Contribution of Liver Fat to Weight Loss-Induced Changes in Serum Hepatokines: A Randomized Controlled Trial

Context: Hepatokines have emerged as potential mediators of obesity-associated comorbidities, such as type 2 diabetes, cardiovascular disease, fractures, and central hypogonadism. Objective: To assess whether weight loss-induced changes in hepatokines are mediated by intrahepatic triglyceride (IHTG) content. Design: Cross-sectional study and randomized controlled trial. Setting: General community. Participants: Metabolically healthy, lean men (waist <94 cm; n = 25) and men with abdominal obesity (waist 102 to 110 cm; n = 52). Intervention: Men with abdominal obesity were randomized to 8-week dietary weight loss or no weight loss. Main Outcome Measures: IHTG and serum hepatokines, that is, serum IGF1, IGF binding protein 1 (IGFBP1), SHBG, fibroblast growth factor 21 (FGF21), fetuin A, and plasma fetuin B. Results: All hepatokines, except for fetuin B, were significantly different between lean men and men with obesity. After the weight-loss intervention (-10.3 kg; 95% CI, -11.4 to-9.2), serum IGF1, IGFBP1, SHBG, and fetuin A approached the values observed in lean men. Cross-sectional associations were observed between IHTG and IGF1 (beta = -0.51; 95% CI, -0.82 to -0.20), IGFBP1 (beta = -4.2; 95% CI, -7.7 to -0.7), and FGF21 (beta = 2.1; 95% CI, 1.3 to 2.9) in lean men and men with abdominal obesity combined. Weight loss resulted in a reduction of IHTG (treatment effect, -2.2%; 95% CI, -3.4% to -1.2%) that was associated with a change in IGF1 (beta = -0.9; 95% CI, -1.3 to -0.4), IGFBP1 (beta = -0.17; 95% CI, -0.31 to -0.03), and SHBG levels (beta = -0.18; 95% CI, -0.29 to -0.07). Mediation analyses showed that only the weight loss-induced change in serum IGF1 was mediated by IHTG (mediated effect, 32.7%; 95% CI, 4.6% to 79.2%). Conclusions: Dietary weight loss has differential effects on hepatokines. This study shows that the change in serum IGF1 levels after dietary weight loss is mediated by the change in IHTG content.