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Prospective influences of circadian clocks in adipose tissue and metabolism

Abstract

Circadian rhythms make a critical contribution to endocrine functions that involve adipose tissue. These contributions are made at the systemic, organ and stem cell levels. The transcription factors and enzymes responsible for the maintenance of circadian rhythms in adipose depots and other peripheral tissues that are metabolically active have now been identified. Furthermore, the circadian regulation of glucose and lipid metabolism is well-established. Animal and human models provide strong evidence that disturbances in circadian pathways are associated with an increased risk of type 2 diabetes mellitus, obesity and their comorbidities. Thus, circadian mechanisms represent a novel putative target for therapy in patients with metabolic diseases.

Key Points

  • Circadian mechanisms oscillate because of the continuous operation of a transcriptional regulatory feedback loop

  • Although circadian mechanisms were first associated with the body's central clock in the brain, they also operate in adipose tissue and other metabolically active peripheral tissues

  • Adipose tissue function exhibits circadian oscillations in adipokine secretion, glucose and lipid metabolism and stem cell differentiation pathways

  • Heme is an agonist for a specific nuclear hormone receptor protein in the circadian feedback loop, and studies are underway to uncover related molecules

  • Oncologists have successfully exploited chronotherapy and the timing of drug delivery to maximize the benefits and minimize the adverse effects of chemotherapy

  • Circadian-selective drugs and knowledge of adipose chronobiology could improve the prevention and treatment of endocrine disorders related to adipose tissue, including diabetes mellitus, the metabolic syndrome and obesity

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Figure 1: Feedback loop in the core circadian oscillator.
Figure 2: The anti-phase expression of representative positive and negative arm mRNA in adipose tissue.
Figure 3: Temporal restricted feeding and jet lag.

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References

  1. Bray, G. A. Medical consequences of obesity. J. Clin. Endocrinol. Metab. 89, 2583–2589 (2004).

    CAS  PubMed  Google Scholar 

  2. Marcheva, B., Ramsey, K. M., Affinati, A. & Bass, J. Clock genes and metabolic disease. J. Appl. Physiol. 107, 1638–1646 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Duez, H. & Staels, B. Rev-erbα gives a time cue to metabolism. FEBS Lett. 582, 19–25 (2008).

    CAS  PubMed  Google Scholar 

  4. Bray, M. S. & Young, M. E. The role of cell-specific circadian clocks in metabolism and disease. Obes. Rev. 10 (Suppl. 2), 6–13 (2009).

    CAS  PubMed  Google Scholar 

  5. Yin, L., Wu, N. & Lazar, M. A. Nuclear receptor Rev-erbα: a heme receptor that coordinates circadian rhythm and metabolism. Nucl. Recept. Signal. 8, e001 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Maury, E., Ramsey, K. M. & Bass, J. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ. Res. 106, 447–462 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lowrey, P. L. & Takahashi, J. S. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407–441 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gangwisch, J. E. Epidemiological evidence for the links between sleep, circadian rhythms and metabolism. Obes. Rev. 10 (Suppl. 2), 37–45 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. Hirota, T. & Fukada, Y. Resetting mechanism of central and peripheral circadian clocks in mammals. Zoolog. Sci. 21, 359–368 (2004).

    PubMed  Google Scholar 

  11. Hardin, P. E., Hall, J. C. & Rosbash, M. Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540 (1990).

    CAS  PubMed  Google Scholar 

  12. Wager-Smith, K. & Kay, S. A. Circadian rhythm genetics: from flies to mice to humans. Nat. Genet. 26, 23–27 (2000).

    CAS  PubMed  Google Scholar 

  13. Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. King, D. P. et al. Positional cloning of the mouse circadian Clock gene. Cell 89, 641–653 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hogenesch, J. B. et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272, 8581–8593 (1997).

    CAS  PubMed  Google Scholar 

  16. Ikeda, M. & Nomura, M. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem. Biophys. Res. Commun. 233, 258–264 (1997).

    CAS  PubMed  Google Scholar 

  17. Reick, M., Garcia, J. A., Dudley, C. & McKnight, S. L. NPAS2: an analog of clock operative in the mammalian forebrain. Science 293, 506–509 (2001).

