Circadian integration of metabolism and energetics

Abstract

Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.

Figure 1. Central and peripheral clocks coordinate external cues with behavior and metabolic outputs

Light entrains the master pacemaker in the suprachiasmatic nucleus (SCN), which in turn synchronizes extra-SCN and peripheral clocks. Brain clock outputs include behavioral rhythms (i.e., sleep, feeding), while peripheral clock outputs include metabolic rhythms (i.e., glucose and lipid homeostasis, etc). The hierarchical organization of the mammalian clock is highlighted, with “non-autonomous” regulation of peripheral tissue clocks denoting the regulation of peripheral tissue oscillators through direct neural and humoral signals, and “autonomous” regulation indicating the intrinsic regulation of local cellular oscillators independently of the brain clock. Highlighted to the right are the three possible ways to disrupt the clock, by changing either period, phase, or amplitude, each of which can trigger disorders of metabolism. Phase resetting can be broadly classified into two groups based upon phase response following delivery of the agent at sequential time points across the 24 hr cycle. Type 1 resetting indicates that the slope of the plot relating the new to old circadian phase is 1 (interventions that cause different phase shifts at different circadian times). Type 0 resetting indicates that the slope of the new to old circadian phase is 0 (i.e., interventions that cause the same phase at all circadian times). Abbreviations: PVN, paraventricular nucleus; PIT, pituitary; ARC, arcuate nucleus; LHA, lateral hypothalamic area.

Figure 2. Direct and indirect outputs of the core clock mechanism

The core clock consists of a series of transcription/translation feedback loops that synchronize diverse metabolic processes through both direct and indirect outputs including gluconeogenesis and oxidative metabolism (see text for details). The clock also receives reciprocal input from nutrient signaling pathways (including SIRT1 and AMPK), which function as rheostats to couple circadian cycles to metabolic flux especially in peripheral tissues.

Figure 3. The clock partitions behavioral and metabolic processes according to time of day

The clock coordinates appropriate metabolic responses within peripheral tissues with the light-dark cycle. For example, the liver clock promotes gluconeogenesis and glycogenolysis during the sleep/fasting period, while it promotes glycogen and cholesterol synthesis during the wake/feeding period. Proper functioning of peripheral clocks keeps metabolic processes in sync with the environment, which is critical for maintaining health of the organism. Different tissues exhibit distinct clock-controlled properties thus ablation of the clock in certain tissues will cause opposing effects on metabolic function as uncovered through dynamic challenges at different times in the cycle under different nutrient conditions. Aging, diet, and environmental disruption such as shift-work may also impact the integration of circadian and metabolic systems.