The screen quickly yielded several compounds that had a strong effect in promoting fat-cell fat storage. The researchers then used a method called "activity-based profiling" to identify the fat-cell serine hydrolases that the compounds inhibited most strongly. One of the most potent compounds, WWL113, turned out to work principally by inhibiting Ces3, a serine hydrolase enzyme that scientists have not studied in the context of obesity or diabetes.
The researchers quickly demonstrated WWL113's effectiveness in two different mouse models of obesity-linked diabetesone in which the mice are genetically programmed to become obese and diabetic, and another in which normal mice are made obese and diabetic with a high-fat diet. "The treated animals showed resistance to weight gainthey were not putting on as much weight as the controls," said Saez. "Their blood biochemistry also was getting normalized; their glucose, triglyceride and cholesterol levels were coming down towards normal levels."
In these mouse tests, WWL113without any optimization for use as a drugperformed about as well as the FDA-approved diabetes treatment rosiglitazone (Avandia). Notably, the new compound lacked one of the side effects that drugs in rosiglitazone's class have in mice: the toxic accumulation of lipids in the liver.
"Our compound clears lipids from the diabetic mouse liver, whereas rosiglitazone has the opposite effect," said Saez.
To explore the relevance of these results to humans, the TSRI team worked with collaborating researchers in Australia to test fat samples from obese humans and diabetics. The tests confirmed that the human version of Ces3 also is unusually active in such patients. This suggests that an inhibitor may also w
|Contact: Mika Ono|
Scripps Research Institute