    CAS  PubMed  Google Scholar 

  18. Rutter, J., Reick, M., Wu, L. C. & McKnight, S. L. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514 (2001).

    CAS  PubMed  Google Scholar 

  19. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006).

    CAS  PubMed  Google Scholar 

  20. Alenghat, T. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Akashi, M., Tsuchiya, Y., Yoshino, T. & Nishida, E. Control of intracellular dynamics of mammalian period proteins by casein kinase I ɛ (CKIɛ) and CKIδ in cultured cells. Mol. Cell. Biol. 22, 1693–1703 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kwon, I. et al. BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer. Mol. Cell. Biol. 26, 7318–7330 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Busino, L. et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316, 900–904 (2007).

    CAS  PubMed  Google Scholar 

  24. Siepka, S. M., Yoo, S. H., Park, J., Lee, C. & Takahashi, J. S. Genetics and neurobiology of circadian clocks in mammals. Cold Spring Harb. Symp. Quant. Biol. 72, 251–259 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Siepka, S. M. et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell 129, 1011–1023 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee, J. et al. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol. Cell. Biol. 28, 6056–6065 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sahar, S., Zocchi, L., Kinoshita, C., Borrelli, E. & Sassone-Corsi, P. Regulation of BMAL1 protein stability and circadian function by GSK3β-mediated phosphorylation. PLoS ONE 5, e8561 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. Burris, T. P. Nuclear hormone receptors for heme: REV-ERBα and REV-ERBβ are ligand-regulated components of the mammalian clock. Mol. Endocrinol. 22, 1509–1520 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Raghuram, S. et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 14, 1207–1213 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rogers, P. M., Ying, L. & Burris, T. P. Relationship between circadian oscillations of Rev-erbα expression and intracellular levels of its ligand, heme. Biochem. Biophys. Res. Commun. 368, 955–958 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar, N. et al. Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 151, 3015–3025 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Yin, L. et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 318, 1786–1789 (2007).

    CAS  PubMed  Google Scholar 

  33. Wang, J. & Lazar, M. A. Bifunctional role of Rev-erbα in adipocyte differentiation. Mol. Cell. Biol. 28, 2213–2220 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yin, L., Joshi, S., Wu, N., Tong, X. & Lazar, M. A. E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erbα. Proc. Natl Acad. Sci. USA 107, 11614–11619 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Yin, L. & Lazar, M. A. The orphan nuclear receptor Rev-erbα recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Mol. Endocrinol. 19, 1452–1459 (2005).

    CAS  PubMed  Google Scholar 

  36. Cailotto, C. et al. The suprachiasmatic nucleus controls the daily variation of plasma glucose via the autonomic output to the liver: are the clock genes involved? Eur. J. Neurosci. 22, 2531–2540 (2005).

    PubMed  Google Scholar 

  37. Morris, M. E., Viswanathan, N., Kuhlman, S., Davis, F. C. & Weitz, C. J. A screen for genes induced in the suprachiasmatic nucleus by light. Science 279, 1544–1547 (1998).

    CAS  PubMed  Google Scholar 

  38. Weaver, D. R. The suprachiasmatic nucleus: a 25-year retrospective. J. Biol. Rhythms 13, 100–112 (1998).

    CAS  PubMed  Google Scholar 

  39. Yoo, S. H. et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl Acad. Sci. USA 101, 5339–5346 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    CAS  PubMed  Google Scholar 

  41. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    CAS  PubMed  Google Scholar 

  42. Duffield, G. E. et al. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr. Biol. 12, 551–557 (2002).

    CAS  PubMed  Google Scholar 

  43. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

    CAS  PubMed  Google Scholar 

  44. Ando, H. et al. Rhythmic mRNA expression of clock genes and adipocytokines in mouse visceral adipose tissue. Endocrinology 146, 5631–5636 (2005).

    CAS  PubMed  Google Scholar 

  45. Zvonic, S. et al. Characterization of peripheral circadian clocks in adipose tissues. Diabetes 55, 962–970 (2006).

    CAS  PubMed  Google Scholar 

  46. Wu, X. et al. Expression profile of mRNAs encoding core circadian regulatory proteins in human subcutaneous adipose tissue: correlation with age and body mass index. Int. J. Obes. (Lond.) 33, 971–977 (2009).

