Sleep, Circadian Rhythms and Metabolism

  • Eleonore Maury
  • Kathryn Moynihan Ramsey
  • Joseph Bass


Obesity and cardiometabolic disease are closely linked disorders that have recently accelerated throughout the industrialized world, coincident with more sedentary lifestyle and poor nutrition; however a complete understanding of the environmental precipitants underlying metabolic disease remains obscure. Mounting evidence from epidemiological studies has pointed towards a novel yet less appreciated factor that correlates with the recent expansion of these epidemics, namely, the introduction of artificial light and work at night-time, in addition to the rise in sleep curtailment. At the physiological level, it has been well-documented that many processes, including glucose and lipid metabolism, body temperature, and corticosterone production vary in a circadian fashion; moreover, there is an established temporal variation to health catastrophes such as myocardial infarction, cerebrovascular accident, and hypertensive crises. Over the past decade, major advances have emerged in our understanding of the underlying molecular mechanisms linking circadian rhythms, sleep, and metabolism, primarily through studies in experimental genetic models that became available following the landmark discovery of the first mammalian circadian clock gene Clock in 1997 [1, 2].


Circadian Rhythm Sleep Deprivation Clock Gene Circadian System Circadian Cycle 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank members of the Bass, Takahashi, Turek, and Allada laboratories for helpful discussions, and especially M. Flourakis for his help with the figures. This work was supported by grants from Alfediam to E.M.; NIDDK (T32 DK007169) to K.M.R.; NIH (PO1 AG011412 and R01HL097817-01), ADA, Chicago Biomedical Consortium Searle Funds, and JDRF to J.B., and the University of Chicago DRTC (P60 DK020595).


J.B. is a member of the scientific advisory board of a cofounder of ReSet Therapeutics Inc. J.B. is also an advisor and receives support from Amylin Pharmaceuticals.


  1. 1.
    King, D. P., Zhao, Y., Sangoram, A. M., Wilsbacher, L. D., Tanka, M., Antoch, M. P., et al. (1997). Positional cloning of the mouse circadian clock gene. Cell, 89(4), 641–653.PubMedCrossRefGoogle Scholar
  2. 2.
    Vitaterna, M. H., King, D. P., Chang, A. M., Kornhauser, J. M., Lowrey, P. L., McDonald, J. D., et al. (1994 ).Mutagenesis and mapping of a mouse gene, clock, essential for circadian behavior. Science, 264(5159), 719–725.PubMedCrossRefGoogle Scholar
  3. 3.
    Green, C. B., Takahashi, J. S., & Bass, J. (2008). The meter of metabolism. Cell, 134(5), 728–742.PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi, J. S., Hong, H. K., Ko, C. H., & McDearmon, E. L. (2008). The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nature Review Genetics, 9(10), 764–775.CrossRefGoogle Scholar
  5. 5.
    Martinek, S., Inonog, S., Manoukian, A. S., & Young, M. W. (2001). A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell, 105(6), 769–779.PubMedCrossRefGoogle Scholar
  6. 6.
    Spengler, M. L., Kuropatwinski, K. K., Schumer, M., & Antoch, M. P. (2009). A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle, 8(24), 4138–4146.PubMedGoogle Scholar
  7. 7.
    Yoshitane, H., Takao, T., Satomi, Y., Du, N. H., Okano, T., & Fukada, Y. (2009). Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription. Molecular and Cellular Biology, 29(13), 3675–3686.PubMedCrossRefGoogle Scholar
  8. 8.
    Kornmann, B., Schaad, O., Bujard, H., Takahashi, J. S., & Schibler, U. (2007). System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biology, 5(2), e34.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang, J., Yin, L., & Lazar, M. A. (2006). The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. The Journal of Biological Chemistry, 281(45), 33842–33848.PubMedCrossRefGoogle Scholar
  10. 10.
    Raghuram, S., Stayrook, K. R., Huang, P., et al. (2007). Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta. Nature Structural & Molecualr Biology, 14(12), 1207–1213.CrossRefGoogle Scholar
  11. 11.
    Yin, L., Wu, N., Curtin, J. C., et al. (2007). Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways. Science, 318(5857), 1786–1789.PubMedCrossRefGoogle Scholar
  12. 12.
    Wang, Y., Kumar, N., Solt, L. A., et al. (2010). Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. The Journal of Biological Chemistry, 285(7), 5013–5025.PubMedCrossRefGoogle Scholar
  13. 13.
