Timing of meals: when is as critical as what and how much

Abstract

Over the past decade, a large body of literature has demonstrated that disruptions of the endogenous circadian clock, whether environmental or genetic, lead to metabolic dysfunctions that are associated with obesity, diabetes, and other metabolic disorders. The phrase, "It is not only what you eat and how much you eat, but also when you eat" sends a simple message about circadian timing and body weight regulation. Communicating this message to clinicians and patients, while also elucidating the neuroendocrine, molecular, and genetic mechanisms underlying this phrase is essential to embrace the growing knowledge of the circadian impact on metabolism as a part of healthy life style as well as to incorporate it into clinical practice for improvement of overall human health. In this review, we discuss findings from animal models, as well as epidemiological and clinical studies in humans, which collectively promote the awareness of the role of circadian clock in metabolic functions and dysfunctions.

Keywords: circadian clock; metabolism; obesity.

Copyright © 2017 the American Physiological Society.

Figures

Fig. 1.

A summary of the current status of circadian-metabolic research.

Fig. 2.

A multilayer molecular network couples the circadian clock to metabolic functions. The core circadian clock machinery consists of a transcriptional and translational feedback loop, in which transcription of the repressors (PER1/2/3 and CRY1/2) is activated by the transcriptional activators (CLOCK and BMAL1) and is turned off as the repressor proteins accumulate and suppress the activity of the CLOCK-BMAL1 heterodimers. CSNK1 phosphorylates the PER proteins to reregulate PER nuclear entry and turnover, controlling the velocity of the clock. This transcriptional/translational clock machinery produces a cyclic transcriptional profile of metabolic genes and is coupled with metabolic functions via multiple mechanisms. The clock is stabilized by a feedback loop involving nuclear receptors RORs and REV-ERBs, which is sensitive to cellular metabolic state and is involved in the transcriptional programming of tissue-specific metabolic output. The clock also directs NAD+ biosynthesis, which, in turn, negatively feeds back on CLOCK-BMAL1 transcriptional activity through the NAD+-dependent deacetylases (SIRTs). SIRT1 and SIRT6 are involved in the epigenetic regulation of metabolic genes, and SIRT3 regulates mitochondrial activity. Through this link and many others, the clock is coupled with daily fluctuations of the cellular redox state, which involves mitochondrial fission and fusion, NAD+/NADH flux, and peroxiredoxin hyperoxidation (PRX-SO2/3). These cellular circadian-metabolic mechanisms are also coordinated at the whole organism level among multiple tissues and interact with the microbiota to shape the overall profile of metabolic health.