Clock genes and metabolic disease

Abstract

The circadian system is a key integrator of behavior and metabolism that synchronizes physiological processes with the rotation of the Earth on its axis. In mammals, the clock is present not only within the central pacemaker neurons of the hypothalamus, but also within extra-suprachiasmatic nucleus (SCN) regions of brain and nearly all peripheral tissues. Recent evidence suggests that the complex feedback networks that encompass both the circadian and metabolic systems are intimately intertwined and that disruption of either system leads to reciprocal disturbances in the other. We anticipate that improved understanding of the interconnections between the circadian and metabolic networks will open new windows on the treatment of sleep and metabolic disorders, including diabetes mellitus and obesity.

Fig. 1.

Core circadian clock network. The core molecular clock machinery is encoded by interlocking transcription-translation feedback loop that oscillates with a 24-h periodicity. The core mammalian clock comprises transcription factors CLOCK and BMAL1, which heterodimerize to drive the transcription of downstream target genes containing E-box enhancer elements. Among these, the period (PER) and cryptochrome (CRY) proteins then multimerize and inhibit the action of the CLOCK:BMAL1 complex, resulting in a rhythmic oscillation of the core clock genes and many of their downstream targets. In addition, the CLOCK:BMAL1 heterodimer also drives the transcription of metabolic target genes in the central nervous system (CNS) and in the peripheral tissues. CKIε/δ, casein kinase I-epsilon and -delta; ROR, retinoid-related orphan receptors; RORE, ROR-binding element; PPARα, peroxisome proliferator-activated receptor-α; SCF, Skp/Cullin/F-box.

Fig. 2.

Negative-feedback loop linking NAD⁺/SIRT1 with the Clock network. NAMPT, the rate-limiting enzyme in NAD biosynthesis, oscillates in a circadian pattern under the transcriptional control of the CLOCK:BMAL1 heterodimer. Alterations in NAMPT drive oscillation in NAD biosynthesis, which in turn modulates the nutrient responsive deacetylase SIRT1. SIRT1 plays an important role in energy homeostasis and has recently been discovered to function in the control of the circadian clock. SIRT1 activity, dependent on the metabolic state of the cell, inhibits CLOCK:BMAL1 activity and prevents the transcription of both circadian and metabolic downstream target genes. The CLOCK:BMAL1-NAMPT-SIRT1 pathway comprises a novel metabolic feedback that may integrate the daily cycles of activity, feeding, and energy homeostasis. Ac, acetyl.