    Fontaine, C., & Staels, B. (2007). The orphan nuclear receptor Rev-erbalpha: A transcriptional link between circadian rhythmicity and cardiometabolic disease. Current Opinion in Lipidology, 18(2), 141–146.PubMedCrossRefGoogle Scholar
  14. 14.
    Bensinger, S. J., & Tontonoz, P. (2008). Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature, 454(7203), 470–477.PubMedCrossRefGoogle Scholar
  15. 15.
    Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M., & Sassone-Corsi, P. (2009). Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science, 324(5927), 654–657.PubMedCrossRefGoogle Scholar
  16. 16.
    Ramsey, K. M., Yoshino, J., Brace, C. S., et al. (2009). Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science, 324(5927), 651–654.PubMedCrossRefGoogle Scholar
  17. 17.
    Lamia, K. A., Sachdeva, U. M., DiTacchio, L., et al. (2009). AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science, 326(5951), 437–440.PubMedCrossRefGoogle Scholar
  18. 18.
    Canto, C., Gerhart-Hines, Z., Feige, J. N., et al. (2009). AMPK regulates energy expenditure by modulating NAD(+) metabolism and SIRT1 activity. Nature, 458, 1056.PubMedCrossRefGoogle Scholar
  19. 19.
    Bunger, M. K., Wilsbacher, L. D., Moran, S. M., et al. (2000). Mop3 is an essential component of the master circadian pacemaker in mammals. Cell, 103(7), 1009–1017.PubMedCrossRefGoogle Scholar
  20. 20.
    DeBruyne, J. P., Weaver, D. R., & Reppert, S. M. (2007). CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nature Neuroscience, 10(5), 543–545.PubMedCrossRefGoogle Scholar
  21. 21.
    DeBruyne, J. P., Weaver, D. R., & Reppert, S. M. (2007). Peripheral circadian oscillators require CLOCK. Current Biology, 17(14), R538–R539.PubMedCrossRefGoogle Scholar
  22. 22.
    Bae, K., Jin, X., Maywood, E. S., Hastings, M. H., Reppert, S. M., & Weaver, D. R. (2001). Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron, 30(2), 525–536.PubMedCrossRefGoogle Scholar
  23. 23.
    Cermakian, N., Monaco, L., Pando, M. P., Dierich, A., & Sassone-Corsi, P. (2001). Altered behavioral rhythms and clock gene expression in mice with a targeted mutation in the Period1 gene. The Embo Journal, 20(15), 3967–3974.PubMedCrossRefGoogle Scholar
  24. 24.
    van der Horst, G. T., Muijtjens, M., Kobayashi, K., et al. (1999). Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature, 398(6728), 627–630.PubMedCrossRefGoogle Scholar
  25. 25.
    Vitaterna, M. H., Selby, C. P., Todo, T., et al. (1999). Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proceedings of the National Academy of Sciences of the United States of America, 96(21), 12114–12119.PubMedCrossRefGoogle Scholar
  26. 26.
    Zheng, B., Albrecht, U., Kaasik, K., et al. (2001). Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell, 105(5), 683–694.PubMedCrossRefGoogle Scholar
  27. 27.
    Godinho, S. I., Maywood, E. S., Shaw, L., et al. (2007). The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science, 316(5826), 897–900.PubMedCrossRefGoogle Scholar
  28. 28.
    Siepka, S. M., Yoo, S. H., Park, J., et al. (2007). Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell, 129(5), 1011–1023.PubMedCrossRefGoogle Scholar
  29. 29.
    Liu, C., Li, S., Liu, T., Borjigin, J., & Lin, J. D. (2007). Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism. Nature, 447(7143), 477–481.PubMedCrossRefGoogle Scholar
  30. 30.
    Yamazaki, S., Numano, R., Abe, M., et al. (2000). Resetting central and peripheral circadian oscillators in transgenic rats. Science, 288(5466), 682–685.PubMedCrossRefGoogle Scholar
  31. 31.
    Yoo, S. H., Yamazaki, S., Lowrey, P. L., et al. (2004). PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proceedings of the National Academy of Sciences of the United States of America, 101(15), 5339–5346.PubMedCrossRefGoogle Scholar
  32. 32.
    Maury, E., Ramsey, K. M., & Bass, J. (2010). Circadian rhythms and metabolic syndrome: From experimental genetics to human disease. Circulation Research , 106(3), 447–462.PubMedCrossRefGoogle Scholar
  33. 33.