    CAS  Google Scholar 

  47. Gómez-Abellán, P., Hernández-Morante, J. J., Luján, J. A., Madrid, J. A. & Garaulet, M. Clock genes are implicated in the human metabolic syndrome. Int. J. Obes. (Lond.) 32, 121–128 (2008).

    Google Scholar 

  48. Otway, D. T., Frost, G. & Johnston, J. D. Circadian rhythmicity in murine pre-adipocyte and adipocyte cells. Chronobiol. Int. 26, 1340–1354 (2009).

    CAS  PubMed  Google Scholar 

  49. Zvonic, S. et al. Circadian oscillation of gene expression in murine calvarial bone. J. Bone Miner. Res. 22, 357–365 (2007).

    CAS  PubMed  Google Scholar 

  50. Ptitsyn, A. A., Zvonic, S. & Gimble, J. M. Permutation test for periodicity in short time series data. BMC Bioinformatics 7 (Suppl. 2), S10 (2006).

    PubMed  PubMed Central  Google Scholar 

  51. Ptitsyn, A. A., Zvonic, S. & Gimble, J. M. Digital signal processing reveals circadian baseline oscillation in majority of mammalian genes. PLoS Comput. Biol. 3, e120 (2007).

    PubMed  PubMed Central  Google Scholar 

  52. Gimble, J. M. et al. Delta sleep-inducing peptide and glucocorticoid-induced leucine zipper: potential links between circadian mechanisms and obesity? Obes. Rev. 10 (Suppl. 2), 46–51 (2009).

    CAS  PubMed  Google Scholar 

  53. McIntosh, K. et al. The immunogenicity of human adipose derived cells: temporal changes in vitro. Stem Cells 24, 1245–1253 (2006).

    Google Scholar 

  54. Mitchell, J. B. et al. Immunophenotype of human adipose derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 24, 376–385 (2006).

    PubMed  Google Scholar 

  55. Gimble, J. M., Katz, A. J. & Bunnell, B. A. Adipose-derived stem cells for regenerative medicine. Circ. Res. 100, 1249–1260 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Busik, J. V. et al. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J. Exp. Med. 206, 2897–2906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lucas, D., Battista, M., Shi, P. A., Isola, L. & Frenette, P. S. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3, 364–366 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Méndez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    PubMed  Google Scholar 

  59. Smaaland, R., Sothern, R. B., Laerum, O. D. & Abrahamsen, J. F. Rhythms in human bone marrow and blood cells. Chronobiol. Int. 19, 101–127 (2002).

    CAS  PubMed  Google Scholar 

  60. Gimble, J. M., Floyd, Z. E. & Bunnell, B. A. The 4th dimension and adult stem cells: can timing be everything? J. Cell. Biochem. 107, 569–578 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zuk, P. A. et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211–228 (2001).

    CAS  PubMed  Google Scholar 

  62. Wu, X. et al. Induction of circadian gene expression in human subcutaneous adipose-derived stem cells. Obesity (Silver Spring) 15, 2560–2570 (2007).

    CAS  Google Scholar 

  63. Ross, S. E. et al. Inhibition of adipogenesis by Wnt signaling. Science 289, 950–953 (2000).

    CAS  PubMed  Google Scholar 

  64. Aratani, Y., Sugimoto, E. & Kitagawa, Y. Lithium ion reversibly inhibits inducer-stimulated adipose conversion of 3T3-L1 cells. FEBS Lett. 218, 47–51 (1987).

    CAS  PubMed  Google Scholar 

  65. Atmaca, M., Kuloglu, M., Tezcan, E. & Ustundag, B. Weight gain and serum leptin levels in patients on lithium treatment. Neuropsychobiology 46, 67–69 (2002).

    CAS  PubMed  Google Scholar 

  66. Baptista, T. et al. Lithium and body weight gain. Pharmacopsychiatry 28, 35–44 (1995).

    CAS  PubMed  Google Scholar 

  67. Chengappa, K. N. et al. Changes in body weight and body mass index among psychiatric patients receiving lithium, valproate, or topiramate: an open-label, nonrandomized chart review. Clin. Ther. 24, 1576–1584 (2002).

