Abstract:

The SCN conveys circadian rhythmicity to peripheral tissue clocks in the body to segregate opposing metabolic processes temporally. Recently, research has suggested that desynchronization of these clocks contributes to metabolic disorders such as, obesity, type 2 diabetes, and glucose intolerance, among others. In this review, we summarize recent studies attempting to discover the causes and pathways implicated in the disruption of metabolic homeostasis. While the studies uncovered important knowledge regarding metabolic function, more experiments involving humans should be conducted in order for results to be better applied.

Introduction:

Nearly all life on Earth has established inherent biological clocks, termed circadian rhythms, that coincide with the light/dark cycles produced by the rotation of Earth around its own axis. In mammals, the suprachiasmatic nuclei (SCN) residing in the hypothalamus is considered to be the ‘master’ clock that synchronizes the peripheral tissue clocks to perform physiological functions in accordance with time of day sensed through light signals transmitted by the retina [1]. This system is based on a series of negative feed back loops (Fig. 1) based on an approximate 24-hour rhythm that function to generate tissue-specific gene expression via transcriptional and post-transcriptional techniques. The master function of this process is to provide a means to temporally segregate opposing biological processes in order to increase efficiency and pair peak energy extraction with peak energy expenditure [2]. The microbiota in the gut, important to the health of mammals, also display circadian rhythmicity conveyed by the SCN, and influenced by feeding habits [3]. Disruption of circadian rhythms and dysbiosis of microbial communities have shown to have deleterious metabolic effects manifested in obesity, type 2 diabetes, impaired glucose tolerance and many more [4]. In the the United States alone obesity effects 93.3 million adults or approximately 39.8% of the population ages 20 and above [5]. More over 30.3 million Americans have diabetes, while another 84.1 million have pre-diabetes which typically leads to development of diabetes within 5 years of initial onset [6]. The overwhelming prevalence of these diseases in today’s society has prompted researchers to achieve a better understanding of how circadian oscillations and clock genes in the SCN and peripheral tissue clocks communicate to maintain metabolic homeostasis. In this review, we will highlight recent advances in insight into the role of the circadian clocks, both of the host and symbionts there-in, in assuring proper metabolic function.

Eating Patterns and Diet Composition Affect Metabolism

SCN hormone secretions vary throughout the active/rest (light/dark) periods, so that physiological processes correlate with energy expenditure [7]. Evidence of this is demonstrated in multiple studies where mice possessing mutant type-, or absence of-, core clock genes show arrhythmic feeding patterns as well as severely disturbed metabolic function [8]. This suggests that the SCN circadian hormone release is key in maintaining metabolic homeostasis. In mice, when a regular chow diet is restricted to the light phase (the normal rest phase in mice) energy balance patterns become significantly altered compared to mice fed regular chow

ad libitum

[9]. In addition, high fat diets have been shown to dampen feeding/fasting cycles in

ad libitum

fed mice by modifying circadian rhythms of gene expression in peripheral tissues while the SCN is unaffected [10]. These studies exemplify that uncoupling of circadian rhythms between the central and peripheral clocks produce deleterious metabolic disorders such as weight gain, increased insulin sensitivity, impaired glucose tolerance, and hyperglycemia. Indeed, one experiment revealed that a time restricted feeding schedule alleviated the negative metabolic disruptions associated with a high-fat diet[11]. In addition, other dietary factors such as caffeine, have been shown to cause phase delays or advancements depending on the time of ingestion. When caffeine was consumed 3 hours prior to bed time, a 40-min delay in melatonin release was observed [12]. The results obtained from all of these studies clearly show that circadian rhythmicity is expressed in metabolic function but the mechanisms through which transcription is controlled is still yet to be discovered, although recent research suggests involvement of the gut and intestinal microbiome.