    McIntosh, B. E., Hogenesch, J. B., & Bradfield, C. A. (2010). Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annual Review of Physiology, 72, 625–645.PubMedCrossRefGoogle Scholar
  34. 34.
    Xu, K., Zheng, X., & Sehgal, A. (2008). Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metabolism, 8(4), 289–300.PubMedCrossRefGoogle Scholar
  35. 35.
    Lamia, K. A., Storch, K. F., & Weitz, C. J. (2008). Physiological significance of a peripheral tissue circadian clock. Proceedings of the National Academy of Sciences of the United States of America, 105(39), 15172–15177.PubMedCrossRefGoogle Scholar
  36. 36.
    Gangwisch, J. E., Malaspina, D., Boden-Albala, B., & Heymsfield, S. B. (2005). Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep, 28(10), 1289–1296.PubMedGoogle Scholar
  37. 37.
    Kawakami, N., Takatsuka, N., & Shimizu, H. (2004). Sleep disturbance and onset of type 2 diabetes. Diabetes Care, 27(1), 282–283.PubMedCrossRefGoogle Scholar
  38. 38.
    Knutson, K. L., Spiegel, K., Penev, P., & Van Cauter, E. (2007). The metabolic consequences of sleep deprivation. Sleep Medicine Reviews, 11(3), 163–178.PubMedCrossRefGoogle Scholar
  39. 39.
    Knutson, K. L., & Van Cauter, E. (2008). Associations between sleep loss and increased risk of obesity and diabetes. Annals of the New York Academy of Sciences, 1129, 287–304.PubMedCrossRefGoogle Scholar
  40. 40.
    Spiegel, K., Tasali, E., Leproult, R., & Van Cauter, E. (2009). Effects of poor and short sleep on glucose metabolism and obesity risk. Nature Reviews. Endocrinology, 5(5), 253–261.PubMedCrossRefGoogle Scholar
  41. 41.
    Yaggi, H. K., Araujo, A. B., & McKinlay, J. B. (2006). Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care, 29(3), 657–661.PubMedCrossRefGoogle Scholar
  42. 42.
    Watanabe, M., Kikuchi, H., Tanaka, K., & Takahashi, M. (2010). Association of short sleep duration with weight gain and obesity at 1-year follow-up: A large-scale prospective study. Sleep , 33(2), 161–167.PubMedGoogle Scholar
  43. 43.
    Danielsen, Y. S., Pallesen, S., Stormark, K. M., Nordhus, I. H., & Bjorvatn, B. (2010). The relationship between school day sleep duration and body mass index in Norwegian children (aged 10–12). International Journal of Pediatric Obesity, 5(3), 214–220.PubMedCrossRefGoogle Scholar
  44. 44.
    Lumeng, J. C., Somashekar, D., Appugliese, D., Kaciroti, N., Corwyn, R. F., & Bradley, R. H. (2007). Shorter sleep duration is associated with increased risk for being overweight at ages 9 to 12 years. Pediatrics, 120(5), 1020–1029.PubMedCrossRefGoogle Scholar
  45. 45.
    de Sousa, A. G., Cercato, C., Mancini, M. C., & Halpern, A. (2008). Obesity and obstructive sleep apnea-hypopnea syndrome. Obesity Reviews, 9(4), 340–354.PubMedCrossRefGoogle Scholar
  46. 46.
    Burioka, N., Koyanagi, S., Endo, M., et al. (2008). Clock gene dysfunction in patients with obstructive sleep apnoea syndrome. The European Respiratory Journal, 32(1), 105–112.PubMedCrossRefGoogle Scholar
  47. 47.
    Kok, S. W., Meinders, A. E., Overeem, S., et al. (2002). Reduction of plasma leptin levels and loss of its circadian rhythmicity in hypocretin (orexin)-deficient narcoleptic humans. The Journal of Clinical Endocrinology and Metabolism, 87(2), 805–809.PubMedCrossRefGoogle Scholar
  48. 48.
    Laposky, A. D., Bass, J., Kohsaka, A., & Turek, F. W. (2008). Sleep and circadian rhythms: Key components in the regulation of energy metabolism. FEBS Letters, 582(1), 142–151.PubMedCrossRefGoogle Scholar
  49. 49.
    Knutsson, A. (2003). Health disorders of shift workers. Occupational Medicine (London), 53(2), 103–108.CrossRefGoogle Scholar
  50. 50.
