Phenotypic Discovery of SB1501, an Anti-obesity Agent, through Modulating Mitochondrial Activity.


Jo A(1), Kim M(1), Kim JI(2), Ha J(3), Hwang YS(1), Nam H(1), Hwang I(2), Kim JB(2), Park SB(1)(3).
Author information:
(1)CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, Korea.
(2)CRI Center for Adipocyte Structure-Function, School of Biological Sciences, Seoul National University, Seoul, 08826, Korea.
(3)Department of Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, Korea.


Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α-UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities.