Insulin suppresses glucose output from the liver via Akt activation; however, which substrate of Akt plays the major role in transducing this effect is unclear. We tested the postnatal expression of Akt-unresponsive, constitutively active mutants of three major Akt substrates widely considered to regulate glucose metabolism [i.e., FoxO1, PGC1α, and glycogen synthase kinase-3β (GSK3β)] using adenoviral gene delivery to the mouse liver. We performed physiological hyperinsulinemic-euglycemic clamp studies using these mice under awake and nonrestrained conditions with blood sampling via an arterial catheter. Hepatic expression of constitutively active FoxO1 induced significant hepatic and systemic insulin resistance. However, neither the expression of constitutively active PGC1α nor that of GSK3β significantly changed insulin sensitivity. Simultaneous expression of all three mutants together induced no further insulin resistance compared with that of the FoxO1 mutant. The glycogen content in the liver was significantly reduced by constitutively active GSK3β expression. In cultured hepatocytes, constitutively active PGC1α induced markedly stronger transcriptional enhancement of gluconeogenic key enzymes than did constitutively active FoxO1. From these results, we conclude that FoxO1 has the most prominent role in transducing insulin's effect downstream from Akt to suppress hepatic glucose output, involving mechanisms independent of the transcriptional regulation of key gluconeogenic enzymes.
Pubmed ID: 28498916 RIS Download
Mesh terms: Animals | Cell Line | Gene Expression Regulation | Glucose | Glucose Clamp Technique | Glycogen | Hepatocytes | Lipid Metabolism | Liver | Male | Mice | Mice, Inbred C57BL | Mutation | Proto-Oncogene Proteins c-akt | Triglycerides
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal antibody targets Akt (pan) (C67E7) Rabbit mAbView all literature mentions
This polyclonal antibody targets Actin antibody produced in rabbitView all literature mentions
This monoclonal antibody targets GSK-3beta (27C10) Rabbit mAbView all literature mentions
This monoclonal antibody targets Ser473View all literature mentions
This monoclonal antibody targets FoxO1 (C29H4) Rabbit mAbView all literature mentions
This monoclonal antibody targets Phospho-Akt (Thr308) (C31E5E) Rabbit mAbView all literature mentions
Software tool as an open source Java-based image processing program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.View all literature mentions
Matlab code for two-factor (location and year) analysis-of-variance model for the calculation of climate anomalies, in which the reference interval is specified as the full length of the dataset. This scheme avoids the affects of shorter (e.g. 1961-1990) reference intervals on the temporal evolution of the spatial standard deviation of climate anomalies. Data files provided.View all literature mentions