Chronobiology and Obesity: The Orchestra Out of Tune

Marta Garaulet; Purificación Gómez-Abellán; Juan Antonio Madrid

Disclosures

Clin Lipidology. 2010;5(2):181-188. 

In This Article

The Orchestra Director: The Supraquiasmatic Nucleus

From microarrays studies, it is now accepted that 10–25% of total genes expressed, depending on the tissue, have significant changes in their expression levels during the course of the day.[9,10] This implies that most behavioral, physiological and biochemical variables display circadian rhythms in their expression. However, together with the existence of circadian rhythmicity, the importance of the maintenance of an adequate internal temporal order between different variables has been demonstrated. According to this, the peaks and troughs of every variable have to be finely tuned by the circadian system to maintain a healthy status, similar to in a musical orchestra when playing a classical tune (Figure 1).

Figure 1.

Organization of the circadian orchestra. The orchestra (circadian) director (suprachiasmatic nucleus) acts as a circadian pacemaker because each of its neurons have a molecular clock consisting of a feedback loop composed of positive (Clock and Bmal1) and negative (Per and Cry) elements. In addition, the circadian director receives light information directly from melanopsin-containing ganglion cells of the retina. This photic input modifies its pace to synchronize its activity with periodical environmental cues. The circadian director synchronizes the activity of orchestra instruments (peripheral clocks) through cyclically secreted hormones and the activity of the peripheral nervous system. Finally, the difference between the maintenance of a healthy internal temporal order and an unhealthy circadian status (chronodisruption) depends only if sounds (peaks) and silences (troughs) of each of the peripheral clocks are ordered accurately by the orchestra director.
GH: Growth hormone.

As with a symphony orchestra, the circadian orchestra is hierarchically organized, with the suprachiasmatic nucleus (SCN) of hypothalamus as its conductor. Its rhythm is generated by a transcriptional–translational feedback loop between two groups of clock genes: positive and negative elements. The circadian locomotor output cycles kaput (CLOCK) and the brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1), acting as positive elements, are responsible of the synthesis of two transcriptional factors, which after heterodimerization induce the expression of negative components of the molecular circadian clock such as periods (Pers 1, 2 and 3), cryptochromes (Cry1 and Cry2) and nuclear receptor subfamily 1 (REV-ERB-α). These negative elements, after dimerization (PER–CRY) undergo a nuclear translocation and act as suppressors of CLOCK and BMAL1 expression. Thus, the levels of positive and negative elements oscillate in antiphase with a period of approximately 24 h in SCN in vitro.

Some components of the molecular clock, such as REV-ERB-α, BMAL1 and CLOCK also induce a number of extra-clock genes, termed clock-controlled genes (CCG), which are not directly involved in the clock machinery but are able to induce the expression of many target genes.[7]

In 1972, this structure was discovered by two groups, Stephan and Zucker[11] and Moore and Erlich.[12] Each neuron of the SCN has a circadian molecular clock, which when isolated is able to maintain an approximate 24-h rhythmic activation in the firing rate of neurons for many days. In addition, some environmental cues with a period of nearly 24-h are able to synchronize the phase and period of SCN. Among them, the light–dark cycle is the main circadian synchronizer. Recently, the entrainment of the clock of blood cells in subjects undergoing a stimulated night-shift protocol with bright light treatment – known to efficiently reset the central clock – has been monitered.[13] Other external factors such as scheduled exercise and social contacts are also synchronizers.[14]

In the circadian orchestra, different circadian rhythms are the output of rhythmic activity of organs and physiological systems driven by the central pacemaker. Thus, for example, melatonin peaks during the night in response to nocturnal activation by SCN of the limiting enzyme AANAT (arylalkylamine N-acetyltransferase) in the pineal gland.[15] Cortisol peak should occur in the morning in response to suprarenal activation by ACTH (adrenocorticotropic hormone), which in turn, is under SCN control.[1,16] Body temperature has to increase during the daytime, peaking in the afternoon and so on with hundreds and hundreds of biological variables. In the symphonic orchestra, melatonin could be represented by the violins, cortisol by the drums and temperature by woodwind instruments.

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