Hepatic Gi signaling regulates whole-body glucose homeostasis.
J Clin Invest
; 128(2): 746-759, 2018 02 01.
Article
en En
| MEDLINE
| ID: mdl-29337301
ABSTRACT
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic Gi signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic Gi-coupled GPCRs may prove beneficial as antidiabetic drugs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Subunidades alfa de la Proteína de Unión al GTP Gi-Go
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Glucosa
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Hígado
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Invest
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos