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4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue


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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Data availability

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


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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.

Author information

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.

Correspondence to Maria Grandoch.

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Further reading

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.