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Regulation of Glucose and Lipid Metabolism by Akt/PKB
Author(s) -
Birnbaum Morris J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a44-e
Subject(s) - medicine , endocrinology , protein kinase b , foxo1 , akt2 , insulin , glut4 , glucose uptake , lipogenesis , insulin receptor , phosphoenolpyruvate carboxykinase , carbohydrate metabolism , glycogen synthase , biology , glucose homeostasis , akt3 , lipid metabolism , glycogen , akt1 , insulin resistance , phosphorylation , biochemistry , enzyme
In mammals, insulin stimulates the biosynthesis of macromolecules utilized to store energy, such as protein, triglyceride and glycogen. Type 2 diabetes mellitus is a disease characterized by a lack of responsiveness to insulin in regard to glucose uptake into muscle and adipose tissue and suppression of hepatic glucose output, and an absolute or relative deficiency in the secretion of insulin. Interestingly, though insulin role in the regulation of glucose metabolism is severely compromised in Type 2 diabetes, the lipid load remains high suggesting a persistence of insulin's ability to promote hepatic lipogenesis. In these studies, we aimed to understand how the serine/threonine protein kinase Akt, also known as protein kinase B, might mediate insulin's effects on glucose and lipid metabolism in the liver. There are three closely related Akt isoforms each encoded by a distinct gene. Disruption of Akt2 in mice produces a diabetes‐like syndrome, in which insulin is impaired in its ability to stimulate glucose uptake into muscle and adipocytes and to shut off hepatic glucose output. In liver, insulin stimulated phosphorylation of FoxO1, a forkhead transcription factor and substrate of Akt, is reduced about 80% in the Akt2 ( − / − ) mice, which is consistent with our measurement of Akt contributing about 85% of the total Akt in the liver. Nonetheless, activity of the FoxO1 target genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase) are reduced appropriately by insulin in primary hepatocytes lacking Akt2. It is likely that the residual Akt1 activity accounts for this regulation, as treatment with an inhibitor of Akt1 and Akt2 completely abrogates the effects of insulin on PEPCK and G6Pase gene expression. Nonetheless, since there is hepatic insulin resistance in the absence of Akt2, we sought an alterative target of the kinase. PGC‐1α is a co‐activator protein whose levels rise during fasting and is critical to the enhanced transcription of genes regulating glucose synthesis (including FoxO1‐regulated genes) and fatty acid metabolism. We have found that Akt phosphorylates PGC‐1α on serine 570, which is located in the SR domain involved in FoxO1 binding. Mutation of S570 to alanine eliminates the ability of PGC‐1α to stimulate transcription of PEPCK and G6Pase gene transcription, as well as the activity of genes associate with fat metabolism. We believe that this provides a novel mechanism by which insulin regulates fat metabolism in liver through Akt, and suggest that this pathway is selectively preserved in insulin resistant states.