Cryptochrome 1 (CRY1) is a core clock repressor that maintains clock periodicity. CRY1 robustly suppresses hepatic gluconeogenesis by regulating CREB/cAMP and glucocorticoid receptor signaling and by reducing levels of FoxO1—a transcription factor that drives gluconeogenesis. Autophagy degrades cytoplasmic contents in lysosomes for maintenance of quality control and provision of energy. Since the liver clock and autophagy are each regulated by insulin and glucagon, we hypothesized that the control of autophagy, the circadian clock, and glucose homeostasis are interlinked. We have shown that induction of circadian autophagy between 3pm-7pm degrades CRY1, which releases its inhibition of gluconeogenesis and promotes glucose production. Acutely blocking autophagy or inactivating the LC3-Interacting-Region (LIR) motifs of CRY1, which allow it to interact with the autophagy marker LC3, led to accumulation of CRY1 and suppression of gluconeogenesis. Thus, autophagy drives glucose production in liver by timed degradation of CRY1. Interestingly, high-fat feeding accelerates the autophagic degradation of CRY1, which contributes to obesity-associated hyperglycemia. Since phosphorylation of CRY1 triggers its proteasomal degradation, and since phosphorylation in the vicinity of LIRs is thought to facilitate interaction with LC3, we hypothesized that phosphorylation of CRY1 leads to its degradation through autophagy and increases glucose production. Accordingly, we generated specific phosphorylation-resistant and constitutively-phosphorylated CRY1 mutants that were delivered to the liver. While the phosphorylation-resistant CRY1 mutant accumulated in liver and lowered blood glucose levels, the constitutively-phosphorylated CRY1 mutation that favors its rapid degradation resulted in increased blood glucose. Our results show that CRY1 phosphorylation couples its turnover by autophagy to regulation of gluconeogenesis—revealing novel targets to prevent obesity-associated hyperglycemia.
M. Toledo Soler: None. R. Singh: None.
American Diabetes Association (1-18-IBS-062 to R.S.)