Phenotypic Discovery of SB1501, an Anti-obesity Agent, through Modulating Mitochondrial Activity.
ChemMedChem
; 16(7): 1104-1115, 2021 04 08.
Article
em En
| MEDLINE
| ID: mdl-33538065
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fármacos Antiobesidade
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Descoberta de Drogas
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Mitocôndrias
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Obesidade
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article