A wheel of time: the circadian clock, nuclear receptors, and physiology

Light from the sun sustains life on earth. The 24-h rotation of the earth exposes a vast number of plants and animals to the light/dark cycle. Consequently, the behavior and physiology of numerous living organisms exhibit circadian rhythms. The word “circadian” is derived from Latin circa diem, which means “about a day.” Behavioral rhythms such as sleeping, food seeking, and predator avoidance are thought to help animals survive. Physiological rhythms such as body temperature, blood pressure, and metabolism also anticipate and adapt to predictable changes in the environment to maintain the overall well-being of animals (Young 2000). Circadian rhythms are controlled by evolutionarily conserved internal clocks residing in most tissues of the body. The central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is entrained directly by light (Hatings et al. 2008). This master pacemaker can synchronize circadian oscillators in peripheral tissues, yet underlying neural and humoral mechanisms remain obscure. Besides light, other external cues such as feeding and ambient temperature are also powerful Zeitgebers (from German for time givers) for peripheral clocks (Damiola et al. 2000; Brown et al. 2002). How these time cues act in concert to entrain tissue-specific oscillators and evoke diverse physiological responses is poorly understood. Nevertheless, these processes clearly involve the endocrine system. The rhythmic production and circulation of many hormones and metabolites within the endocrine system is instrumental in regulating regular physiological processes such as reproduction, blood pressure, and metabolism. Levels of circulating estrogen and progesterone fluctuate with the menstrual cycle, which in turn affect circadian rhythms in women (Shechter and Boivin 2010). In parallel with a diurnal rhythm in circulating adrenocorticotropic hormone, secretion of glucocorticoids and aldosterone from the adrenal gland rises before awakening (Weitzman 1976). Glucocorticoids boost energy production, and aldosterone increases blood pressure, together gearing up the body for the activity phase. Similarly, plasma levels of thyroid-stimulating hormone and triiodothyronine have a synchronous diurnal rhythm (Russell et al. 2008). A broad range of metabolites—such as glucose, free fatty acids, cholesterol, and bile acids—also exhibit diurnal fluctuation. A number of these hormones and metabolites serve as ligands for nuclear receptors that direct a large array of transcriptional programs involved in lipid and carbohydrate metabolism (Chawla et al. 2001). A survey of the diurnal expression profile of the mRNAs encoding all 49 mouse nuclear receptors revealed that more than half of receptors follow rhythmic cycles in key metabolic tissues (Yang et al. 2006). Together, these observations suggest a complex interaction between the circadian clock and nuclear receptor signaling (Yang et al. 2007; Teboul et al. 2008). Several recent studies lend further insight into an elaborate “wheel of time” composed of molecular clocks and nuclear receptors, which together help shape an emerging perspective on “design principles” and biological implications of the clock–receptor signaling network.