A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders.
Obesity (Silver Spring)
; 32(2): 324-338, 2024 Feb.
Article
en En
| MEDLINE
| ID: mdl-37974549
ABSTRACT
OBJECTIVE:
Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.METHODS:
To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes.RESULTS:
We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).CONCLUSIONS:
The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
/
Proteína Desacopladora 1
/
Obesidad
Límite:
Animals
Idioma:
En
Revista:
Obesity (Silver Spring)
Asunto de la revista:
CIENCIAS DA NUTRICAO
/
FISIOLOGIA
/
METABOLISMO
Año:
2024
Tipo del documento:
Article
País de afiliación:
Japón