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Randomized Controlled Trial
. 2025 Aug:169:156261.
doi: 10.1016/j.metabol.2025.156261. Epub 2025 Apr 7.

Leptin acutely increases hepatic triglyceride secretion in patients with lipodystrophy

Marianna Beghini  1 , Matthäus Metz  1 , Clemens Baumgartner  1 , Peter Wolf  1 , Magdalena Bastian  1 , Martina Hackl  1 , Sabina Baumgartner-Parzer  1 , Rodrig Marculescu  2 , Michael Krebs  1 , Jürgen Harreiter  1 , Stephanie Brandt  3 , Konstanze Miehle  4 , Giovanni Ceccarini  5 , Silvia Magno  5 , Caterina Pelosini  6 , Christel Tran  7 , Alessandra Gambineri  8 , Carolina Cecchetti  8 , Liliana-Imi Gard  1 , Robert Risti  9 , Aivar Lõokene  9 , Martin Krššák  10 , Lorenz Pfleger  1 , Michael Trauner  11 , Alexandra Kautzky-Willer  1 , Michael Stumvoll  4 , Martin Wabitsch  3 , Ferruccio Santini  5 , Ihsan Turan  12 , Baris Akinci  13 , Florian Frommlet  14 , Herbert Stangl  15 , Clemens Fürnsinn  1 , Thomas Scherer  16
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Free article
Randomized Controlled Trial

Leptin acutely increases hepatic triglyceride secretion in patients with lipodystrophy

Marianna Beghini et al. Metabolism. 2025 Aug.
Free article

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.

Keywords: Lipodystrophy; Metabolic dysfunction-associated steatotic liver disease; Metabolic syndrome; Metreleptin; Very low-density lipoprotein triglycerides.

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Conflict of interest statement

Declaration of competing interest The following individuals have received fees for consulting and/or received travel funds and/or grant support and/or participated in studies sponsored by Amryt Pharmaceuticals now a wholly owned subsidiary of Chiesi Farmaceutici SpA: M. Beghini, K.M., G.C., S.M., C.P., A.G., M.S., M.W., F.S., B.A. and T.S. M. Krebs has received research support from AstraZeneca and Fit for Me, speaker and consulting fees from Merck, Wörwag, Lilly, Takeda, Ipsen and Sanofi and travel support from Pfizer, Novo Nordisk, Merck, Ipsen, HRA Pharma and Boehringer-Ingelheim. K.M. received speaker's honoraria and acted as a scientific advisor for Amryt Pharmaceuticals now a wholly owned subsidiary of Chiesi Farmaceutici SpA. G.C. has received fees for consulting and/or received travel funds or participated in studies sponsored by Rhythm Pharmaceuticals. M.T. has received research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and Ultragenyx and travel grants from Abbvie, Falk, Gilead Intercept and Jannsen. He further has advised for Abbvie, Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire and has served as speaker for BMS, Falk, Gilead, Intercept, Madrigal and MSD. He is a co-inventor of patents for the medical use of norUDCA (nor-ursodeoxycholic acid/norucholic acid) filed by the Medical Universities of Graz and Vienna. B.A. ran projects for and/or served as a consultant, board member, steering committee member, and/or speaker to Amryt Pharmaceuticals now a wholly owned subsidiary of Chiesi Farmaceutici SpA, Alnylam, Regeneron, ThirdRock Ventures, Astra Zeneca, Novonordisk, Boehringer Ingelheim, Sanofi, Bilim Ilac, ARIS, and Servier.

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