Epigenetic control and the circadian clock: linking metabolism to neuronal responses

Abstract

Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape.

Keywords: SIRT1; clock; epigenetic mechanism; metabolism; nutrients; social zeitgebers.

Figure 1. The SCN interacts with several brain areas

A) Representative schema depicting the efferent and afferent signaling to the suprachiasmatic nucleus (SCN) from different brain regions. These include limbic structures such as infralimbic cortex (LC), lateral septal nucleus (LSN), basal forebrain of the stria terminalis (BST), ventral subiculum (VS), paraventricular thalamic nuclei (PVT), accumbens nucleus (NA), dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and hypothalamic nuclei such as ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), paraventricular hypothalamus (PVN), and the retino-hypothalamic tract (RHT). B) Schema representing the possible link between the hypothalamic clocks and the metabolic sensors influencing the clock in peripheral tissues (See also Table 1).

Figure 2. The NAD⁺ salvage pathway is controlled by the circadian clock

The biosynthesis of NAD⁺ follows a circadian pattern, which is caused by the circadian expression of NAMPT, a rate-limiting enzyme in the NAD⁺ biosynthetic salvage pathway. The Nampt gene contains E-boxes in its promoter, leading to direct transcriptional control by the dimer CLOCK:BMAL1. The fluctuating levels of NAD⁺ modulate the activity of SIRT1 which in turn regulates the transcriptional activity of CLOCK:BMAL on their targets genes.

Figure 3. Social environment acting as zeitgeber

The central nervous system receives time cues through different pathways. The central clock residing in the suprachiasmatic nucleus (SCN) directly receives light inputs through the retino-hypothalamic tract (RHT). The food entrainable oscillators (FEOs) localized in different areas in the brain receive metabolic and non-metabolic signals. Further signals might modulate the endogenous clock through cortico-limbic structures which are sensible to socio-enviromental factors. These stressors in turn might alter the endogenous clock generating a plethora of circadian-related diseases.