Randomized placebo-controlled trial of tesamorelin in 50 HIV-infected adults with increased abdominal adiposity, demonstrating that tesamorelin—by reducing liver fat—decreases serum FGF21 levels despite initial GH-mediated increases, revealing a paradoxical relationship where liver fat reduction suppresses the compensatory FGF21 elevation seen in hepatic steatosis. First examination of FGF21 dynamics during tesamorelin treatment. Establishes that tesamorelin's liver fat reduction resolves the compensatory FGF21 elevation that marks hepatic steatosis—demonstrating that FGF21 normalization is a biomarker of tesamorelin's hepatic efficacy and providing insight into the interplay between the GH/IGF axis and the FGF21 hepatokine system in fatty liver disease.
Abstract
OBJECTIVE: Fibroblast growth factor 21 (FGF21) ameliorates steatohepatitis but is increased in humans with fatty liver, potentially due to compensatory mechanisms and/or FGF21 resistance. Further, animal models suggest that GH increases serum FGF21. Tesamorelin, a growth hormone releasing hormone agonist, reduces liver fat in HIV-infected individuals. The objectives of this study were to investigate changes in FGF21 during tesamorelin treatment, to elucide the interplay between FGF21, GH augmentation, and liver fat reduction in humans.
METHODS: 50 HIV-infected men and women with increased abdominal adiposity participated in this randomized, placebo-controlled trial of tesamorelin, 2mg vs. identical placebo daily for six months. Fasting laboratory measures, liver fat byH-magnetic resonance spectroscopy, and visceral adipose tissue (VAT) by computed tomography were obtained. Euglycemic hyperinsulinemic clamp was performed in a randomly selected subset.
RESULTS: At baseline, serum logFGF21 was significantly associated with logliver fat (r=0.32, p=0.03). LogFGF21 tended to decrease in the tesamorelin group compared to placebo (p=0.06). Among the entire cohort, reductions in FGF21 were significantly associated with reductions in liver fat (ρ=0.41, p=0.01), loggamma glutamyl tran speptidase (GGT, r=0.40, p=0.009), and FIB4 index (r=0.37, p=0.02).
CONCLUSIONS: In HIV-infected individuals, FGF21 is significantly positively associated with liver fat. FGF21 decreases in association with reductions in liver fat, GGT, and FIB4, suggesting that FGF21 is upregulated in the context of steatosis and steatohepatitis and is reduced when these conditions improve. Moreover, these data suggest that tesamorelin improves liver fat via pathways other than increasing serum FGF21.
TRIAL REGISTRATION: clinicaltrials.govNCT01263717.
Authors
Braun, Laurie R; Feldpausch, Meghan N; Czerwonka, Natalia; Torriani, Martin; Grinspoon, Steven K; Stanley, Takara L