Circadian rhythms, sleep, and metabolism

Abstract

The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.

Figure 1. Circadian control of energy metabolism.

(A) In plants, cyanobacteria, and fungi, energy is available during the light period within the light/dark cycle, while in metazoa, alternating periods of sleep and wakefulness, closely associated with the light/dark cycle, impart cyclicity on feeding behavior and fuel utilization. (B) The master clock in the SCN sends signals to the extra-SCN regions, which in turn entrain peripheral tissues via hormonal, autonomic nervous system (ANS), and behavioral pathways in order to regulate peripheral clock control of fuel utilization and energy harvesting. Extra-SCN regions also regulate energy homeostasis by controlling cyclic energy intake and locomotor activity. Through regulation of food intake, physical activity, and metabolic processes, both brain and peripheral clocks contribute to long-term weight stability by maintaining a precise balance between energy intake and energy expenditure. A positive energy balance deposits stored energy mostly into adipose tissue, leading to obesity, while a negative energy balance results in leanness. BMR, basal metabolic rate.

Figure 2. Map of neural circuits linking SCN and extra-SCN regions important in circadian and energetic control.

CNS centers receive dual input of light and metabolic signals. Light reaches the SCN via the RHT, which in turn sends neural projections to various extra-SCN regions in the hypothalamus and brainstem that are critical for energy homeostasis and sleep, including the ARC, PVN, and ventrolateral preoptic nucleus (VLPO). The hypothalamus also receives metabolic inputs, including peptidergic hormones and nutrient metabolites, which modulate the CNS signaling. Thus signals from the exogenous environment (i.e., light) and endogenous metabolism (i.e., metabolic cues) are integrated in the CNS, the output of which in turn imparts rhythmicity on sleep and a variety of metabolic outputs, such as thermogenesis, feeding behavior, hormone secretion, and locomotor activity. IML, intermediolateral nucleus; NTS, nucleus tractus solitarius. dSPZ, dorsal subparaventricular zone; RHT, retinohypothalamic tract; vSPZ, ventral subparaventricular zone; MCH, melanocyte concentrating hormone.

Figure 3. Interactions between the molecular clock and downstream metabolic genes.

The core molecular clock consists of several transcription/translation feedback loops, including posttranscriptional regulation (yellow), that oscillate with an approximately 24-hour periodicity. CLOCK and BMAL1 heterodimerize to drive rhythmic expression of downstream target genes (shown in red), which in turn regulate diverse metabolic processes, including glucose metabolism, lipid homeostasis, and thermogenesis. Many of these clock target genes in turn reciprocally regulate the clock in response to changes in nutrient status (shown in blue) via cellular nutrient sensors (shown in orange), generating a complex network of interlocking feedback loops that fine-tune the clock and coordinate metabolic processes with the daily cycles of sleep/wakefulness and fasting/feeding. Dashed lines represent metabolic inputs; solid lines depict interactions among core clock genes, clock-controlled genes, and nutrient sensors.