In translational obesity research, pharmacological activation of brown adipose tissue (BAT) thermogenesis is being investigated as a potential weight loss strategy. Current efforts, however, require further optimization.

Credit: Springer Nature Limited

Now, in a new study, Grandoch and co-workers test the effects of a prescription-free drug, 4-methylumbelliferone (4-MU), on BAT activity in mice. 4-MU, which inhibits the synthesis of the extracellular matrix component hyaluronan, is marketed as a choleretic drug in Europe and Asia.

“The hyaluronan-rich extracellular matrix of adipose tissue is highly responsive to inflammatory and metabolic changes,” says lead author Maria Grandoch. The authors hypothesized that inhibiting hyaluronan synthesis in BAT could alter intracellular substrate flux and thus promote BAT function.

In mice that were fed a fat- and carbohydrate-rich diet, supplementation with 4-MU reduced weight gain, improved glucose homeostasis and limited white adipose tissue hypertrophy and inflammation. The authors also observed beneficial metabolic effects when feeding already obese, insulin-resistant mice with 4-MU.

In order to assess the effects of 4-MU on BAT activity in the mice, the authors first developed a new, non-invasive MRI approach. “For this technique, we harnessed the susceptibility of MRI relaxation time, T2, to regional magnetic-field inhomogeneities,” explains Grandoch. “Because of its heterogeneous tissue composition, high iron content and rich vasculature, BAT has substantially lower baseline T2 values than other tissues. We expected that this effect would be even more pronounced under BAT activation.”

Using this approach, the authors determined that 4-MU treatment activated BAT in a manner that was not affected by inhibition of the β3-adrenergic receptor, suggesting that 4-MU activates BAT via mechanisms independent of adrenergic receptor signalling.

To better understand how 4-MU enhances BAT activation, the authors examined changes in metabolites in BAT from animals treated with the drug. They observed that glucose and lactate concentrations were increased. In fact, inhibiting glycolysis blocked the expression of thermogenic gene Ucp1.

Genetic deletion of the two most abundant hyaluronan-synthase enzymes, HAS2 and HAS3, mimicked some of the beneficial metabolic effects of 4-MU treatment.

Both 4-MU treatment as well as MRI-based BAT imaging could prove to be clinically meaningful. “4-MU’s beneficial effects occurred independent of adrenergic stimulation thereby minimizing unwanted side effects,” highlights Grandoch. “The described T2 mapping approach has the potential to assess BAT activity in humans without the use of a harmful contrast agent or radiation and works furthermore independent from any substrate uptake.”

4-MU treatment activated BAT in a manner that was not affected by inhibition of the β3-adrenergic receptor

Further studies are needed to test 4-MU treatment and the MRI imaging approach in humans.