by weight loss (residual regression analyses; P < 0.05). Conclusion: Diet-induced FGL elevation may reflect insulin sensitivity recovery and VAT regression beyond weight loss, specifically among men. Green-MED diet is associated with greater FGL elevation.