The circadian clock and metabolic homeostasis: entangled networks

Abstract

The circadian clock exerts an important role in systemic homeostasis as it acts a keeper of time for the organism. The synchrony between the daily challenges imposed by the environment needs to be aligned with biological processes and with the internal circadian clock. In this review, it is provided an in-depth view of the molecular functioning of the circadian molecular clock, how this system is organized, and how central and peripheral clocks communicate with each other. In this sense, we provide an overview of the neuro-hormonal factors controlled by the central clock and how they affect peripheral tissues. We also evaluate signals released by peripheral organs and their effects in the central clock and other brain areas. Additionally, we evaluate a possible communication between peripheral tissues as a novel layer of circadian organization by reviewing recent studies in the literature. In the last section, we analyze how the circadian clock can modulate intracellular and tissue-dependent processes of metabolic organs. Taken altogether, the goal of this review is to provide a systemic and integrative view of the molecular clock function and organization with an emphasis in metabolic tissues.

Keywords: Circadian rhythms; Clock genes; Energy metabolism; SCN; Tissue clocks.

Fig. 1

The molecular mechanism of the circadian clock in mammals. Every 24 h, a complex machinery comprised of genes and proteins undergoes changes in mRNA and protein levels through interlocked transcriptional-translational feedback loops (TTFLs). The reader is referred to the text for a detailed description of this mechanism. Abbreviation of the genes: Per = Period; Cry = Cryptochrome; Clock = Circadian Locomotor Output Cycles Kaput; Bmal1 = Brain and Muscle ARNT-Like 1; CKδ = Casein Kinase 1δ; CK1ε = Casein Kinase 1ε; Nfil3 = Nuclear Factor, Interleukin‑3 Regulated; Rev-erbα/β = Nuclear Receptor Subfamily 1 group D Member 1 and 2; Rorα/β = Nuclear Receptor Subfamily 1 Group F Member 1/2; Dbp = Albumin D‑site Binding Protein

Fig. 2

Current model of circadian network organization in mammals. The suprachiasmatic nucleus (SCN) is regulated by environmental light that is sensed by OPN4 in ganglion cells of the retina. Light information is transformed into electrical stimuli that reach the SCN. Upon SCN synchronization, the organism uses redundant temporal timing cues such as temperature, hormones, and autonomic nervous input to ensure systemic synchronization of biological processes across organs. In addition, behavior can be modulated by a direct effect of environmental light, the SCN, or by food availability which, in turn, can directly affect the molecular clocks of peripheral organs

Fig. 3

Bidirectional communication between central and peripheral tissue clocks. Temporal cues controlled by the central pacemaker (SCN) and other CNS clocks such as glucocorticoid and melatonin secretion, autonomic inputs, and body temperature are known to affect the molecular clocks in peripheral organs. At the same time, peripheral clocks, through molecules like leptin, ghrelin, FGF21, and adiponectin can feed back on the SCN and other brain region clocks. The overall result of this entangled communication network is an integrated rhythmic control of behavior and metabolic outputs. In this figure, it is didactically represented the phase (day or night) in which each factor has its highest value in humans

Fig. 4

The classic cellular information flow from DNA to RNA and to protein is subject to circadian control at all levels. This rhythmic biological information flow contributes to the circadian control of cellular physiology and downstream biological processes. Among these, we highlight DNA repair, oxidative stress, and cell cycle regulation

Fig. 5

Overview of the main clock regulated biological processes of energy metabolic tissues. Each organ is represented in the figure with major clock-dependent biological functions