    Ribeiro, D. C., Hampton, S. M., Morgan, L., Deacon, S., & Arendt, J. (1998). Altered postprandial hormone and metabolic responses in a simulated shift work environment. Journal of Endocrinology, 158(3), 305–310.PubMedCrossRefGoogle Scholar
  51. 51.
    Janszky, I., & Ljung, R. (2008). Shifts to and from daylight saving time and incidence of myocardial infarction. The New England Journal of Medicine, 359(18), 1966–1968.PubMedCrossRefGoogle Scholar
  52. 52.
    Scheer, F. A., Hilton, M. F., Mantzoros, C. S., & Shea, S. A. (2009). Adverse metabolic and cardiovascular consequences of circadian misalignment. Proceedings of the National Academy of Sciences of the United States of America, 106(11), 4453–4458.PubMedCrossRefGoogle Scholar
  53. 53.
    Ekmekcioglu, C., & Touitou, Y. (2010). Chronobiological aspects of food intake and metabolism and their relevance on energy balance and weight regulation. Obesity Reviews Epub ahead of print.Google Scholar
  54. 54.
    Farshchi, H. R., Taylor, M. A., & Macdonald, I. A. (2005). Deleterious effects of omitting breakfast on insulin sensitivity and fasting lipid profiles in healthy lean women. The American Journal of Clinical Nutrition, 81(2), 388–396.PubMedGoogle Scholar
  55. 55.
    Ekmekcioglu C, Touitou Y. Chronobiological aspects of food in take and metabolism and their relevance on energy balance and weight regulation. Obes RevGoogle Scholar
  56. 56.
    Kohsaka, A., Laposky, A. D., & Ramsey, K. M., et al. (2007). High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metabolism, 6(5), 414–421.PubMedCrossRefGoogle Scholar
  57. 57.
    Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H., & Turek, F. W. (2009). Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring), 17(11), 2100–2102.CrossRefGoogle Scholar
  58. 58.
    Uebele, V. N., Gotter, A. L., & Nuss, C. E., et al. (2009). Antagonism of T-type calcium channels inhibits high-fat diet-induced weight gain in mice. The Journal of Clinical Investigation, 119(6), 1659–1667.PubMedCrossRefGoogle Scholar
  59. 59.
    Carpen, J. D., von Schantz, M., Smits, M., Skene, D. J., & Archer, S. N. (2006). A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans. Journal of Human Genetics, 51(12), 1122–1125.PubMedCrossRefGoogle Scholar
  60. 60.
    Ptacek, L. J., Jones, C. R., & Fu, Y. H. (2007). Novel insights from genetic and molecular characterization of the human clock. Cold Spring Harbor Symposia on Quantitative Biology, 72, 273–277.PubMedCrossRefGoogle Scholar
  61. 61.
    Takano, A., Uchiyama, M., Kajimura, N., et al. (2004). A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology, 29(10), 1901–1909.PubMedCrossRefGoogle Scholar
  62. 62.
    Xu, Y., Padiath, Q. S., Shapiro, R. E., et al. (2005). Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature, 434(7033), 640–644.PubMedCrossRefGoogle Scholar
  63. 63.
    Toh, K. L., Jones, C. R., He, Y., et al. (2001). An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science, 291(5506), 1040–1043.PubMedCrossRefGoogle Scholar
  64. 64.
    Antoch, M. P., Song, E. J., Chang, A. M., et al. (1997). Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell, 89(4), 655–667.PubMedCrossRefGoogle Scholar
  65. 65.
    Naylor, E., Bergmann, B. M., Krauski, K., et al. (2000). The circadian Clock mutation alters sleep homeostasis in the mouse. Journal of Neuroscience, 20(21), 8138–8143.PubMedGoogle Scholar
  66. 66.
    Okamura, H., Miyake, S., Sumi, Y., et al. (1999). Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science, 286(5449), 2531–2534.PubMedCrossRefGoogle Scholar
  67. 67.
    Wisor, J. P., O’Hara, B. F., Terao, A., et al. (2002). A role for cryptochromes in sleep regulation. BMC Neuroscience, 3, 20.PubMedCrossRefGoogle Scholar
  68. 68.
    Laposky, A., Easton, A., Dugovic, C., Walisser, J., Bradfield, C., & Turek, F. (2005). Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. Sleep, 28(4), 395–409.PubMedGoogle Scholar
  69. 69.
    Saper, C. B., Scammell, T. E., & Lu, J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437(7063), 1257–1263.PubMedCrossRefGoogle Scholar
  70. 70.
