Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health

Abstract

BackgroundWhile additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders.Scope of reviewThis article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations.Major conclusionsTargeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.

The Circadian NAD+Metabolism: Impact on Chromatin Remodeling and Aging

“…The accumulating evidence to date reveals the interconnection between circadian clock and aging/age-related diseases [59–62], and, as discussed in this review, NAD + metabolism has a close relationship with both the circadian clock and aging/age-related diseases. However, no direct evidence has so far demonstrated the role of NAD + as the linking hub between circadian clock and aging and age-related diseases.…”

“…At the tissue and cellular levels, aging weakens or reduces the amplitude of circadian gene expression patterns [57, 58]. Age-related diseases as well as aging can therefore have adverse effects on circadian clock [59–62]. For instance, mice fed with HFD demonstrate a lengthened free-running period [63], while db/db mice, which are an animal model of type 2 diabetes, show attenuated locomotor activity rhythms with diminished per2 mRNA and advanced bmal1 oscillation [64].…”

“…In addition, clock Δ19/Δ19 or clock −/− mice displayed age-related diseases such as hyperlipidemia, hyperleptinemia, hyperglycemia, and hypoinsulinaemia with shorter average lifespan of 100.8 ± 13.5 wk, compared to that of wild type mice (115.5 ± 18.9 wk) [70, 73]. In addition to the mouse studies, a large array of epidemiological surveys have provided evidence supporting the link between metabolic disorders, especially obesity, insulin resistance, cardiovascular disease, and cancer, and circadian disruption in humans [62, 74]. …”

Matching Meals to Body Clocks—Impact on Weight and Glucose Metabolism

“…This abnormal pattern of eating, and the lack of a defined fasting period disrupts the cyclic pattern of expression of peripheral clocks and downstream targets, and may explain at least some of the metabolic consequences that are observed as a result of a high fat diet [27,28]. Whilst discussion of the effects of nutrients on circadian rhythms is beyond the scope of this review, and this has been extensively reviewed by others [29], it is important to acknowledge that nutrients have the potential to act as zeitgebers. As such, the composition of the diet may impact the degree of de-synchrony that occurs.…”

Response to Wood re: “Oxidative Priority, Meal Frequency, and the Energy Economy of Food and Activity: Implications for Longevity, Obesity, and Cardiometabolic Disease”

“…12,13 However, the chronic postprandial state, extended periods of artificial light, and a chronically warm environment-all elements we would classify as characteristics of a ''metabolic summer''-may act synergistically to contribute to cardiometabolic and other disease states, and this appears to stand in stark contrast of seasonally imposed environmental effects throughout biology.…”