hymecromone and Obesity

Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low concentrations of HA were present in healthy pancreatic islets. However, HA substantially accumulated in cadaveric islets of T2D patients and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the main HA receptor CD44, preserved glycemic control and insulin concentrations in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserved glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we found that 4-MU increased the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation did not result in β-cell apoptosis. These data indicated a role for HA accumulation in diabetes pathogenesis and suggested that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hymecromone; Islets of Langerhans; Mice; Obesity

Topics: Adipose Tissue, Brown; Animals; Humans; Hymecromone; Magnetic Resonance Imaging; Mice; Obesity; Sensitivity and Specificity

Pleurotus eryngii water extract (PEE), which showed the most significant inhibitory activity against pancreatic lipase in vitro among eight edible mushrooms, was investigated to determine the mechanism of its anti-lipase activity in vitro and its hypolipidemic effect in fat-loaded mice. The inhibitory effects of mushroom extracts on pancreatic lipase activity were examined using 4-methylumbelliferyl oleate (4-MUO) or trioleoylglycerol emulsified with lecithin, gum arabic or Triton X-100 as a substrate. For in vivo experiments, blood samples were taken after oral administration of corn oil and [(3)H]trioleoylglycerol with or without PEE to food-deprived mice. PEE inhibited hydrolysis of 4-MUO and trioleoylglycerol emulsified with lecithin or Triton X-100, but not that of trioleoylglycerol emulsified with gum arabic. PEE suppressed the elevations of plasma and chylomicron triacylglycerol levels after oral administration of corn oil, but had no effect on lipoprotein lipase activity. [(3)H]Trioleoylglycerol absorption was also decreased by administration of PEE. The results of in vitro studies suggest that PEE may prevent interactions between lipid emulsions and pancreatic lipase. The hypolipidemic effect of PEE in fat-loaded mice may be due to low absorption of fat caused by the inhibition of pancreatic lipase.

Topics: Animals; Biological Products; Chylomicrons; Corn Oil; Dietary Fats; Disease Models, Animal; Emulsions; Food Deprivation; Hydrolysis; Hymecromone; Hyperlipidemias; Hypolipidemic Agents; Lipase; Lipoprotein Lipase; Male; Mice; Mice, Inbred ICR; Obesity; Phytotherapy; Plant Extracts; Pleurotus; Triglycerides; Triolein