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.

The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1–3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, and both Clock5,6 and Bmal17 mutants exhibit impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival, and synaptic vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger onset of diabetes mellitus.

The circadian clock is encoded by a transcription-translation feedback loop that synchronizes behavior and metabolism with the light-dark cycle. Here we report that both the rate-limiting enzyme in mammalian NAD+ biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+, display circadian oscillations which are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1.