Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting

Marta Cruces-Sande, Alba C. Arcones, Rocío Vila-Bedmar, Almudena Val-Blasco, Kfir Sharabi, Daniel Díaz-Rodríguez, Pere Puigserver, Federico Mayor*, Cristina Murga

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)399-409
Number of pages11
JournalFASEB Journal
Volume34
Issue number1
DOIs
StatePublished - 1 Jan 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 Federation of American Societies for Experimental Biology

Keywords

  • GPCR
  • GRK2
  • autophagy
  • calorie restriction
  • fasting
  • glucagon signaling
  • gluconeogenesis
  • intermittent fasting

Fingerprint

Dive into the research topics of 'Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting'. Together they form a unique fingerprint.

Cite this