Endothelial hyaluronan synthase 3 aggravates acute colitis in an experimental model of inflammatory bowel disease.

The association between hyaluronan (HA) accumulation and increased inflammation in the colon suggests that HA is a potential therapeutic target in inflammatory bowel disease (IBD). However, whether patients with IBD would benefit from interference with HA synthesis is unknown. Here, we used pharmacological and genetic approaches to investigate the impact of systemic and partial blockade of HA synthesis in the Dextran Sodium Sulfate (DSS)-induced colitis model. To systemically inhibit HA production, we used 4-Methylumbelliferone (4-MU), whereas genetic approaches included the generation of mice with global or inducible cell-type specific deficiency in the Hyaluronan synthase 3 (Has3). We found that 4-MU treatment did not ameliorate but exacerbated disease severity characterized by increased body weight loss and enhanced colon tissue destruction compared to control mice without colitis. In contrast, global Has3 deficiency had a profound protective effect as reflected by a low colitis score and reduced infiltration of immune cells into the colon. To get further mechanistic insight into the proinflammatory role of HAS3, we deleted Has3 in a cell-type specific manner. Interestingly, while lack of Has3 expression in intestinal epithelial and smooth muscle cells had no effect or was rather proinflammatory, mice with Has3 deficiency in the endothelium were strongly protected against acute colitis. We conclude that endothelium-derived HAS3 plays a critical role in driving experimental colitis, warranting future studies on cell type-specific therapeutic interference with HA production in human IBD.

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

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.