Clock遺伝子と肥満
詳細
Recent studies of clock genes have revealed that an autoregulatory transcriptional feedback loop forms the core circadian rhythm generating mechanism in mammals. Clock is the first clock gene identified in vertebrates by forward mutagenesis using N-ethyl-N-nitrosourea in a behavioral screening, and encodes a basic helix-loop-helix (bHLH)-PAS transcription factor. Previously, we identified putative CLOCK target genes in the mouse liver using microarray analyses and found that in addition to being a core component of the circadian oscillator, CLOCK is involved in various physiological functions. We show here that serum levels of triglyceride and free fatty acid were significantly lower in circadian Clock mutant ICR than in wild-type control mice, whereas total cholesterol and glucose levels did not differ. Moreover, an increase in body weight induced by a high-fat diet was attenuated in homozygous Clock mutant mice. We also found that dietary fat absorption was extremely impaired in Clock mutant mice. Circadian expressions of cholecystokinin-A (CCK-A) receptor and lipase mRNAs were damped in the pancreas of Clock mutant mice. We therefore showed that a Clock mutation attenuates obesity induced by a high-fat diet in mice with an ICR background through impaired dietary fat absorption. I will also talk about our recent findings that CLOCK is involved in the diabetes- and obesity-induced cardiovascular diseases by increasing the expression of plasminogen activator inhibitor-1 (PAI-1). [J Physiol Sci. 2006;56 Suppl:S16]
