Leptin acutely increases hepatic triglyceride secretion in patients with lipodystrophy

Abstract

Background and aims

Metreleptin ameliorates hepatic steatosis partially independent of its anorexic action. We previously showed that metreleptin increases hepatic very low-density lipoprotein triglycerides (VLDL1-TG) export in rodents and healthy humans requiring intact hepatic autonomic innervation. The primary aim of this study was to investigate whether metreleptin has anti-steatotic properties in patients with lipodystrophy by increasing VLDL1-TG export. In addition, we present a case of generalized lipodystrophy undergoing metreleptin treatment after liver transplantation, a model for hepatic autonomic denervation.

Methods

In this randomized, placebo-controlled, crossover trial (EudraCT 2017-003014-22) we assessed the acute effects of a single metreleptin injection in 10 patients (8 females, 2 males; mean age ± SD: 49 ± 14 yrs; 9 familial partial and 1 generalized lipodystrophy) on hepatic VLDL1-TG secretion and hepatocellular lipid content (HCL) measured via an intravenous fat emulsion test and ¹H-magnetic resonance spectroscopy, respectively.

Results

We found that a single injection of metreleptin increased hepatic VLDL1-TG secretion by 75 % (mean difference ± SD: +219 ± 149 mg/h metreleptin vs. placebo; p = 0.001), without significant changes in HCL within 3 h (mean difference ± SD: −8 ± 14 % metreleptin vs. placebo, p = 0.14). Metreleptin therapy in a patient with generalized lipodystrophy following liver transplantation failed to ameliorate hepatic steatosis despite improving glucose and lipid metabolism.

Conclusions

Leptin acutely increases hepatic VLDL1-TG secretion in patients with lipodystrophy, likely contributing to metreleptin's body weight-independent anti-steatotic effects. The case report suggests that intact autonomic liver innervation may be required for this action, warranting further research.