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.

Notes:

Cruces-Sande, MartaArcones, Alba CVila-Bedmar, RocioVal-Blasco, AlmudenaSharabi, KfirDiaz-Rodriguez, DanielPuigserver, PereMayor, Federico JrMurga, CristinaengR01 DK089883/DK/NIDDK NIH HHS/R01 DK089883/GF/NIH HHS/SAF2017-84125-R/MINECOFASEB J. 2020 Jan;34(1):399-409. doi: 10.1096/fj.201901444R. Epub 2019 Nov 22.