ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure
Wieneke Dijk,
Markus Heine,
Laurent Vergnes,
Mariëtte R Boon,
Gert Schaart,
Matthijs KC Hesselink,
Karen Reue,
Wouter D van Marken Lichtenbelt,
Gunilla Olivecrona,
Patrick CN Rensen,
Joerg Heeren,
Sander Kersten
Affiliations
Wieneke Dijk
Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
Markus Heine
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Laurent Vergnes
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States
Mariëtte R Boon
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden Univeristy Medical Center, Leiden, The Netherlands
Gert Schaart
Department of Human Movement Sciences, Maastricht University, Maastricht, The Netherlands
Matthijs KC Hesselink
Department of Human Movement Sciences, Maastricht University, Maastricht, The Netherlands
Karen Reue
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, United States
Wouter D van Marken Lichtenbelt
Department of Human Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
Gunilla Olivecrona
Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
Patrick CN Rensen
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden Univeristy Medical Center, Leiden, The Netherlands
Joerg Heeren
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Sander Kersten
Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
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.