Intestinal Microbiota Mediate Communication Between Central and Peripheral Clocks

Microbial symbionts in the body out number human cells 10 to 1. A large number of these cells reside in the gastrointestinal tract where they function to ensure proper digestion and help fight off infection. In the gut, microbiota aid in nutrient extraction and energy harvesting and in turn produce metabolites. The two main phyla of bacteria that colonize the gut are Firmicutes and Bacteriodites. Obese mice show an increased ratio of Firmicutes to Bacteroidetes, whereas Bacteroidetes dictate the gut of lean mice [13]. The microbiota composition is directly influenced by the type of food ingested, and can shift in accordance with dietary alterations, Fecal transplant studies in which the microflora of obese mice is transferred to germ free mice resulted in dramatic weight gain with an increase in metabolism of simple sugars and short-chain fatty acids  [14]. These results corroborate the idea that Firmicutes and Bacteroidetes exhibit differential energy extraction and perhaps preferentially extract said energy from molecules of distinct compositions. Certain microbiota, most importantly Firmicutes and Bacteroidetes, express circadian rhythmicity, where Firmicutes are observed to be more abundant during the active phase and Bacteroidetes more abundant during the rest phase and overall average abundance of all microbes highest at the onset of the active phase [15]. This pattern of circadian expression coincides with that of other metabolically important processes carried out in other organs such as gastrointestinal motility, and blood glucose levels which are thought to be part of “food-anticipatory” behavior

⁽³⁾

. Another study was done, where the gut microbiota of mice deficient in Per1 and Per2 (Per1/2

^-/-

) clock genes (and thus do not possess a functional host clock) was analyzed at each phase of the dark/light cycle over a 48-hour period and then compared to that of the wild-type. The microbiota of Per1/2

^-/-

mice displayed complete loss of diurnal oscillatory fluctuations both in time-specific accumulation and in preferential activity patterns [16]. Thus a functional host clock is mandatory for microbe diurnal rhythm expression. In combination, these studies indicate an association between oscillating gut microbes and metabolic intermediates integrated with host circadian rhythms.

A proposed pathway for communication between metabolites and physiologically processes involves a pathway where commensal bacteria, recognized by intestinal epithelial cells (IEC), have the power to control IEC transcripts of NR’s (nuclear receptors) and clock gene components indicating an involvement in regulating whole body metabolism [17]. The IEC is able to recognize symbionts arrhythmic signals through toll-like receptors which were absent in antibiotic treated mice. Other studies conducted using germ-free mice (GF) showed that under high-fat diet feeding regiments, GF mice gained significantly less weight, reduced gonadal fad pad and liver weight compared to specific-pathogen free mice [18]. It was also discovered that high-fat diet reduces the abundance of cyclic microbiota and dampens the amplitude of those present as well as decreasing the overall diversity of microbial communities in the gut[19].  In light of these recent findings, the variables involved in managing metabolic homeostasis, constitute a highly complex system of molecular gene expression that must balance internal and external cues in an attempt to function most efficiently.

Discussion:

The current research examining the influence of circadian rhythms and metabolism is pertinent to clear public health issues involving metabolic disorders but despite the new information discovered the cause of dysfunction seems to all stem from the same source: an unsound diet and an unhealthy lifestyle. Foods today are much more complex than ever before. The market is saturated with processed foods that are more likely to contain harmful or nutrient poor substances, thus not providing the body with what it needs for proper function. Considering that Firmicutes are more abundant than Bacteroidetes in obese mice, perhaps could be a facultative adaptive response attempting to overcompensate for nutrient deficiencies by extracting more energy from the molecules ingested which end up being mostly fats, processed grains, and simple sugars that instead enhance the effects of an unbalanced diet. The fact that Firmicutes abundance, even in healthy individuals, is increased after a period of fasting [15] (i.e. beginning of the active phase) suggests that there is an innate response to low levels of metabolites. More research needs to be conducted using humans as test subjects to evaluate how a truly typical local diet (especially that of North Americans) influences the composition of the gut microbiota and their diurnal oscillations. In particular, what dietary components are processed by which phyla of bacteria. Many studies were conducted by observing different outcomes induced from high-fat diets compared to “regular” (whatever that encompasses) but no other diet compositions were tested. It would be interesting to see if other studies involving different diel alterations, such as a vegetarian, vegan, ketogenic, etc., showed that diets of these sorts could attenuate the negative effects associated with metabolic disorder shown to persist in chronic shift workers and frequent over seas travelers. Overall, the studies reviewed provide novel information into the complex biochemical pathways important to maintaining metabolic homeostasis in relation to circadian rhythms.

Conclusion:

Disruption of circadian rhythms in the SCN and peripheral clock tissues can result in dysbiosis. Once further research involving human as test subjects, and more factors that may effect metabolic function are studied, results may be able to aid in treating detrimental metabolic disorders in today’s society. For now, the reviewed research gives us further knowledge into the complexity of metabolism and its integration with circadian rhythmicity.