    CAS  PubMed  Google Scholar 

  68. Shimba, S. et al. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc. Natl Acad. Sci. USA 102, 12071–12076 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V. & Antoch, M. P. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev. 20, 1868–1873 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bunger, M. K. et al. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis 41, 122–132 (2005).

    CAS  PubMed  Google Scholar 

  71. Turek, F. W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Kennaway, D. J., Owens, J. A., Voultsios, A., Boden, M. J. & Varcoe, T. J. Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1528–R1537 (2007).

    CAS  PubMed  Google Scholar 

  73. Oishi, K. et al. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett. 580, 127–130 (2006).

    CAS  PubMed  Google Scholar 

  74. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Rudic, R. D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).

    PubMed  PubMed Central  Google Scholar 

  76. Shi, X. et al. A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells. EMBO Rep. 4, 374–380 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, W., Yang, N. & Shi, X. M. Regulation of mesenchymal stem cell osteogenic differentiation by glucocorticoid-induced leucine zipper (GILZ). J. Biol. Chem. 283, 4723–4729 (2008).

    CAS  PubMed  Google Scholar 

  78. Gimble, J. M., Robinson, C. E., Wu, X. & Kelly, K. A. The function of adipocytes in the bone marrow stroma: an update. Bone 19, 421–428 (1996).

    CAS  PubMed  Google Scholar 

  79. Gimble, J. M., Zvonic, S., Floyd, Z. E., Kassem, M. & Nuttall, M. E. Playing with bone and fat. J. Cell Biochem. 98, 251–266 (2006).

    CAS  PubMed  Google Scholar 

  80. Davidson, A. J. et al. Chronic jet-lag increases mortality in aged mice. Curr. Biol. 16, R914–R916 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Deacon, S. & Arendt, J. Adapting to phase shifts, I. An experimental model for jet lag and shift work. Physiol. Behav. 59, 665–673 (1996).

    CAS  PubMed  Google Scholar 

  82. Deacon, S. & Arendt, J. Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment. Physiol. Behav. 59, 675–682 (1996).

    CAS  PubMed  Google Scholar 

  83. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Carneiro, B. T. & Araujo, J. F. The food-entrainable oscillator: a network of interconnected brain structures entrained by humoral signals? Chronobiol. Int. 26, 1273–1289 (2009).

    CAS  PubMed  Google Scholar 

  85. Sutton, G. M. et al. The melanocortin-3 receptor is required for entrainment to meal intake. J. Neurosci. 28, 12946–12955 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Sutton, G. M. et al. Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle. FASEB J. 24, 862–872 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Barnea, M., Madar, Z. & Froy, O. High-fat diet delays and fasting advances the circadian expression of adiponectin signaling components in mouse liver. Endocrinology 150, 161–168 (2009).

    CAS  PubMed  Google Scholar 

  88. Arble, D. M., Bass, J., Laposky, A. D., Vitaterna, M. H. & Turek, F. W. Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring) 17, 2100–2102 (2009).

    Google Scholar 

  89. Bray, M. S. et al. Time-of-day-dependent dietary fat consumption influences multiple cardiometabolic syndrome parameters in mice. Int. J. Obes. (Lond.) doi: 10.1038/ijo.2010.63.

    CAS  PubMed  Google Scholar 

  90. de Castro, J. M. The time of day and the proportions of macronutrients eaten are related to total daily food intake. Br. J. Nutr. 98, 1077–1083 (2007).

    CAS  PubMed  Google Scholar 

  91. Kaasik, K. & Lee, C. C. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature 430, 467–471 (2004).

    CAS  PubMed  Google Scholar 

  92. Lewy, A. J., Ahmed, S. & Sack, R. L. Phase shifting the human circadian clock using melatonin. Behav. Brain Res. 73, 131–134 (1996).

    CAS  PubMed  Google Scholar 

  93. Stunkard, A. J., Grace, W. J. & Wolff, H. G. The night-eating syndrome; a pattern of food intake among certain obese patients. Am. J. Med. 19, 78–86 (1955).

    CAS  PubMed  Google Scholar 

  94. Stunkard, A. J., Allison, K. C., Lundgren, J. D. & O'Reardon, J. P. A biobehavioural model of the night eating syndrome. Obes. Rev. 10 (Suppl. 2), 69–77 (2009).

