Interorgan rhythmicity as a feature of healthful metabolism

Abstract

The finding that animals with circadian gene mutations exhibit diet-induced obesity and metabolic syndrome with hypoinsulinemia revealed a distinct role for the clock in the brain and peripheral tissues. Obesogenic diets disrupt rhythmic sleep/wake patterns, feeding behavior, and transcriptional networks, showing that metabolic signals reciprocally control the clock. Providing access to high-fat diet only during the sleep phase (light period) in mice accelerates weight gain, whereas isocaloric time-restricted feeding during the active period enhances energy expenditure due to circadian induction of adipose thermogenesis. This perspective focuses on advances and unanswered questions in understanding the interorgan circadian control of healthful metabolism.

Keywords: circadian; diabetes; epigenetics; insulin; metabolism; molecular clock; obesity; sleep; thermogenesis; transcription.

Figure 1:. Interorgan Synchrony in 24/7 Metabolism. Top panel:

Circadian clocks are encoded by an autoregulatory transcription feedback loop present in the brain and peripheral tissues that acts as an integrator of environmental signals to align physiological systems in anticipation of the daily rising of the sun. The clock system is organized hierarchically in animals with signals from light received through melanopsin neurons of the retina that project to pacemaker neurons anterior to the optic chiasm in the suprachiasmatic nucleus. Pacemaker neurons entrain circadian transcriptional oscillators within both extra-pacemaker cells in the brain and most peripheral tissues through a combination of direct neural and indirect humoral signals. Bottom panel: Within peripheral tissues, genetic analyses show that cell autonomous clocks govern a wide range of physiological processes to maintain homeostasis and drive catabolic and anabolic phases of metabolism in anticipation of the feeding/fasting-sleep/wake cycle.

Figure 2:. Tissue-specific mechanisms in time-restricted feeding.

High-fat diet causes animals to extend their feeding time into the light period when they are normally asleep, whereas dark-only time-restricted feeding reduces weight gain and averts development of metabolic syndrome in response to high-fat diet. Providing animals high-fat diet only during the dark period results in increased energy expenditure through creatine-induced thermogenesis in brown adipose tissue, in parallel with increased glucose and lipid tolerance, increased creatine cycling, and reduced weight gain. Design of experiments that control diet, temperature, and timing will enable analysis of unanswered questions such as: How do central and peripheral clocks coordinate rhythmic response to obesogenic diet? How does the response to undernutrition differ from circadian response to overnutrition at the molecular level? How does time-restricted feeding determine transcriptional identity of cell types within multicellular tissues?

Figure 3:. Molecular mechanisms underlying interorgan circadian homeostasis:

Top panel: Forward genetics identified the core molecular clock as an autoregulatory transcription feedback loop involving activators in the forward limb (CLOCK/BMAL1) that induced transcriptional repressors within the negative limb (PERs/CRYs) and a second stabilizing loop involving REV-ERB/ROR that controls BMAL1 oscillation. Repressors in the negative limb form a large oligomeric complex following nuclear translocation involving tissue-specific recruitment of corepressors. Middle panel: Activation of both core repressors and downstream oscillating genes occurs within specific windows of time when these factors bind to DNA within tissue-specific regions of chromatin accessibility. Both lineage-determining transcription factors (LDTFs) and core clock factors influence chromatin accessibility at specific times of day, and rhythmic transcription cycles are also dynamically controlled through collaboration with signal-dependent transcription factors (SDTFs). Environmental conditions feedback to modulate clock cycles in part via the regulation of the phosphorylation and proteasomal degradation of the repressor components as indicated. Bottom panel: Application of unbiased transcriptomic approaches (as depicted), together with proteomic and metabolomic approaches (not illustrated), can be combined with conditional genetic and cell based circadian models to dissect the mechanisms underlying interorgan physiology.