A Role Of Suprachiasmatic Nucleus In Response To Time-restricted Feeding

Circadian clocks regulate many physiological processes and drive widespread rhythmic gene expression in mammals.At the molecular level,circadian autoregulatory negative feedback loops drive endogenous rhythmic gene expression in almost all cells.Both light input and non-photic cues(such as restricted feeding and nutritional challenges)can also act as zeitgebers to reset and reprogram circadian rhythms of gene expression in peripheral tissues.The suprachiasmatic nucleus(SCN)in the hypothalamus is the master circadian pacemaker in mammals;it coordinates and synchronizes slave oscillators in peripheral tissues to drive rhythmic events such as physical activity,sleep,immune functions and body temperature cycles.The disruption of SCN function will abolish these rhythms.Thus,the coupling between the SCN and peripheral tissues achieves circadian rhythms at a whole-body level to allow mammals to better adapt to daily environmental cycles.The negative impact of such a coupling mechanism to mammalian physiology,however,is not known.Time-restricted feeding(TRF),which restricts food consumption to certain hours of the day,has been shown to have health benefits,including protection against obesity,hepatic steatosis,inflammation,and nutritional challenges,and has been shown to enhance circadian clock gene expression.TRF therefore has potential as a preventative or as a therapeutic approach against aging-related diseases and metabolic and cardiovascular disorders.The potential side effects of TRF,if any,have not been carefully investigated.In most mammals,body temperature oscillates daily within a narrow range that is governed by both homeostatic and circadian regulation.The maintenance of body temperature homeostasis is critical for animal survival.In humans and rodents,the hypothalamus acts as the temperature control center and works with other body temperature regulating systems,such as the muscle,skin,and blood vessels,to maintain the body temperature homeostasis so that body temperature at close to 37 ?.Within the hypothalamus,the dorsomedial hypothalamus(DMH)is an important region that regulates body temperatures.The DMH is also critical for mouse behavior and the expression of food-entrainable circadian rhythms.The SCN projects directly into the DMH and other hypothalamus regions and drives the daily oscillation of body temperature.The body temperature cycle serves as a mechanism that can synchronize circadian rhythms in peripheral tissues.How SCN functions as the master circadian pacemaker to maintain the homeostasis of body temperature is not clear.Here we show that TRF in mice can severely impair body temperature homeostasis and can result lethality.Nearly half of the mice died at 21 ?,and all mice died at 18 ? during TRF.This effect was modulated by the circadian clock and was caused by severe hypothermia due to loss of body temperature homeostasis.TRF reprograms circadian gene expression in the dorsomedial hypothalamus(DMH)and suppresses expression of genes involved in thermoregulation.Disrupting the circadian clock by SCN lesions altered gene expression and rescued survival during TRF.These results demonstrate an unexpected effect of TRF on body temperature control and the inhibitory function of SCN in body temperature homeostasis.