Editors' ChoiceCircadian Rhythms

Metabolism OutFOXes Circadian Rhythm

Sci. Signal.  10 Jun 2014:
Vol. 7, Issue 329, pp. ec155
DOI: 10.1126/scisignal.2005580

The mammalian circadian master clock resides in the suprachiasmatic nucleus (SCN) and synchronizes peripheral clocks that operate in various organs and tissues throughout the body. However, input from metabolic processes can reset peripheral clocks so that they oscillate out of phase with the master clock. Chaves et al. report that the transcription factor Forkhead box O3 (FOXO3) links metabolism to the circadian clock in the liver. Knocking down FOXO3 in cultured NIH 3T3 cells reduced the amplitude, but not the periodicity, with which a fluorescent reporter of the circadian clock oscillated. Microarray analysis revealed Clock, which encodes a central regulator of the circadian clock, as a target for FOXO3-mediated transcriptional control. Indeed, FOXO3-binding sites were identified upstream of and in the first intron of Clock, and chromatin immunoprecipitation showed that FOXO3 associated with these binding sites in cells. Circadian behaviors were normal in FoxO3–/– mice, and a fluorescent clock reporter oscillated normally in the SCN, in lung explants, and in fibroblasts from FoxO3–/– mice. However, the reporter oscillated very weakly in liver explants from the knockout mice. These findings were consistent with the previous observation that the amplitude of oscillations in FoxO3 expression is much greater in the liver than in the SCN. Oscillations in the expression of genes encoding clock components, including Clock, and clock-controlled genes were reduced in liver tissues from FoxO3–/– mice compared with wild-type controls. Insulin signaling though phosphatidylinositol 3-kinase (PI3K) inhibits FOXO3 activity, and exposing cultured liver cells to insulin reduced Clock expression and reduced the amplitude of circadian clock reporter oscillations. Application of a PI3K inhibitor or overexpression of FOXO3 prevented this insulin-induced down-regulation of Clock. Insulin-mediated regulation of FOXO3 activity is also important for coordinating changes in liver metabolism, including lipid metabolism and gluconeogenesis, in response to feeding and fasting. These findings imply that FOXO3 is a central player linking metabolism to circadian cycling in the liver and imply that insulin-PI3K-FOXO3 signaling can uncouple the hepatic clock from the master clock.

I. Chaves, G. T. J. van der Horst, R. Schellevis, R. M. Nijman, M. G. Koerkamp, F. C. P. Holstege, M. P. Smidt, M. F. M. Hoekman, Insulin-FOXO3 signaling modulates circadian rhythms via regulation of clock transcription. Curr. Biol. 24, 1248–1255 (2014). [PubMed] [Abstract]