High-throughput screening: A chemical-genomic investigation of adipogenesis

BIOL 121

Bridget K. Wagner, bwagner@broad.harvard.edu1, Yu-Hua Tseng2, Young-kwon Kim, ykkim@fas.harvard.edu1, C. Ronald Kahn2, and Stuart L. Schreiber3. (1) Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, 3027, Cambridge, MA 02142, (2) Research Division, Joslin Diabetes Center, Boston, MA 02215, (3) Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142
Adipocyte differentiation in cell culture occurs through a stereotyped transcriptional cascade induced by hormonal stimulation. While many groups have reported perturbations capable of affecting adipogenesis, a systematic method of measuring the relationship between chemical structure and differentiation remains to be described. We report the development of a cell-based assay based on Nile Red, a neutral lipid dye. Using 3T3-L1 preadipocytes as well as brown preadipocytes isolated from wild-type mice or mice containing targeted deletions of the insulin receptor substrate (IRS) family, we have screened small-molecule libraries for adipogenic activity. We have identified small molecules with cell-specific activity in inducing adipogenesis. In particular, we have confirmed the importance of protein kinase C (PKC) in certain aspects of insulin signaling; PKC activators such as bryostatin 2 can overcome the inhibition of adipogenesis caused by a lack of IRS-1. This class of compounds is now being tested for amelioration of insulin resistant states.
 

Chemistry and Metabolism
4:30 PM-6:30 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster

Division of Biological Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006