The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.

The circadian clock programs daily rhythms and coordinates multiple behavioral and physiological processes, including activity, sleep, feeding, and fuel homeostasis. Recent studies indicate that genetic alteration in the core molecular clock machinery can have pronounced effects on both peripheral and central metabolic regulatory signals. Many metabolic systems also cycle and may in turn affect function of clock genes and circadian systems. However, little is known about how alterations in energy balance affect the clock. Here we show that a high-fat diet in mice leads to changes in the period of the locomotor activity rhythm and alterations in the expression and cycling of canonical circadian clock genes, nuclear receptors that regulate clock transcription factors, and clock-controlled genes involved in fuel utilization in the hypothalamus, liver, and adipose tissue. These results indicate that consumption of a high-calorie diet alters the function of the mammalian circadian clock.

In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are ''interacting epidemics.'' The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease. OverviewA major aspect of virtually all behavioral and physiological processes is daily variation mediated by the circadian timing system. Diurnal rhythms are generated by an internal biological clock that is synchronized to the 24-h day by environmental cues, primarily the light:dark cycle. When external timing signals are absent, the 24-h rhythms ''free run'' with a period close to 24 h, and are called ''circadian'' (about a day) rhythms. Many rhythms are overt and easy to recognize, such as the sleep-wake cycle, locomotor activity, and feeding behavior. The sleep-wake cycle is arguably the master output rhythm of the circadian clock, because the regulation of most behaviors and physiological activities depend on whether the organism is asleep or awake. A wide-range of less-easily observed rhythms occurs internally and includes the daily regulation of body temperature, adrenal corticosterone and pituitary hormone release, neuropeptide and neurotransmitter levels, sympathetic activation, energy metabolism (e.g., lipolysis, gluconeogenesis, insulin sensitivity, basal metabolic rate), as well as gene transcription. The evolution of a circadian system suggests that the ability of an organism to coordinate itself with the environment (external synchronization) and to maintain temporal organization of endogenous processes (internal synchronization) confers optimal health and survival potential. As we begin to unravel the many links between sleep, circadian rhythms, and metabolism, the survival benefits of temporal organization are beginning to emerge.The first mammalian circadian clock gene was discovered in 1997 by researchers at Northwestern University, and was given the name Clock (Circadian locomotor output cycles kaput), to represent the altered circadian phenotype in the Clock mutant mouse [1,2]. Since that time, there have been major advances in understanding the molecular basis of the circadian clock, including the discovery of many other circadian clock genes and the ongoing elucidation of transcriptional-translational feedback loops through which these clock genes interact [3]. Two important studies in the Clock mutant mouse provided evidence that circadian clock genes may be involved in more than just keeping time. First, it wa...