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11:10
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange
Yi Liu1, Renaud Dentin, Danica Chen
1The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd, La Jolla, California 92037, USA.
Nature
|October 14, 2008
Summary
Fasting regulates energy balance by switching between CRTC2 and FOXO1. Sirtuin 1 (SIRT1) deacetylates CRTC2, promoting FOXO1 activity and maintaining glucose homeostasis during prolonged fasting.
Area of Science:
- Metabolic regulation
- Molecular endocrinology
- Nutrient sensing
Background:
- Fasting triggers hepatic gluconeogenesis via glucagon, involving CRTC2 and FOXO1.
- Insulin signaling decreases, augmenting gluconeogenesis during fasting.
- Ketone bodies provide compensatory fuel during late-stage fasting.
Purpose of the Study:
- Investigate the role of p300 and SIRT1 in maintaining energy balance during fasting.
- Elucidate the sequential induction and regulation of CRTC2 and FOXO1.
Main Methods:
- Utilized mouse models with liver-specific Sirt1 gene knockout.
- Administered SIRT1 antagonists and agonists.
- Assessed protein dephosphorylation, acetylation, and ubiquitination.
- Measured gluconeogenic gene expression and glucose output.
Main Results:
- Fasting induces a switch involving p300 and SIRT1 to regulate CRTC2 and FOXO1.
- p300 acetylates and activates CRTC2; SIRT1 deacetylates and downregulates CRTC2.
- SIRT1 activation reciprocally activates FOXO1 and PGC-1alpha.
- Disrupting SIRT1 increases CRTC2 activity and glucose output.
Conclusions:
- A fasting-inducible switch of p300 and SIRT1 maintains energy balance.
- The sequential activation of CRTC2 and FOXO1 by this switch is crucial for glucose homeostasis.
- SIRT1 plays a key role in regulating gluconeogenesis during fasting.
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