Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration.
Mol Metab
; 9: 28-42, 2018 03.
Article
en En
| MEDLINE
| ID: mdl-29428596
ABSTRACT
OBJECTIVE:
The peroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1α1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1α1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1α1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC-1α1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions.METHODS:
We designed a cell-based high-throughput screening system to identify PGC-1α1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1α1 protein accumulation and activate target gene expression in brown adipocytes. Select compounds were analyzed for their effects on global gene expression and cellular respiration in adipocytes.RESULTS:
Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by PGC-1α1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes.CONCLUSIONS:
We identify compounds that induce PGC-1α1 protein accumulation and show that this increases uncoupled respiration in brown adipocytes. This screening platform establishes the foundation for a new class of therapeutics with potential use in obesity and associated disorders.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Desacopladores
/
Fármacos Antiobesidad
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Adipocitos Marrones
/
Bibliotecas de Moléculas Pequeñas
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Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma
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Proteína Desacopladora 1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Metab
Año:
2018
Tipo del documento:
Article
País de afiliación:
Suecia