Abstract

Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold1,2 and has recently been shown to be present in humans3,4,5. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL)6. Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver6. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease7,8,9,10,11. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.

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Acknowledgements

We thank S. Ehret, B. Henkel, E.-M. Azizi, W. Tauscher, C. Edeling, M. Warmer and M. Holthaus for excellent technical assistance. We thank U. Beisiegel for support and critical reading of the manuscript. We thank G. Adam for helpful discussions and support. We thank L. Scheja for helpful discussions and expert technical advice. We are grateful to K.J. Moore (New York University), A. Roebroeck (Katholieke Universiteit Leuven), E.M. Rubin (University of California–Berkeley) and L.A. Pennacchio (University of California–Berkeley) for providing transgenic mouse models. A.B. is a fellow of the Ernst Schering Foundation and is supported by the Graduiertenkolleg der Deutschen Forschungsgemeinschaft 1459. This work was supported by the Landesexzellenzinitiative Hamburg, by Norgenta and by grants from the Deutsche Forschungsgemeinschaft to J.H. and M.M. (ME1507) and A.E. (Schwerpunktprogramm 1313), from the Institute for the Promotion of Innovation through Science and Technology in Flanders to P.L.S.M.G. and from the Bundesministerium für Bildung und Forschung for the Tailored Magnetic Nanoparticles for Cancer Targeting project (TOMCAT, 01 EZ 0824) to H.H., H.I. and P.N. Intravital imaging was performed in collaboration with the Nikon-Applikationszentrum Norddeutschland (Nikon GmbH) at the Heinrich-Pette-Institute.

Author information

Affiliations

  1. Institute of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Alexander Bartelt
    • , Karoline Bruegelmann
    • , Barbara Freund
    • , Peter Nielsen
    • , Martin Merkel
    •  & Joerg Heeren
  2. Department of Electron Microscopy and Micro Technology, Heinrich-Pette Institute, Hamburg, Germany.

    • Oliver T Bruns
    • , Rudolph Reimer
    •  & Heinz Hohenberg
  3. Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Harald Ittrich
    • , Kersten Peldschus
    •  & Michael G Kaul
  4. Institute of Physical Chemistry, University of Hamburg, Hamburg, Germany.

    • Ulrich I Tromsdorf
    •  & Horst Weller
  5. Physical Chemistry, Technical University Dresden, Dresden, Germany.

    • Christian Waurisch
    •  & Alexander Eychmüller
  6. Department of Human Genetics, University of Leuven, Leuven, Belgium.

    • Philip L S M Gordts
  7. III. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Franz Rinninger
  8. Asklepios Clinic St. Georg, Department of Internal Medicine, Hamburg, Germany.

    • Martin Merkel

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Contributions

A.B. and J.H. designed the study, were involved in all aspects of the experiments and co-wrote the manuscript. O.T.B., R.R. and H.H. were responsible for electron microscopy and intravital imaging. H.I., K.P., O.T.B. and M.G.K. were responsible for MRI measurements. C.W., A.E., U.I.T., H.W., B.F. and P.N. were responsible for design and preparation of hydrophobic QD and SPIO, respectively. O.T.B., P.L.S.M.G., F.R., K.B., B.F., P.N. and M.M. were involved in turnover studies. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alexander Bartelt or Joerg Heeren.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures and Tables

Videos

  1. 1.

    Supplementary Video 1

    MRI of SPIO-TRL uptake into BAT.A representative MRI movie of a cold-exposed (cold) and a control mouse (control). After tail vein injection TRL labeled with super-paramagnetic iron-oxide nanocrystals (SPIO-TRL; start of the clock), liver contrast increases as a result of SPIO-TRL uptake in both mice. BAT contrast increase is only observed in the cold mouse.

  2. 2.

    Supplementary Video 2

    Intravital imaging of BAT after QD-TRL injection. High-speed confocal intravital imaging was established to visualize the vascular circulation and structure of interscapular BAT in real time (reflection mode, grey). In cold-exposed mice, TRL which were labeled with hydrophobic fluorescent nanocrystals (QD-TRL; green) are injected via the tail vein. BAT-mediated processing of QD-TRL reveals a rapid attachment to the endothelium. Nuclei are stained with Hoechst (blue) and blood flow is visualized with FITC-dextran (red).

  3. 3.

    Supplementary Video 3

    Intravital imaging of BODIPY-TRL uptake into BAT. High-speed confocal intravital imaging was established to visualize the vascular circulation and structure of interscapular BAT in real time (reflection mode, grey; movie is fourfold accelerated). In cold-exposed mice, TRL which were labeled with BODIPY-TG (BODIPY-TRL, red) are injected via the tail vein at the beginning of the movie. After approx. 2 min, 50 U heparin are injected and initially bound TRL are released from the vessel wall.

  4. 4.

    Supplementary Video 4

    Intravital imaging of BODIPY-QD-double-labeled TRL uptake into BAT (heparin intervention). High-speed confocal intravital imaging was established to visualize the vascular circulation and structure of interscapular BAT in real time (reflection mode, grey). In cold-exposed mice, TRL which were double-labeled with BODIPY-TG and QD (BODIPY-TRL, red; QD-TRL, green) were injected via the tail vein 30 min before the movie starts. At the beginning of the movie only the QD signal is detectable. Next, 50 U heparin are injected, however, the QD signal cannot be released indicating internalization of TRL cores. Thereafter, a second bolus of double-labeled TRL is injected but the particles cannot bind to the endothelium and display prolonged circulation.

  5. 5.

    Supplementary Video 5

    Intravital imaging of BODIPY-labeled TRL uptake into BAT (heparin intervention). This movie is identical to Supplementary Movie 4 except that only the BODIPY channel (BODIPY-TRL, red) is shown to demonstrate prolonged circulation of TRL while the binding to BAT endothelium is abolished in heparin-treated mice.

  6. 6.

    Supplementary Video 6

    CD36-deficient mice after cold-exposure #1. A representative movie of a wild-type and Cd36-/- mouse. After 12 h cold exposure, Cd36-/- mice are characterized by low locomotor activity and noticeable shivering compared to wild-type control.

  7. 7.

    Supplementary Video 7

    CD36-deficient mice after cold-exposure #2. Another example of a wild-type and Cd36-/- mouse. After 12 h cold exposure, Cd36-/- mice are characterized by low locomotor activity and noticeable shivering compared to wild-type control.

  8. 8.

    Supplementary Video 8

    CD36-deficient mice after recovery. A representative movie of a wild-type and Cd36-/- mouse after 12 h recovery at room temperature. Under these conditions, Cd36-/- mice are indistinguishable from wild-type mice.

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DOI

https://doi.org/10.1038/nm.2297

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