    Wulff, K., Porcheret, K., Cussans, E., & Foster, R. G. (2009). Sleep and circadian rhythm disturbances: Multiple genes and multiple phenotypes. Current Opinion in Genetics & Development, 19(3), 237–246.CrossRefGoogle Scholar
  71. 71.
    Bouatia-Naji, N., Bonnefond, A., Cavalcanti-Proenca, C., et al. (2009). A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nature Genetics, 41(1), 89–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Dupuis, J., Langenberg, C., Prokopenko, I., et al. (2010). New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics, 42(2), 105–116.PubMedCrossRefGoogle Scholar
  73. 73.
    Turek, F. W., Joshu, C., Kohsaka, A., et al. (2005). Obesity and metabolic syndrome in circadian Clock mutant mice. Science, 308(5724), 1043–1045.PubMedCrossRefGoogle Scholar
  74. 74.
    Rudic, R. D., McNamara, P., Curtis, A. M., et al. (2004). BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biology, 2(11), e377.PubMedCrossRefGoogle Scholar
  75. 75.
    Shimba, S., Ishii, N., Ohta, Y., et al. (2005). Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proceedings of the National Academy of Sciences of the United States of America, 102(34), 12071–12076.PubMedCrossRefGoogle Scholar
  76. 76.
    Yang, S., Liu, A., Weidenhammer, A., et al. (2009). The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology, 150(5), 2153–2160.PubMedCrossRefGoogle Scholar
  77. 77.
    Green, C. B., Douris, N., Kojima, S., et al. (2007). Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America, 104(23), 9888–9893.PubMedCrossRefGoogle Scholar
  78. 78.
    Ralph, M. R., Foster, R. G., Davis, F. C., & Menaker, M. (1990). Transplanted suprachiasmatic nucleus determines circadian period. Science, 247(4945), 975–978.PubMedCrossRefGoogle Scholar
  79. 79.
    Andretic, R., Franken, P., & Tafti, M. (2008). Genetics of sleep. Annual Review of Genetics, 42, 361–388.PubMedCrossRefGoogle Scholar
  80. 80.
    Easton, A., Meerlo, P., Bergmann, B., & Turek, F. W. (2004). The suprachiasmatic nucleus regulates sleep timing and amount in mice. Sleep, 27(7), 1307–1318.PubMedGoogle Scholar
  81. 81.
    Schmidt, C., Collette, F., Leclercq, Y., et al. (2009). Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area. Science, 324(5926), 516–519.PubMedCrossRefGoogle Scholar
  82. 82.
    Ramsey, K. M., Marcheva, B., Kohsaka, A., & Bass, J. (2007). The clockwork of metabolism. Annual Review of Nutrition, 27, 219–240.PubMedCrossRefGoogle Scholar
  83. 83.
    Vanitallie, T. B. (2006). Sleep and energy balance: Interactive homeostatic systems. Metabolism, 55(10 Suppl. 2), S30–S35.PubMedCrossRefGoogle Scholar
  84. 84.
    Farooqi, I. S., Bullmore, E., Keogh, J., Gillard, J., O’Rahilly, S., & Fletcher, P. C. (2007). Leptin regulates striatal regions and human eating behavior. Science, 317(5843), 1355.PubMedCrossRefGoogle Scholar
  85. 85.
    Fulton, S., Pissios, P., Manchon, R. P., et al. (2006). Leptin regulation of the mesoaccumbens dopamine pathway. Neuron, 51(6), 811–822.PubMedCrossRefGoogle Scholar
  86. 86.
    Fuller, P. M., Lu, J., & Saper, C. B. (2008). Differential rescue of light- and food-entrainable circadian rhythms. Science, 320(5879), 1074–1077.PubMedCrossRefGoogle Scholar
  87. 87.
    Gooley, J. J., Schomer, A., & Saper, C. B. (2006). The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nature Neuroscience, 9(3), 398–407.PubMedCrossRefGoogle Scholar
  88. 88.
    Mieda, M., Williams, S. C., Richardson, J. A., Tanaka, K., & Yanagisawa, M. (2006). The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker. Proceedings of the National Academy of Sciences of the United States of America, 103(32), 12150–12155.PubMedCrossRefGoogle Scholar
  89. 89.
    Storch, K. F., & Weitz, C. J. (2009). Daily rhythms of food-anticipatory behavioral activity do not require the known circadian clock. Proceedings of the National Academy of Sciences of the United States of America, 106(16), 6808–6813.PubMedCrossRefGoogle Scholar
  90. 90.
