Zhang G, Cai D. Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment. Am J Physiol Endocrinol Metab 301: E1004 -E1012, 2011. First published August 9, 2011; doi:10.1152/ajpendo.00196.2011.-The obesity pandemic can be viewed as a result of an imbalanced reaction to changing environmental factors. Recent research has linked circadian arrhythmicity to obesity and related diseases; however, the underlying mechanisms are still unclear. In this study, we found that high-fat diet (HFD) feeding strikingly promoted daytime rather than nighttime caloric intake in mice, leading to feeding circadian arrhythmicity. Using scheduled feeding with a defined amount of daily HFD intake, we found that an increase in the ratio of daytime to nighttime feeding promoted weight gain, whereas a decrease of this ratio rebalanced energy expenditure to counteract obesity. In identifying the underlying mechanism, we found that hypothalamic release of anorexigenic neuropeptide oxytocin displayed a diurnal rhythm of daytime rise and nighttime decline, which negatively correlated with the diurnal feeding activities of normal chow-fed mice. In contrast, chronic HFD feeding abrogated oxytocin diurnal rhythmicity, primarily by suppressing daytime oxytocin rise. Using pharmacological experiments with hypothalamic injection of oxytocin or oxytocin antagonist, we showed that daytime manipulation of oxytocin can change feeding circadian patterns to reprogram energy expenditure, leading to attenuation or induction of obesity independently of 24-h caloric intake. Also importantly, we found that peripheral injection of oxytocin activated hypothalamic oxytocin neurons to release oxytocin, and exerted metabolic effects similar to central oxytocin injection, thus offering a practical clinical avenue to use oxytocin in obesity control. In conclusion, resting-stage oxytocin release and feeding activity represent a critical circadian mechanism and therapeutic target for obesity.oxytocin; obesity; feeding; circadian OBESITY IS AN OUTCOME OF IMBALANCED interactions between environmental factors and the body's metabolic regulation (13,38). Recent research has established that the hypothalamus in the brain plays an essential role in the regulation of appetite and body weight balance (9,17,37,44,57). The underlying molecular basis involves hormone-dependent and nutrientdependent pathways in the mediobasal hypothalamus (1,3,4,9,12,17,25,29,37,44). In addition to metabolic regulation, the hypothalamus governs the circadian rhythms of various physiological activities, primarily dictated by the circadian pacemaker in the hypothalamic suprachiasmatic nucleus (14,40,51,52). The circadian pace in this hypothalamic region is predominantly exerted by the Clock-directed transcriptiontranslation oscillation loop (16,20,52), which can synchronize the physiological activities of various organs, including peripheral metabolic tissues (2, 53, 54). A recent study revealed that knockout of the Clock gene led to the prominent met...