Circadian Metabolic Regulation through Crosstalk between Casein Kinase 1δ and Transcriptional Coactivator PGC-1α

Circadian clock coordinates behavior and physiology in mammals in response to light and feeding cycles. Disruption of normal clock function is associated with increased risk for cardiovascular and metabolic diseases, underscoring the emerging concept that temporal regulation of tissue metabolism is a fundamental aspect of energy homeostasis. We have previously demonstrated that transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), coordinates circadian metabolic rhythms through simultaneous regulation of metabolic and clock gene expression. In this study, we found that PGC-1 alpha physically interacts with, and is phosphorylated by, casein kinase 1 alpha (CK1 delta), a core component of the circadian pacemaker. CK1 delta represses the transcriptional function of PGC-1 alpha in cultured hepatocytes, resulting in decreased gluconeogenic gene expression and glucose secretion. At the molecular level, CK1 delta phosphorylation of PGC-1 alpha within its arginine/serine-rich domain enhances its degradation through the proteasome system. Together, these results elucidate a novel mechanism through which circadian pacemaker transduces timing signals to the metabolic regulatory network that controls hepatic energy metabolism. (Molecular Endocrinology 25:2084-2093, 2011)