    Sutton, G. M., Perez-Tilve, D., Nogueiras, R., et al. (2008). The melanocortin-3 receptor is required for entrainment to meal intake. Journal of Neuroscience, 28(48), 12946–12955.PubMedCrossRefGoogle Scholar
  91. 91.
    Challet, E. (2010). Interactions between light, mealtime and calorie restriction to control daily timing in mammals. Journal of Comparative Physiology B, Biochemical, Systemic, and Environmental Physiology, 180(5), 631–644.PubMedCrossRefGoogle Scholar
  92. 92.
    Heller, H. C., & Ruby, N. F. (2004). Sleep and circadian rhythms in mammalian torpor. Annual Review of Physiology, 66, 275–289.PubMedCrossRefGoogle Scholar
  93. 93.
    Cirelli, C. (2006). Cellular consequences of sleep deprivation in the brain. Sleep Medicine Reviews, 10(5), 307–321.PubMedCrossRefGoogle Scholar
  94. 94.
    Cirelli, C. (2009). The genetic and molecular regulation of sleep: From fruit flies to humans. Nature Reviews. Neuroscience, 10(8), 549–560.PubMedCrossRefGoogle Scholar
  95. 95.
    Lakin-Thomas, P. L., & Brody, S. (1985). Circadian rhythms in Neurospora crassa: interactions between clock mutations. Genetics, 109(1), 49–66.PubMedGoogle Scholar
  96. 96.
    Lam, T. K., Schwartz, G. J., & Rossetti, L. (2005). Hypothalamic sensing of fatty acids. Nature Neuroscience, 8(5), 579–584.PubMedCrossRefGoogle Scholar
  97. 97.
    Sandoval, D., Cota, D., & Seeley, R. J. (2008). The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annual Review of Physiology, 70, 513–535.PubMedCrossRefGoogle Scholar
  98. 98.
    Chakravarthy, M. V., Zhu, Y., Lopez, M., et al. (2007). Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis. The Journal of Clinical Investigation, 117(9), 2539–2552.PubMedCrossRefGoogle Scholar
  99. 99.
    Basterfield, L., Lumley, L. K., & Mathers, J. C. (2009). Wheel running in female C57BL/6J mice: impact of oestrus and dietary fat and effects on sleep and body mass. International Journal of Obesity (London), 33(2), 212–218.CrossRefGoogle Scholar
  100. 100.
    Wang, J., & Lazar, M. A. (2008). Bifunctional role of Rev-erbalpha in adipocyte differentiation. Molecular and Cellular Biology, 28(7), 2213–2220.PubMedCrossRefGoogle Scholar
  101. 101.
    Anan, F., Masaki, T., Fukunaga, N., et al. (2007). Pioglitazone shift circadian rhythm of blood pressure from non-dipper to dipper type in type 2 diabetes mellitus. European Journal of Clinical Investigation, 37(9), 709–714.PubMedCrossRefGoogle Scholar
  102. 102.
    Diabetes Atherosclerosis Intervention Study Investigators. (2001). Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: The Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet, 357(9260), 905–910.Google Scholar
  103. 103.
    Chew, G. T., Watts, G. F., Davis, T. M., et al. (2008). Hemodynamic effects of fenofibrate and coenzyme Q10 in type 2 diabetic subjects with left ventricular diastolic dysfunction. Diabetes Care, 31(8), 1502–1509.PubMedCrossRefGoogle Scholar
  104. 104.
    Keech, A., Simes, R. J., Barter, P., et al. (2005). Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet, 366(9500), 1849–1861.PubMedCrossRefGoogle Scholar
  105. 105.
    Cretenet, G., Le Clech, M., & Gachon, F. (2010). Circadian clock-coordinated 12 Hr period rhythmic activation of the IRE1alpha pathway controls lipid metabolism in mouse liver. Cell Metabolism , 11(1), 47–57.PubMedCrossRefGoogle Scholar
  106. 106.
    Bjedov, I., Toivonen, J. M., Kerr, F., et al. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metabolism , 11(1), 35–46.PubMedCrossRefGoogle Scholar
  107. 107.
    Grandison, R. C., Piper, M. D., & Partridge, L. (2009). Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature, 462(7276), 1061–1064.PubMedCrossRefGoogle Scholar
  108. 108.
    Froy, O., Chapnik, N., & Miskin, R. (2008). Relationship between calorie restriction and the biological clock: Lessons from long-lived transgenic mice. Rejuvenation Research, 11(2), 467–471.PubMedCrossRefGoogle Scholar
  109. 109.
