ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure

Wageningen University, Netherlands
University of Hamburg, Germany
University of California, Los Angeles, United States
Leiden University, Netherlands
Maastricht University, Netherlands
European Society for Medical Oncology, Netherlands
Umeå University, Sweden
Leiden University Medical Center, Netherlands

Oct 17, 2015

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Abstract

Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.

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Wieneke Dijk

Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, Netherlands

Competing interests
The authors declare that no competing interests exist.
Markus Heine

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany

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The authors declare that no competing interests exist.
Laurent Vergnes

Department of Human Genetics, David Geffen School of Medicine, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States

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Mariëtte R Boon

Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden University, Leiden, Netherlands

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The authors declare that no competing interests exist.
Gert Schaart

Department of Human Movement Sciences, Maastricht University, Maastricht, Netherlands

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Matthijs KC Hesselink

Department of Human Movement Sciences, Maastricht University, Maastricht, Netherlands

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Karen Reue

Department of Human Genetics, David Geffen School of Medicine, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States

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Wouter D van Marken Lichtenbelt

Department of Human Biology, Maastricht University Medical Centre, European Society for Medical Oncology, Maastricht, Netherlands

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Gunilla Olivecrona

Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden

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Patrick CN Rensen

Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands

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The authors declare that no competing interests exist.
Joerg Heeren

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany

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The authors declare that no competing interests exist.
Sander Kersten

Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, Netherlands

For correspondence
sander.kersten@wur.nl

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The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in accordance with Directive 2010/63/EU from the European Union. All of the animals were handled according to protocols approved by the Animal Ethics Committees of Wageningen University and Hamburg University (2013007.d, 2013100.b and 34/12).

Human subjects: All subjects signed an informed consent for the study protocol, which was approved by the institutional review board of Maastricht University Medical Centre.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.