FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress.
Circadian rhythms can be regulated by many environmental and endogenous factors. We show here a sensitivity of circadian clock function to oxidative stress that is revealed in flies lacking the foxo gene product. When exposed to oxidative stress, wild-type flies showed attenuated clock gene cycling in peripheral tissues, whereas foxo mutants also lost behavioral rhythms driven by the central clock. FOXO is expressed predominantly in the fat body, and transgenic expression in this tissue rescued the mutant behavioral phenotype, suggesting that foxo has non-cell-autonomous effects on central circadian clock function. Overexpression of signaling molecules that affect FOXO activity, such as the insulin receptor or Akt, in the fat body also increased susceptibility of the central clock to oxidative stress. Finally, foxo mutants showed a rapid decline in rest:activity rhythms with age, supporting the idea that the increase of oxidative stress contributes to age-associated degeneration of behavioral rhythms and indicating the importance of FOXO in mitigating this deterioration. Together these data demonstrate that metabolism affects central clock function and provide a link among insulin signaling, oxidative stress, aging, and circadian rhythms.
Zheng
Xiangzhong
X
Howard Hughes Medical Institute and Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Yang
Zhaohai
Z
Yue
Zhifeng
Z
Alvarez
John D
JD
Sehgal
Amita
A
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000502:physiology*; D007328:Insulin / Q000502:physiology*; D008317:Malpighian Tubules / Q000502:physiology; D009043:Motor Activity; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D056950:Period Circadian Proteins; D012146:Rest; D015398:Signal Transduction
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins