Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting.
GPCR
GRK2
autophagy
calorie restriction
fasting
glucagon signaling
gluconeogenesis
intermittent fasting
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
12
06
2019
revised:
07
10
2019
accepted:
21
10
2019
entrez:
10
1
2020
pubmed:
10
1
2020
medline:
9
7
2020
Statut:
ppublish
Résumé
The liver plays a key role during fasting to maintain energy homeostasis and euglycemia via metabolic processes mainly orchestrated by the insulin/glucagon ratio. We report here that fasting or calorie restriction protocols in C57BL6 mice promote a marked decrease in the hepatic protein levels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein-coupled receptors (GPCRs) and insulin signaling. Such downregulation of GRK2 levels is liver-specific and can be rapidly reversed by refeeding. We find that autophagy, and not the proteasome, represents the main mechanism implicated in fasting-induced GRK2 degradation in the liver in vivo. Reducing GRK2 levels in murine primary hepatocytes facilitates glucagon-induced glucose production and enhances the expression of the key gluconeogenic enzyme Pck1. Conversely, preventing full downregulation of hepatic GRK2 during fasting using adenovirus-driven overexpression of this kinase in the liver leads to glycogen accumulation, decreased glycemia, and hampered glucagon-induced gluconeogenesis, thus preventing a proper and complete adaptation to nutrient deprivation. Overall, our data indicate that physiological fasting-induced downregulation of GRK2 in the liver is key for allowing complete glucagon-mediated responses and efficient metabolic adaptation to fasting in vivo.
Identifiants
pubmed: 31914606
doi: 10.1096/fj.201901444R
pmc: PMC7184883
mid: NIHMS1579716
doi:
Substances chimiques
Gastrointestinal Agents
0
Glucagon
9007-92-5
GRK2 protein, mouse
EC 2.7.11.15
G-Protein-Coupled Receptor Kinase 2
EC 2.7.11.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
399-409Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK089883
Pays : United States
Informations de copyright
© 2019 Federation of American Societies for Experimental Biology.
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