The meter of metabolism

Abstract

The circadian system orchestrates the temporal organization of many aspects of physiology, including metabolism, in synchrony with the 24 hr rotation of the Earth. Like the metabolic system, the circadian system is a complex feedback network that involves interactions between the central nervous system and peripheral tissues. Emerging evidence suggests that circadian regulation is intimately linked to metabolic homeostasis and that dysregulation of circadian rhythms can contribute to disease. Conversely, metabolic signals also feed back into the circadian system, modulating circadian gene expression and behavior. Here, we review the relationship between the circadian and metabolic systems and the implications for cardiovascular disease, obesity, and diabetes.

Figure 1. The sleep/wake and fasting/feeding cycles

Genetic and molecular evidence suggest that within both the central nervous system (CNS) and peripheral tissues, co-regulation of the daily alteration between the sleep/wake and fasting/feeding cycles reflects coupling of both behavioral and metabolic pathways. Because the availability of food and the risk of predators are tied to the environmental cycle of light and darkness, these interlinked cycles may have provided selective advantages. Although this review focuses primarily on the interdependence of circadian and metabolic systems, it is important to note that the circadian system also impacts sleep, the restriction of which is sufficient to lead to abnormalities in metabolic homeostasis.

Figure 2. Building blocks of the molecular clock

The discovery of the core components of the circadian clock was first revealed through forward genetics showing that the clock is encoded by a transcription-translation feedback loop that oscillates with a periodicity of 24 hr in pacemaker neurons and peripheral cells. Subsequent analyses have identified robust outputs of the clock on metabolic pathways in liver, fat and muscle, suggesting convergence of circadian and metabolic pathways at the transcriptional level. The core mammalian clock is comprised of the heterodimeric activators CLOCK and BMAL1 that activate transcription of the genes encoding the repressors PERIOD (PER) and CRYPTOCHROME (CRY). An interlocked regulatory loop directs alternating activation and repression of BMAL1 expression by the nuclear receptors RORα and REV-ERBα, respectively, via binding at the ROR enhancer elements (ROREs) in the BMAL1 promoter. Several other metabolically active nuclear receptors have been identified as modulators of BMAL and CLOCK, including PPARγ and PGC1α. DBP, Albumin D-binding protein; TEF, thyrotroph embryonic factor; HLF, hepatocyte leukemia factor; HSF-1, heat shock factor 1.

Figure 3. Central pacemaker and peripheral clocks

The master pacemaker encoding the mammalian clock resides within the suprachiasmatic nucleus (SCN), although clock genes are also expressed in other regions of the brain and in most peripheral tissues. Emerging evidence suggests that peripheral tissue clocks are synchronized through humoral, nutrient, and autonomic wiring, and that the cell autonomous function of the clock is important in pathways involved in fuel storage and consumption. A hierarchical model indicates that all peripheral clocks are subordinate to the SCN. However, more recent work suggests that peripheral clocks play a broader role than previously realized in health and disease.

Figure 4. External cues and clock outputs

The predominant external cue (zeitgeber) of the SCN clock is light. Clocks in peripheral tissues such as the liver also can be entrained by food. Nutrient and hormonal cues may also affect the period and phase characteristics of the master clock neurons, although little is known about how metabolic signals are communicated to the SCN. Outputs of both the SCN and peripheral clocks impact behavioral and metabolic responses such as feeding, sleep-wakefulness, hormone secretion, and metabolic homeostasis.

Figure 5. Neural pathways linking circadian and metabolic systems

Neuroanatomical studies have implicated several nodal points that may connect circadian, sleep, and metabolic centers within the brain. External cues such as light are transmitted from the eyes via the retinohypothalamic tract to the SCN. Projections from the suprachiasmatic nucleus (SCN) extend toward the subparaventricular zone (SPZ) and from the SPZ to the dorsomedial hypothalamus (DMH). Clock gene expression has been identified in DMH neurons, and the DMH has emerged as an important site in the activity response to food (the food entrainable oscillator). The DMH has many outputs to other regions of the brain, including the lateral hypothalamus (LHA), which controls circadian regulation of the sleep/wakefulness and fasting/feeding cycles. (Inset) The LHA also receives neuroendocrine input from the arcuate (ARC) neurons producing anorexigenic and orexigenic neuropeptides .The hormone leptin produced by adipose tissue activates the production of anorexigenic neuropeptides such as αMSH/CART, which in turn blocks production of the orexigenic peptides orexin (ORX) and melanin concentrating hormone (MCH) in the LHA. In the absence of leptin, orexigenic neurons in the ARC produce the neuropeptide NPY/AgRP that stimulates hunger and decreased energy expenditure via signaling to the LHA.

Figure 6. Circadian synchrony and metabolic disease

Many aspects of metabolic physiology are known to occur at specific times each day. Gene expression patterns corresponding to periods of energy storage and energy utilization have been tied to the function of the peripheral clock in the liver and are shown as outputs of the clock (the cycle of energy storage and utilization). Many disorders such as myocardial infarction peak at certain times during a 24 hr day, suggesting a potential link between disruption of circadian rhythms and disease pathology. Emerging evidence suggests that disruption of synchrony between periods of rest/activity with feeding/fasting and energy storage/utilization may be tied to dysregulation of not only body weight but also diverse metabolic processes such as glucose metabolism, vascular reactivity, thrombosis, and lipid homeostasis.