METZ Matthäus

Previous University and Subject: Medical University of Vienna, Human Medicine

Thesis since: 12/2019

The Role of Leptin in Regulating Hepatic Lipid Metabolism in Humans

Non-alcoholic fatty liver disease (NAFLD) is one of the most common hepatic diseases worldwide and is highly associated with obesity, diabetes mellitus and the metabolic syndrome. Hence, the current obesity and diabetes epidemic will inevitably lead to an increase in NAFLD, which is already the second leading cause of liver transplantation in the U.S.

Although the pathophysiological mechanisms of NAFLD are still incompletely understood, it is conceivable that an imbalance between lipid accrual and disposal contributes to the disease development. In obese patients with NAFLD the ability to increase lipid disposal through fat oxidation and very low density lipoprotein triglyceride (VLDL-TG) secretion appears to partially compensate the elevated lipid content but reaches a plateau and declines with the progression of the disease. Insufficient VLDL secretion in patients with hypobetalipoproteinemia or pharmacological inhibition of the microsomal triglyceride transfer protein (MTTP), the rate-limiting enzyme for VLDL assembly, leads to hepatic steatosis. Several reports indicate that VLDL secretion and hepatic lipid metabolism in rodents is orchestrated by the central nervous system (CNS) through the autonomic nervous system. Central insulin administration into the 3rd ventricle increases hepatic VLDL-TG secretion and reduces hepatic lipid content suggesting that brain insulin resistance, which develops early in the course of diabetes, contributes to the imbalance between lipid export and import. Beside insulin, leptin also boosts hepatic VLDL secretion and reduces de novo lipogenesis and hepatic lipid content via a brain-vagus-liver axis. It is therefore tempting to speculate that leptin resistance, which is commonly observed in obese individuals, plays a role in NAFLD development. Overcoming leptin resistance appears to be a promising therapeutic strategy to fight NAFLD, for which currently no effective treatment is available.

On the basis of the rodent models, we hypothesize that, like in rodents, metreleptin increases hepatic VLDL secretion and decreases hepatic de novo lipogenesis via a brain-vagus-liver axis thereby reducing hepatic lipid content and protecting the liver from ectopic lipid accumulation. To investigate this hypothesis the following strategies will be applied:

Aim 1: Defining the role of leptin action in regulating hepatic VLDL secretion, lipid content and energy metabolism in healthy human subjects.

a) Assessing the impact of s.c. metreleptin injection on VLDL secretion and LPL activity using an established Intralipid infusion protocolb) Measuring hepatic lipid content non-invasively using 1H-magnetic resonance spectroscopy (1H-MRS) to examine if leptin changes hepatic lipidsc) Simultaneously assessing the effects of metreleptin on hepatic energy metabolism using 31P-MRS.d) Metabolomics, lipidomics and fatty acid profile analysis of blood samples will provide further insight into the effects of metreleptin on whole body lipid metabolism and may allow conclusions on hepatic de novo lipogenesis

Aim 2: Assessing leptin action in denervated livers and testing if vagal stimulation elicits similar effects like leptin on hepatic metabolism. To investigate whether leptin affects hepatic lipid metabolism mainly via the autonomic nervous system or directly through leptin receptors expressed on hepatocytes, VLDL secretion after acute s.c. metreleptin administration will be assessed in patients who had undergone liver transplantation (LTX). Furthermore, a modified sham-feeding protocol, which stimulates vagal activity, will be used to test whether a vagal stimulus mimics leptin action on VLDL secretion.

Methods and Skills:

FACS analysis; density gradient ultracentrifugation

Publications:

Metz M, O'Hare J, Cheng B, Puchowicz M, Buettner C, Scherer T. Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway. Mol Metab 73: 101723, 2023

Metz M, Baumgartner C, Stangl H, Scherer T. Measuring VLDL₁ secretion in humans with an intravenous fat emulsion test. STAR Protoc 4: 102089, 2023

Metz M, Beghini M, Wolf P, Pfleger L, Hackl M, Bastian M, Freudenthaler A, Harreiter J, Zeyda M, Baumgartner-Parzer S, Marculescu R, Marella N, Hannich JT, Györi G, Berlakovich G, Roden M, Krebs M, Risti R, Lõokene A, Trauner M, Kautzky-Willer A, Krššák M, Stangl H, Fürnsinn C, Scherer T. Leptin increases hepatic triglyceride export via a vagal mechanism in humans. Cell Metab 34: 1719-1731, 2022

Kaplanian M, Philippe C, Eid SA, Hackl MT, Metz M, Beghini M, Luca AC, Kautzky-Willer A, Scherer T, Fürnsinn C. Deciphering metformin action in obese mice: A critical re-evaluation of established protocols. Metabolism 128: 154956, 2022