Mechanism and maladies of the circadian clock synchronization in human and mammals

Abstract

Most eukaryotes exhibit diurnal rhythms in their metabolism, growth, and cell cycle control to accommodate the 24-hour light-dark cycles on earth surface. Circadian rhythm is not a passive response to the exposure of sunlight, but driven by an internal, automated clock system, i.e. the circadian clock. The circadian clock is comprised of multiple feedback loops on the levels of metabolism, transcription, translation, and post-translational modification. Just like any clock, the circadian clock can be reset, i.e. entrained, by multiple environmental/external factors, including light, temperature, and diet. As human bodies and many other organisms are comprised of millions and billions of cells, and not all of them have the build-in capacity to directly sense environmental factors, a hierarchical system is needed to ensure the harmony of circadian clocks throughout the body. On top of the hierarchy is the suprachiasmatic nucleus (SCN). SCN is comprised of ~20000 of neurons that can receive light inputs from the retina and commands the circadian clocks throughout the body via direct and indirect neuronal outputs and hormonal signaling. Second in the hierarchy is the adrenal gland, which receives SCN input through the hypothalamus-pituitary-adrenal gland axis. Adrenal gland secrets glucocorticoids in a diurnal manner to regulate brain function, blood flow and periphery tissue metabolism. As a complement to the neuronal-hormonal hierarchy, metabolic tissues like liver and the intestine also have the capability to sense the dietary input and reset their own circadian clock as well as other organs through oscillations of metabolites and other factors. The circadian system represents one of the most elegant machinery ever evolved. However, due to the rapid changes of our life style, trans-meridian traveling, work-shift and aging, the synchronization of circadian clocks is often disrupted, which may lead to the development of depression and many forms of chronic diseases including diabetes and Alzheimer disease. Therefore, further research into the field of circadian clock resetting and synchronization, and how they are connected to physiology and disease are of great importance both in basic science and translational medicine.