Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis

Martina Theresa Hackl; Clemens Fürnsinn; Christina Maria Schuh; Martin Krssak; Fabrizia Carli; Sara Guerra; Angelika Freudenthaler; Sabina Baumgartner-Parzer; Thomas H Helbich; Anton Luger; Maximilian Zeyda; Amalia Gastaldelli; Christoph Buettner; Thomas Scherer

doi:10.1038/s41467-019-10684-1

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Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis

Journal article

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Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis

Martina Theresa Hackl, Clemens Fürnsinn, Christina Maria Schuh, Martin Krssak, Fabrizia Carli, Sara Guerra, Angelika Freudenthaler, Sabina Baumgartner-Parzer, Thomas H Helbich, Anton Luger, …

Nature communications, Vol.10(1), pp.2717-13

06/20/2019

DOI: https://doi.org/10.1038/s41467-019-10684-1

PMCID: PMC6586634

PMID: 31222048

Abstract

Animals

Blood-Brain Barrier - metabolism

Diet, High-Fat - adverse effects

Disease Models, Animal

Humans

Infusions, Intraventricular

Injections, Intraventricular

Leptin - administration & dosage

Leptin - metabolism

Lipogenesis - physiology

Lipoproteins, VLDL

Liver - innervation

Liver - metabolism

Male

Medulla Oblongata - metabolism

Non-alcoholic Fatty Liver Disease - etiology

Non-alcoholic Fatty Liver Disease - pathology

Polyethylene Glycols - administration & dosage

Rats

Rats, Sprague-Dawley

Stereotaxic Techniques

Sympathectomy

Triglycerides - metabolism

Vagus Nerve - physiology

Vagus Nerve - surgery

Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.

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Title: Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis
Creators: Martina Theresa Hackl - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Clemens Fürnsinn - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Christina Maria Schuh - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Martin Krssak - Christian Doppler Laboratory for Clinical Molecular MR Imaging, MOLIMA, Waehringer Guertel 18-20, 1090, Vienna, Austria
Fabrizia Carli - Institute of Clinical Physiology, National Research Council, Via G. Moruzzi 1, 56124, Pisa, Italy
Sara Guerra - Institute of Life Sciences, Sant'Anna School of Advanced Studies, Via Santa Cecilia 3, 56127, Pisa, Italy
Angelika Freudenthaler - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Sabina Baumgartner-Parzer - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Thomas H Helbich - Department of Biomedical Imaging and Image-Guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Anton Luger - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Maximilian Zeyda - Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
Amalia Gastaldelli - Institute of Life Sciences, Sant'Anna School of Advanced Studies, Via Santa Cecilia 3, 56127, Pisa, Italy
Christoph Buettner - Departments of Medicine and Neuroscience, and Diabetes, Obesity and Metabolism Institute (DOMI), Icahn School of Medicine at Mt Sinai, One Gustave L. Levy Pl, New York, NY, 10029, USA
Thomas Scherer - Department of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria. thomas.scherer@meduniwien.ac.at
Publication Details: Nature communications, Vol.10(1), pp.2717-13
Date published: 06/20/2019
Grant note: P30 DK020541 / NIDDK NIH HHS 634413 / EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) 722619 / EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) P30 DK026687 / NIDDK NIH HHS P 26766 / Austrian Science Fund FWF R03 DK082724 / NIDDK NIH HHS P26766 / Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) K08 DK074873 / NIDDK NIH HHS
Academic Unit: Medicine - Endocrinology, Metabolism and Nutrition (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665518304646