Circadian physiology of metabolism

Abstract

A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

Copyright © 2016, American Association for the Advancement of Science.

Figures

Fig. 1.. Schematics of cell-autonomous transcription-translation feedback loop (TTFL), constituting the core mechanism of mammalian circadian oscillator.

Some of the cellular metabolites and proteins that interact with the clock components are listed. Examples of circadian-regulated transcription factors or systemic factors with daily oscillations further propagate circadian timing to distant genomic and cellular targets.

Fig. 2.. Examples of circadian regulation of metabolic pathways and metabolic pathways affecting clock components.

Cis-acting DNA elements are in green, RNA in blue, proteins in orange; metabolites are shown in black letters, and tissues are underlined. Any RNA, protein, or metabolite (other than clock components) known to show daily rhythms are marked with ↻. Secreted or systemic factors are highlighted in yellow, and behavior or environment factors that can affect the clock are highlighted in gray. (A) Light and food intake can interact through multiple tissues to modulate insulin release from pancreatic islet cells. (B) Feeding-induced glucose metabolism in the liver affects clock components. (C) During fasting, activation of glucagon receptor and AMPK impinge on clock components. (D) Fatty acid synthesis and degradation are under feeding-fasting and circadian regulation. (E) Circadian clock and feeding signals act together to produce a daily rhythm in protein synthesis. (F) Circadian regulation of urea cycle, SAM synthesis, and polyamine production. Polyamines affect interaction between PER2 and CRY1. (G) Reciprocal regulation between circadian clock and NAD production. (H) Circadian production of meme and CO affect the function of core circadian clock components. (I) Fasting and circadian clock regulate cholesterol metabolism and production of several ligands for nuclear hormone receptors. (J) Reciprocal regulation between circadian clock and body-temperature rhythm.

Fig. 3.. Chronic circadian rhythm disruption by erratic lifestyle or high-fat-diet–induced obesity compromises physiology, whereas time-restricted feeding can restore daily rhythms and improve health.

The potential mechanisms are largely based on rodent studies. Few observations have been made in insects (*) and in humans (#). IL, interleukin; TNF, tumor necrosis factor.