(134e) Modeling Convergence of Circadian Clocks and Metabolism
Recent studies suggest that SIRT1 is a key candidate for bridging the circadian clocks and metabolism. SIRT1 (human sirtuin 1) is a class III histone deacetylase (HDAC), a homolog of Sir2 (silence information regulator 2) in yeast . Its activity takes place in the nucleus, modulating lipid metabolism and enhancing mitochondrial activity , in addition to modulating a variety of biological activities such as oncogenesis and aging . SIRT1 has a clear role in metabolism as its enzymatic activity requires binding of NAD+ into its catalytic site along with the substrate, effectively acting as a sensor for the energy state of the cell. Modeling the activity of SIRT1 would require an accurate portrayal of the NAD+ level in the cell, since it directly activates SIRT1. In addition to synthesizing NAD+ from amino acids, cells can also recover NAD+ from the NAD+ salvage pathway , where nicotinamide (NAM) is released from NAD+, NAM is converted to nicotinamide mononucleotide (NMN), and NMN is converted back to NAD+.
SIRT1 activity has complex relationships with the NAD+ salvage pathway and the peripheral clocks. First, SIRT1 activity requires binding of NAD+, thus NAD+ has an activating effect on SIRT1. Second, SIRT1 activity is inhibited by NAM, the precursor of the rate-limiting step. Third, expression of nicotinamide mononucleotide adenylyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage cycle, is under the control of SIRT1, which is a co-transcription factor for the Nampt gene along with peripheral clock genes. In summary, SIRT1 functions as a nutrient sensor, being under the influence of the energy state of the cells, represented by NAD+. It is also under the effect of the circadian rhythmicity presented by NAD+, NAM, and NAMPT.
From the above observations, we propose a mathematical model that describes the interactions among SIRT1, NAD+ salvage cycle, and peripheral clock genes, to study the effects of light and feeding schedules on circadian dynamics and metabolism. Our model builds upon earlier works  of a semi-mechanical model for light entrainment on the peripheral clock genes through the HPA axis. The oscillations in the HPA axis are generated due to the negative feedback between glucocorticoid and corticotropin-releasing hormone (CRH)/adrenocorticotropic hormone (ACTH) using a modified Goodwin oscillator, entrained by light. The oscillating glucocorticoid is secreted into the periphery, scheduling the peripheral clock genes (Per/Cry, Bmal1, and Clock). The new model captures important interactions between this existing light-entrained oscillator and new feeding entrainment. The Clock/Bmal1 complex binds to SIRT1 and activates transcription of NAMPT, which facilitates the NAD+ salvage cycle. NAD+, in turn, activates SIRT1, as well as entraining glucocorticoids through a transit compartment that represents neural input through the ventromedial arcuate nucleus . SIRT1 also facilitates the degradation of PER/CRY proteins in the nucleus, exerting more influence on the peripheral clock genes.
Current model successfully predicts some observations from experimental time-restricted feeding studies. Some basic predictions include that restricting feeding during the active phase results in stronger oscillations of peripheral clock genes . In contrast, restricting feeding to the rest phase results in declined oscillation amplitude for peripheral clock genes. The model also exhibits the â??phase jumpâ? behavior often observed in two-zeitgeber systems , ensuring that both light and feeding entrains the periphery in a significant manner. More interestingly, the model agrees with the recently proposed hypothesis that feeding is a strong zeitgeber for the peripheral clock genes, and light-controlled SCN interferes the entrainment to feeding schedule . This proposal counters the traditional belief that the light/dark cycle most strongly entrains the peripheral clock genes. Our model can demonstrate that removing the light schedule can reduce the time required for the system to equilibrate to a changed feeding schedule, supporting the new hypothesis. Furthermore, the new model provides the foundation for mathematically modeling hepatic gluconeogenesis in future works, in an attempt to potentially elucidate the mechanism of light and feeding zeitgebers resetting the circadian and metabolic clocks.
1. Wu, M.W., et al., Effects of meal timing on tumor progression in mice. Life Sciences, 2004. 75: p. 1181-1193.
2. Maywood, E.S., et al., Disruption of peripheral circadian timekeeping in a mouse model of Huntington's disease and its restoration by temporally scheduled feeding. The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. 30: p. 10199-204.
3. Asher, G. and U. Schibler, Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab, 2011. 13(2): p. 125-37.
4. Bellet, M.M., et al., The time of metabolism: NAD+, SIRT1, and the circadian clock. Cold Spring Harb Symp Quant Biol, 2011. 76: p. 31-8.
5. Eckel-Mahan, K. and P. Sassone-Corsi, Metabolism control by the circadian clock and vice versa. Nat Struct Mol Biol, 2009. 16(5): p. 462-7.
6. Luna, A., et al., Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response. PLoS Comput Biol, 2015. 11(5): p. e1004144.
7. Shi, M. and X. Zheng, Interactions between the circadian clock and metabolism: there are good times and bad times. Acta Biochim Biophys Sin (Shanghai), 2013. 45(1): p. 61-9.
8. Thakran, S., et al., Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone. J Biol Chem, 2013. 288(2): p. 807-18.
9. Bishop, N.A. and L. Guarente, Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet, 2007. 8(11): p. 835-44.
10. Sahar, S. and P. Sassone-Corsi, Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab, 2012. 23(1): p. 1-8.
11. Mavroudis, P.D., et al., Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes. Physiol Genomics, 2014. 46(20): p. 766-78.
12. Yi, C.X., et al., Ventromedial arcuate nucleus communicates peripheral metabolic information to the suprachiasmatic nucleus. Endocrinology, 2006. 147(1): p. 283-94.
13. Hatori, M., et al., Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metabolism, 2012. 15: p. 848-860.
14. Oda, G.A. and W.O. Friesen, Modeling two-oscillator circadian systems entrained by two environmental cycles. PLoS One, 2011. 6(8): p. e23895.
15. Angeles-Castellanos, M., et al., The Suprachiasmatic Nucleus Participates in Food Entrainment: A Lesion Study. Neuroscience, 2010. 165(4): p. 1115-1126.