    Minami, Y., Kasukawa, T., Kakazu, Y., et al. (2009). Measurement of internal body time by blood metabolomics. Proceedings of the National Academy of Sciences of the United States of America, 106(24), 9890–9895.PubMedCrossRefGoogle Scholar
  110. 110.
    Sandoval, D. A., Obici, S., & Seeley, R. J. (2009). Targeting the CNS to treat type 2 diabetes. Nature Reviews. Drug Discovery, 8(5), 386–398.PubMedCrossRefGoogle Scholar
  111. 111.
    Cao, R., Lee, B., Cho, H. Y., Saklayen, S., & Obrietan, K. (2008). Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Molecular and Cellular Neurosciences, 38(3), 312–324.PubMedCrossRefGoogle Scholar
  112. 112.
    Scharf, M. T., Naidoo, N., Zimmerman, J. E., & Pack, A. I. (2008). The energy hypothesis of sleep revisited. Progress in Neurobiology, 86(3), 264–280.PubMedCrossRefGoogle Scholar
  113. 113.
    Um, J. H., Yang, S., Yamazaki, S., et al. (2007). Activation of 5′-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. The Journal of Biological Chemistry, 282(29), 20794–20798.PubMedCrossRefGoogle Scholar
  114. 114.
    Ronnett, G. V., & Aja, S. (2008). AMP-activated protein kinase in the brain. International Journal of Obesity (London), 32(Suppl. 4), S42–S48.CrossRefGoogle Scholar
  115. 115.
    Chikahisa, S., Fujiki, N., Kitaoka, K., Shimizu, N., & Sei, H. (2009). Central AMPK contributes to sleep homeostasis in mice. Neuropharmacology, 57(4), 369–374.PubMedCrossRefGoogle Scholar
  116. 116.
    Zhang, J., Kaasik, K., Blackburn, M. R., & Lee, C. C. (2006). Constant darkness is a circadian metabolic signal in mammals. Nature, 439(7074), 340–343.PubMedCrossRefGoogle Scholar
  117. 117.
    O’Neill, J. S., Maywood, E. S., Chesham, J. E., Takahashi, J. S., & Hastings, M. H. (2008). cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science, 320(5878), 949–953.PubMedCrossRefGoogle Scholar
  118. 118.
    Eckel-Mahan, K. L., Phan, T., Han, S., et al. (2008). Circadian oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. Nature Neuroscience, 11(9), 1074–1082.PubMedCrossRefGoogle Scholar
  119. 119.
    Vecsey, C. G., Baillie, G. S., Jaganath, D., et al. (2009). Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461(7267), 1122–1125.PubMedCrossRefGoogle Scholar
  120. 120.
    Crocker, A., Shahidullah, M., Levitan, I. B., & Sehgal, A. (2010). Identification of a neural circuit that underlies the effects of octopamine on sleep:wake behavior. Neuron , 65(5), 670–681.PubMedCrossRefGoogle Scholar
  121. 121.
    Fulco, M., Cen, Y., Zhao, P., et al. (2008). Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Developmental Cell, 14(5), 661–673.PubMedCrossRefGoogle Scholar
  122. 122.
    Hallschmid, M., Randeva, H., Tan, B. K., Kern, W., & Lehnert, H. (2009). Relationship between cerebrospinal fluid visfatin (PBEF/Nampt) levels and adiposity in humans. Diabetes, 58(3), 637–640.PubMedCrossRefGoogle Scholar
  123. 123.
    Konner, A. C., Klockener, T., & Bruning, J. C. (2009). Control of energy homeostasis by insulin and leptin: Targeting the arcuate nucleus and beyond. Physiology & Behavior, 97(5), 632–638.CrossRefGoogle Scholar
  124. 124.
    Zhang, E. E., Liu, A. C., Hirota, T., et al. (2009). A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell, 139(1), 199–210.PubMedCrossRefGoogle Scholar
  125. 125.
    Ahima, R. S., & Lazar, M. A. (2008). Adipokines and the peripheral and neural control of energy balance. Molecular Endocrinology, 22(5), 1023–1031.PubMedCrossRefGoogle Scholar
  126. 126.
    Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E., & Flier, J. S. (1998). Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell, 1(4), 619–625.PubMedCrossRefGoogle Scholar
  127. 127.
