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Grandoch, M.* ; Flögel, U.* ; Virtue, S.* ; Maier, J.K.* ; Jelenik, T.* ; Kohlmorgen, C.* ; Feldmann, K.* ; Ostendorf, Y.* ; Castañeda, T.R.* ; Zhou, Z.* ; Yamaguchi, Y.* ; Nascimento, E.B.M.* ; Sunkari, V.G.* ; Goy, C.* ; Kinzig, M.* ; Sörgel, F.* ; Bollyky, P.L.* ; Schrauwen, P.* ; Al-Hasani, H.* ; Roden, M.* ; Keipert, S. ; Vidal-Puig, A.* ; Jastroch, M. ; Haendeler, J.* ; Fischer, J.W.*

4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Nat. Metab. 1, 546-559 (2019)

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Therapeutic increase of 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, which is synthesized by HA synthases (Has1/Has2/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 the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 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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