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Published on: November 16, 2011
Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction
Pere Puigserver1, James Rhee, Jerry Donovan
1Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|May 20, 2003
Summary
Hepatic gluconeogenesis, essential for fasting survival, is regulated by FOXO1 and PGC-1alpha. These factors interact to control insulin-regulated glucose production in the liver.
Area of Science:
- Metabolic regulation
- Molecular biology
- Endocrinology
Background:
- Hepatic gluconeogenesis is vital for survival during fasting but dysregulated in diabetes.
- Glucocorticoids and glucagon stimulate hepatic gluconeogenesis, while insulin suppresses it.
- FOXO1 and PGC-1alpha are key regulators, but their interaction was unclear.
Purpose of the Study:
- To elucidate the collaborative mechanism between FOXO1 and PGC-1alpha in regulating hepatic gluconeogenesis.
- To investigate the role of Akt-mediated phosphorylation in FOXO1-PGC-1alpha interaction.
- To determine the impact of insulin on PGC-1alpha-stimulated gluconeogenesis via FOXO1.
Main Methods:
- Utilized wild-type and mutant FOXO1 alleles in cellular and mouse models.
- Investigated PGC-1alpha binding and co-activation of FOXO1.
- Assessed the effect of insulin on PGC-1alpha-stimulated gluconeogenesis in the presence of modified FOXO1.
Main Results:
- PGC-1alpha binds and co-activates FOXO1, a process inhibited by Akt phosphorylation.
- FOXO1 is essential for PGC-1alpha-mediated induction of gluconeogenic gene expression.
- Insulin's suppression of PGC-1alpha-induced gluconeogenesis is reversed by insulin-insensitive FOXO1 mutants.
Conclusions:
- FOXO1 and PGC-1alpha form a critical complex for executing insulin-regulated hepatic gluconeogenesis.
- This interaction highlights a key pathway for controlling glucose production.
- Targeting the FOXO1-PGC-1alpha interaction may offer therapeutic strategies for metabolic disorders.
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