Obeying the clock yields benefits for metabolism.

W hile we can’t choose our parents, we certainly can choose our friends. And just as we choose our friends, it is also a rite of passage that we break the rules that our parents set, even those that provide healthful benefits. In fact, one of the most common patterns to change with entry into adulthood is the adherence to a ‘‘normal’’ bedtime and disruption in the alignment between periods of activity and sleep with the natural day–night cycle. Indeed, the clock that we learn to disobey is an internal genetically programmed timepiece with near 24-h precision that originally evolved to enable the earliest forms of life on Earth to accurately anticipate the rising and setting of the sun. Importantly, there may even have been a survival benefit to this clock because, at least in plants, misalignment of endogenous period length of the clock with the environmental light cycle reduces survival and diminishes reproduction (1). Interestingly, it has recently been suspected that alignment between behavioral cycles and the light–dark cycle may also provide health benefits to humans, since at clinical and epidemiological levels, a strong correlation has emerged between chronic sleep and circadian disruption and metabolic disease (2). Timing also plays an important role in certain cardiovascular catastrophes and in both hypoand hyperglycemic crises. Further, the availability of genetically altered animals with mutations in the genes encoding the core molecular clock has supported the idea that clocks are especially important in the regulation of feeding and body weight, in addition to glucose and lipid homeostasis (3–5). Now, with a new report in this issue of PNAS, Scheer et al. (6) provide evidence to support the hypothesis that circadian systems are important to metabolic health not just in mice but also in humans. It is now well established that 24-h recurring patterns of behavior and physiology are controlled at the molecular level by a transcription–translation feedback loop that is expressed within both the master pacemaker neurons of the brain, located in the suprachiasmatic nucleus (SCN), and also within nearly all peripheral tissues. Although the core components of the clock have emerged over the past 20 years from forward genetic analyses in flies, plants, and mice (7), positional cloning of monogenic circadian disorders in families with the familial advanced sleep phase disorder has proven that conserved clock genes also function to control periodic behavior in humans (8). Moreover, intriguing work in human fibroblasts has shown that, like cell explants from mice, the clock in humans functions as a self-sustained oscillator when maintained in culture (out of the body) and remarkably exhibits a period length that matches each individual’s subjective chronotype (e.g., ‘‘lark’’ versus ‘‘owl’’) (9). As noted above, experimental models in mice have further revealed that a major output of the molecular clock involves the control of neuroendocrine systems involving both brain and peripheral tissues, raising the possibility that alteration of the timing of behavioral cycles (such as the feeding cycle) with the endogenous circadian cycle may adversely affect human health. Although there are limitations to comparisons between mouse and humans, an ultimate goal is to establish the function of the clock across all species. To begin to do so, Scheer and colleagues (6) have applied a so-called ‘‘forced desynchrony’’ protocol in human subjects, in essence carefully rebelling against the internal clock, and then asking how internal desynchrony between the preset clock and the shifting behavioral cycle impacts systems involved in glucose and cardiometabolic physiology (Fig. 1). To achieve desynchrony, 10 subjects were admitted to the clinical research center and, over the ensuing 10 days, were subjected to progressive misalignment of behavioral and circadian cycles by extending their behavioral cycle to a 28-h day, under dim light, with 14 h of rest and fasting alternating with 14 h of wakefulness, interspersed with four evenly spaced and isocaloric meals. Simultaneously, the investigators monitored physiological endpoints including