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

Abstract

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 (β = -0.51; 95% CI, -0.82 to -0.20), IGFBP1 (β = -4.2; 95% CI, -7.7 to -0.7), and FGF21 (β = 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 (β = -0.9; 95% CI, -1.3 to -0.4), IGFBP1 (β = -0.17; 95% CI, -0.31 to -0.03), and SHBG levels (β = -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.

Trial registration: ClinicalTrials.gov NCT01675401.