References

1. Takahashi, S.J.,

Molecuar components of the circadian clock in mammals.

Diabetes Obes Metab., 2015.

17

(1): p. 6-11.

2. Partch, C.L., Green, C.B., & Takahashi, J.S.,

Molecular architecture of the mammalian circadian clock.

Trends in Cell Biology, 2014.

24

(2): p. 90-99.

3. Potter, G., Cade, J.E., Grant, P.J.,  & Hardie, L.,

Nutrition and the circadian system.

British Journal of Nutrition, 2016(116): p. 434-442.

4. Maury, E., Ramsey, K.M., & Bass, J.,

Circadian rhythms and metabolic syndrome.

Circulation Research, 2010.

106

: p. 447-462.

5. Hales, C.M., Carroll,  M.D., Fryar, C.D., & Ogden, C.L.,

Prevalence of Obesity Among Adults and Youth: United State, 2015-2016

, in

NCHS Data Brief

. 2017, U.S. Department of Health and Human Services.

6. Prevention, C.f.D.C.a.,

National Diabetes Statistics Report, 2017

. 2017, U.S. Dept of Health and Human Services: Atlanta, GA.

7. Jha, P.K., Challet, E., & Kalsbeek, A.,

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals.

Molecular and Cellular Endocrinology, 2015(418): p. 74-88.

8. Kalsbeek, A., S. la Fleur, and E. Fliers,

Circadian control of glucose metabolism.

Mol Metab, 2014.

3

(4): p. 372-83.

9. Bray, M.S., Ratcliffe, W.F., Garnett, M.H.,Brewer, R.A., Gamble, K.L. & Young, M.E.,

Quantitative analysis of light-phase restricted feeding revelas metabolic dyssynchrony in mice.

International Journal of Obesity, 2013.

37

: p. 843-852.

10. Garaulet, M., & Gomez-Abellan, P.,

Timing of food intake and obesity: A novel association.

Physiology & Behavior, 2014.

134

: p. 44-50.

11. Duncan, M.J., Smith, J.T.,Narbaiza, J.,Mueez, F.,Bustle, L.B., Qureshi, S., Fieseler, C. & Legan, S.E.,

Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet.

Physiology & Behavior, 2016.

167

: p. 1-9.

12. Tahara, Y.S., Shigenobu,

Entrainment of the mouse circadian clock: Effects of stress, exercise, and nutrition.

Free Radical Biology and Medicine, 2018(119): p. 129-138.

13. Bull, M.J., & Plummer, N.T.,

Part 1: The human gut microbiome in health and disease.

Integrative Medicine, 2014.

13

(6): p. 17-22.

14. Turnbaugh, P.J., et al.,

An obesity-associated gut microbiome with increased capacity for energy harvest.

Nature, 2006.

444

(7122): p. 1027-31.

15. Liang, X., Bushman, F.D., & Fitzgerald, G.,

Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock.

Proceedings of the National Academy of Sciences of the United States of America, 2015.

112

(33): p. 10479-84.

16. Thaiss, C.L., Zeevi, D.,Levy, M., et al. ,

Transkingdom control of microbiota diurnal oscillationx promotes metabolic homeostasis.

Cell, 2014.

159

: p. 514-529.

17. Mukherji, A., Kobiita A., and Chambon, P.,

Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs.

Cell, 2013(153): p. 812-827.

18. Leone, V., Gibbons, S.M., Martinez, K., Hutchison, A.L., Huang, E.Y., Cham, C.M, Pierre, J.F., Heneghan, A.F., Nadimpalli, A., Hubert, N., Zale, E., Wang, Y., Huang, Y., Theriault, B., Dinner, A.R., Musch, M.W., Kudsk, K.A., Prendergast, B.J., et al.,

Effects of dirunal variateion of gut microbes and high-fat feeding on host circadian clock function and metabolism.

Cell Host & Microbe, 2015(17): p. 681-689.

19. Zarrinpar, A., Chaix, A., Yooseph, S., and Panda, S.,

Diet and feeding pattern affect the dirunal dynamics of the gut microbiome.

Cell Metabolism, 2014(20): p. 1006-1017.