    Mori, H., Hanada, R., Hanada, T., et al. (2004). Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature Medicine, 10(7), 739–743.PubMedCrossRefGoogle Scholar
  128. 128.
    Ozcan, L., Ergin, A. S., Lu, A., et al. (2009). Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism, 9(1), 35–51.PubMedCrossRefGoogle Scholar
  129. 129.
    Kubota, N., Yano, W., Kubota, T., et al. (2007). Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metabolism , 6(1), 55–68.PubMedCrossRefGoogle Scholar
  130. 130.
    Minokoshi, Y., Alquier, T., Furukawa, N., et al. (2004). AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature, 428(6982), 569–574.PubMedCrossRefGoogle Scholar
  131. 131.
    Laposky, A. D., Shelton, J., Bass, J., Dugovic, C., Perrino, N., & Turek, F. W. (2006). Altered sleep regulation in leptin deficient mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 290, R894–R903.PubMedGoogle Scholar
  132. 132.
    Laposky, A. D., Bradley, M. A., Williams, D. L., Bass, J., & Turek, F. W. (2008). Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 295(6), R2059–R2066.PubMedGoogle Scholar
  133. 133.
    Kleinridders, A., Schenten, D., Konner, A. C., et al. (2009). MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metabolism, 10(4), 249–259.PubMedCrossRefGoogle Scholar
  134. 134.
    Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell, 135(1), 61–73.PubMedCrossRefGoogle Scholar
  135. 135.
    Hanada, R., Leibbrandt, A., Hanada, T., et al. (2009). Central control of fever and female body temperature by RANKL/RANK. Nature, 462(7272), 505–509.PubMedCrossRefGoogle Scholar
  136. 136.
    Hotamisligil, G. S. (2010). Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell , 140(6), 900–917.PubMedCrossRefGoogle Scholar
  137. 137.
    Shaw, P. J., Cirelli, C., Greenspan, R. J., & Tononi, G. (2000). Correlates of sleep and waking in Drosophila melanogaster. Science, 287(5459), 1834–1837.PubMedCrossRefGoogle Scholar
  138. 138.
    Schwartz, G. J., Fu, J., Astarita, G., et al. (2008). The lipid messenger OEA links dietary fat intake to satiety. Cell Metabolism, 8(4), 281–288.PubMedCrossRefGoogle Scholar
  139. 139.
    Murillo-Rodriguez, E., Desarnaud, F., & Prospero-Garcia, O. (2006). Diurnal variation of arachidonoylethanolamine, palmitoylethanolamide and oleoylethanolamide in the brain of the rat. Life Sciences, 79(1), 30–37.PubMedCrossRefGoogle Scholar
  140. 140.
    Gillum, M. P., Zhang, D., Zhang, X. M., et al. (2008). N-acylphosphatidylethanolamine, a gut-derived circulating factor induced by fat ingestion, inhibits food intake. Cell, 135(5), 813–824.PubMedCrossRefGoogle Scholar
  141. 141.
    Cani, P. D., Amar, J., Iglesias, M. A., et al. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56(7), 1761–1772.PubMedCrossRefGoogle Scholar
  142. 142.
    Mingrone, G., Nolfe, G., Gissey, G. C., et al. (2009). Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion. Diabetologia, 52(5), 873–881.PubMedCrossRefGoogle Scholar
  143. 143.
    Cummings, D. E., Weigle, D. S., Frayo, R. S., et al. (2002). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine, 346(21), 1623–1630.PubMedCrossRefGoogle Scholar
  144. 144.
    Yildiz, B. O., Suchard, M. A., Wong, M. L., McCann, S. M., & Licinio, J. (2004). Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proceedings of the National Academy of Sciences of the United States of America, 101(28), 10434–10439.PubMedCrossRefGoogle Scholar
  145. 145.
    Blum, I. D., Patterson, Z., Khazall, R., et al. (2009). Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice. Neuroscience, 164(2), 351–359.PubMedCrossRefGoogle Scholar
  146. 146.
    Weikel, J. C., Wichniak, A., Ising, M., et al. (2003). Ghrelin promotes slow-wave sleep in humans. American Journal of Physiology. Endocrinology and Metabolism, 284(2), E407–E415.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Eleonore Maury
  • Kathryn Moynihan Ramsey
  • Joseph Bass
    • 1
    • 2
  1. 1.Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of MedicineNorthwestern UniversityEvanstonUSA
  2. 2.Department of Neurobiology and PhysiologyNorthwestern UniversityEvanstonUSA

Personalised recommendations