Document Detail

Insulin-FOXO3 Signaling Modulates Circadian Rhythms via Regulation of Clock Transcription.
MedLine Citation:
PMID:  24856209     Owner:  NLM     Status:  Publisher    
Circadian rhythms are responsive to external and internal cues, light and metabolism being among the most important. In mammals, the light signal is sensed by the retina and transmitted to the suprachiasmatic nucleus (SCN) master clock [1], where it is integrated into the molecular oscillator via regulation of clock gene transcription. The SCN synchronizes peripheral oscillators, an effect that can be overruled by incoming metabolic signals [2]. As a consequence, peripheral oscillators can be uncoupled from the master clock when light and metabolic signals are not in phase. The signaling pathways responsible for coupling metabolic cues to the molecular clock are being rapidly uncovered [3-5]. Here we show that insulin-phosphatidylinositol 3-kinase (PI3K)-Forkhead box class O3 (FOXO3) signaling is required for circadian rhythmicity in the liver via regulation of Clock. Knockdown of FoxO3 dampens circadian amplitude, an effect that is rescued by overexpression of Clock. Subsequently, we show binding of FOXO3 to two Daf-binding elements (DBEs) located in the Clock promoter area, implicating Clock as a transcriptional target of FOXO3. Transcriptional oscillation of both core clock and output genes in the liver of FOXO3-deficient mice is affected, indicating a disrupted hepatic circadian rhythmicity. Finally, we show that insulin, a major regulator of FOXO activity [6-9], regulates Clock levels in a PI3K- and FOXO3-dependent manner. Our data point to a key role of the insulin-FOXO3-Clock signaling pathway in the modulation of circadian rhythms.
Inês Chaves; Gijsbertus T J van der Horst; Raymond Schellevis; Romana M Nijman; Marian Groot Koerkamp; Frank C P Holstege; Marten P Smidt; Marco F M Hoekman
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-5-21
Journal Detail:
Title:  Current biology : CB     Volume:  -     ISSN:  1879-0445     ISO Abbreviation:  Curr. Biol.     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-5-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier Ltd. All rights reserved.
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