title: Circadian metabolic regulation through crosstalk between casein kinase 1δ and transcriptional coactivator PGC-1α.
abstract: 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 γ coactivator 1α (PGC-1α), coordinates circadian metabolic rhythms through simultaneous regulation of metabolic and clock gene expression. In this study, we found that PGC-1α physically interacts with, and is phosphorylated by, casein kinase 1δ (CK1δ), a core component of the circadian pacemaker. CK1δ represses the transcriptional function of PGC-1α in cultured hepatocytes, resulting in decreased gluconeogenic gene expression and glucose secretion. At the molecular level, CK1δ phosphorylation of PGC-1α 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.
authors: Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors: Siming
authors: S
authors: Li
authors: Xiao-Wei
authors: XW
authors: Chen
authors: Lei
authors: L
authors: Yu
authors: Alan R
authors: AR
authors: Saltiel
authors: Jiandie D
authors: JD
authors: Lin
mesh_terms: D048148:Casein Kinase Idelta / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D034622:RNA Interference; D020239:Receptor Cross-Talk; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D048148:Casein Kinase Idelta; D046988:Proteasome Endopeptidase Complex; D005947:Glucose