Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic Gluconeogenesis

During fasting, mammals maintain glucose homeostasis by stimulating hepatic gluconeogenesis1. Elevations in circulating glucagon (GLU) and epinephrine trigger the cAMP mediated phosphorylation of Creb and dephosphorylation of the Creb coactivator Crtc22. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment3–6. Here we show that Creb activity during fasting is modulated by Cryptochromes (Cry1 and Cry2), core components of the clock that are rhythmically expressed in the liver. Cry was elevated during the night/day transition, when it reduced fasting gluconeogenic gene expression by blocking GLU-mediated increases in intracellular cAMP concentrations and in the PKA-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry inhibited accumulation of cAMP in response to G protein coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry appeared to modulate GPCR activity directly through interaction with Gsα . As hepatic over-expression of Cry lowered blood glucose concentrations and improved insulin sensitivity in insulin resistant db/db mice, our results suggest that compounds which enhance Cry activity may provide therapeutic benefit to individuals with type II diabetes.