Phenotypic screening for molecules that affect lipid storage in cells has identified synthetic compounds that can protect against obesity and diabetes in mice, reports work published online this week in Nature Chemical Biology. This research reveals potential strategies for treating metabolic syndromes as well as providing an example of why phenotypic screening is making a comeback in drug discovery efforts.

Lipids are normally stored in fat cells in very specific ways, with the loss of correct storage linked to type 2 diabetes. However, the mechanisms that control lipid storage are not entirely clear.

To identify compounds that could influence this process without knowing specific biomolecular targets, Enrique Saez, Benjamin Cravatt and colleagues conducted phenotypic screening of fat cell differentiation. The panel of compounds used are known to inhibit one class of enzymes called serine hydrolases important for a variety of biochemical processes. The authors identify two compounds that target one serine hydrolase, called carboxylesterase 3, in cell culture. Application of the compounds blocked symptoms of diabetes and obesity in two mouse models. These results provide the first chemical evidence of the role of carboxylesterase 3 in lipid breakdown and may have implications for treatment of metabolic disorders.