4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue

Maria Grandoch*, Ulrich Floegel, Sam Virtue, Julia K. Maier, Tomas Jelenik, Christina Kohlmorgen, Kathrin Feldmann, Yanina Ostendorf, Tamara R. Castaneda, Zhou Zhou, Yu Yamaguchi, Emmani B. M. Nascimento, Vivekananda G. Sunkari, Christine Goy, Martina Kinzig, Fritz Soergel, Paul L. Bollyky, Patrick Schrauwen, Hadi Al-Hasani, Michael RodenSusanne Keipert, Antonio Vidal-Puig, Martin Jastroch, Judith Haendeler, Jens W. Fischer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)546-559
Number of pages14
JournalNature Metabolism
Volume1
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • INSULIN SENSITIVITY
  • GLUCOSE-HOMEOSTASIS
  • HYALURONAN
  • FAT
  • MICE
  • INHIBITION
  • SYNTHASE
  • COLD
  • ACTIVATION
  • MECHANISM

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