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4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue

Nature Metabolism volume 1, pages 546–559 (2019)Cite this article

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Abstract

Therapeutic increase in brown adipose tissue (BAT) thermogenesis is of great interest, as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, that is synthesized by HA synthases (HAS1, HAS2, and HAS3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here we show that inhibition of HA synthesis by 4-MU or genetic deletion of Has2 and Has3 improves the thermogenic capacity of BAT, reduces body-weight gain, and improves glucose homeostasis independently of adrenergic stimulation in mice on a diabetogenic diet. In this context, we validated a novel magnetic resonce T2 mapping approach for in vivo visualization of BAT activation. Inhibition of HA synthesis increases glycolysis, BAT respiration, and uncoupling protein 1 (UCP1) expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved, prescription-free drug, could be repurposed to treat obesity and diabetes.

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Fig. 1: 4-MU prevents diet-induced obesity and increases markers of BAT activation in mice and humans.
Fig. 2: 4-MU treatment improves insulin sensitivity.
Fig. 3: 4-MU increases the thermogenic capacity of BAT.
Fig. 4: Acute 4-MU treatment increases respiration and mitochondrial complex I activity in BAT.
Fig. 5: 4-MU increases glycolysis and vascularization in BAT.
Fig. 6: Has2 and Has3 double-deficient mice have a phenotype resembling that of mice treated with 4-MU.
Fig. 7: Proposed mechanism of action of 4-MU in BAT.

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Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

M. Lombes (INSERM U1185, UMS 32 Institut Biomedical de Bicetre I2B, Faculté de Médecine Paris Sud) kindly provided the T37i cell line. We also thank A. Zimmermann, P. Rompel, I. Rüter, and K. Freidel for excellent technical assistance. All mouse work was carried out in the Disease Model Core (MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5)). We thank the BHF (RG/18/7/33636) and MRC (MC_UU_12012/2) for funding this work. This study was supported in part by the German Research Foundation (DFG; IRTG 1902, SFB1116), the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG), a grant from the Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD; DZD grant 2012), and grants from the Helmholtz portfolio (theme Metabolic Dysfunction and Common Disease), the Helmholtz Alliance to Universities: Imaging and Curing Environmental Metabolic Diseases (ICEMED), and the Research Training Group vivid.

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Authors and Affiliations

  1. Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Maria Grandoch, Julia K. Maier, Christina Kohlmorgen, Kathrin Feldmann, Yanina Ostendorf & Jens W. Fischer

  2. Experimental Cardiovascular Imaging, Molecular Cardiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Ulrich Flögel

  3. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    Sam Virtue & Antonio Vidal-Puig

  4. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Tomas Jelenik & Michael Roden

  5. German Center for Diabetes Research (DZD), Munich, Germany

    Tomas Jelenik, Tamara R. Castañeda, Zhou Zhou, Hadi Al-Hasani, Michael Roden, Susanne Keipert & Martin Jastroch

  6. Institute for Clinical Biochemistry and Pathobiochemistry, Medical Faculty, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Tamara R. Castañeda, Zhou Zhou & Hadi Al-Hasani

  7. Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Yu Yamaguchi

  8. Department of Nutrition and Movement Sciences, Maastricht University Medical Center, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, the Netherlands

    Emmani B. M. Nascimento & Patrick Schrauwen

  9. Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Vivekananda G. Sunkari & Paul L. Bollyky

  10. Institute for Clinical Chemistry, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Christine Goy & Judith Haendeler

  11. Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany

    Martina Kinzig & Fritz Sörgel

  12. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Michael Roden

  13. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Munich, Germany

    Susanne Keipert & Martin Jastroch

  14. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden

    Susanne Keipert & Martin Jastroch

  15. WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    Antonio Vidal-Puig

  16. IUF–Leibniz Research Institute for Environmental Medicine, Heisenberg Group–Environmentally Induced Cardiovascular Degeneration, Düsseldorf, Germany

    Judith Haendeler

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  1. Maria Grandoch
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Contributions

M.G. and J.W.F. developed the study, were involved in the design of all experimental protocols, and wrote the manuscript. M.G., J.K.M., C.K., K.F., and Y.O. were involved in data generation. U.F. developed and performed the MRI approach for assessment of BAT activation; S.V. and A.V.-P. performed experiments for measuring maximum energy expenditure and food-intake experiments, discussed the results, and helped with the manuscript. T.J., C.G., J.H., and M.R. were involved in measurements of mitochondrial respiration. T.R.C., Z.Z., and H.A.-H. were involved in calorimetric measurements at 4 °C and measurements of ex vivo glucose uptake. M.K. and F.S. performed mass spectrometry. E.B.M.N. and P.S. performed experiments in brown adipocytes isolated from humans and analysed and discussed the data. Y.Y. developed the ubiquitous Has1-deficient and inducible Has2-deficient mice. V.G.S., P.L.B., S.K., and M.J. discussed the results and helped with the manuscript. All authors contributed to discussion of the results and writing of the manuscript.

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Correspondence to Maria Grandoch.

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Grandoch, M., Flögel, U., Virtue, S. et al. 4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue. Nat Metab 1, 546–559 (2019). https://doi.org/10.1038/s42255-019-0055-6

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