    PubMed  Google Scholar 

  95. Wade, G. N. & Bartness, T. J. Effects of photoperiod and gonadectomy on food intake, body weight, and body composition in Siberian hamsters. Am. J. Physiol. 246, R26–R30 (1984).

    CAS  PubMed  Google Scholar 

  96. Wade, G. N. Dietary obesity in golden hamsters: reversibility and effects of sex and photoperiod. Physiol. Behav. 30, 131–137 (1983).

    CAS  PubMed  Google Scholar 

  97. Bartness, T. J. & Wade, G. N. Photoperiodic control of body weight and energy metabolism in Syrian hamsters (Mesocricetus auratus): role of pineal gland, melatonin, gonads, and diet. Endocrinology 114, 492–498 (1984).

    CAS  PubMed  Google Scholar 

  98. Van Cauter, E., Polonsky, K. S. & Scheen, A. J. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr. Rev. 18, 716–738 (1997).

    CAS  PubMed  Google Scholar 

  99. Van Cauter, E. V. et al. Abnormal temporal patterns of glucose tolerance in obesity: relationship to sleep-related growth hormone secretion and circadian cortisol rhythmicity. J. Clin. Endocrinol. Metab. 79, 1797–1805 (1994).

    CAS  PubMed  Google Scholar 

  100. Polonsky, K. S., Given, B. D. & Van Cauter, E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J. Clin. Invest. 81, 442–448 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Van Cauter, E. et al. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J. Clin. Invest. 88, 934–942 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Donga, E. et al. Partial sleep restriction decreases insulin sensitivity in type 1 diabetes. Diabetes Care 33, 1573–1577 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Mansour, H. A., Monk, T. H. & Nimgaonkar, V. L. Circadian genes and bipolar disorder. Ann. Med. 37, 196–205 (2005).

    CAS  PubMed  Google Scholar 

  104. Mansour, H. A. et al. Circadian phase variation in bipolar I disorder. Chronobiol. Int. 22, 571–584 (2005).

    PubMed  Google Scholar 

  105. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Göttlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).

    PubMed  PubMed Central  Google Scholar 

  107. Nievergelt, C. M. et al. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 234–241 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lemberger, T. et al. Expression of the peroxisome proliferator-activated receptor α gene is stimulated by stress and follows a diurnal rhythm. J. Biol. Chem. 271, 1764–1769 (1996).

    CAS  PubMed  Google Scholar 

  109. Canaple, L. et al. Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor α defines a novel positive feedback loop in the rodent liver circadian clock. Mol. Endocrinol. 20, 1715–1727 (2006).

    CAS  PubMed  Google Scholar 

  110. Brewer, M., Lange, D., Baler, R. & Anzulovich, A. SREBP-1 as a transcriptional integrator of circadian and nutritional cues in the liver. J. Biol. Rhythms 20, 195–205 (2005).

    CAS  PubMed  Google Scholar 

  111. Yin, L., Wang, J., Klein, P. S. & Lazar, M. A. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 311, 1002–1005 (2006).

    CAS  PubMed  Google Scholar 

  112. Yildiz, B. O., Suchard, M. A., Wong, M. L., McCann, S. M. & Licinio, J. Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc. Natl Acad. Sci. USA 101, 10434–10439 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ahmad, A. M. et al. Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement. J. Clin. Endocrinol. Metab. 86, 3499–3506 (2001).

    CAS  PubMed  Google Scholar 

  114. Kok, S. W. et al. Reduction of plasma leptin levels and loss of its circadian rhythmicity in hypocretin (orexin)-deficient narcoleptic humans. J. Clin. Endocrinol. Metab. 87, 805–809 (2002).

    CAS  PubMed  Google Scholar 

  115. Sinha, M. K. et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 97, 1344–1347 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Gavrila, A. et al. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J. Clin. Endocrinol. Metab. 88, 2838–2843 (2003).

    CAS  PubMed  Google Scholar 

  117. De Gasquet, P., Griglio, S., Pequignot-Planche, E. & Malewiak, M. I. Diurnal changes in plasma and liver lipids and lipoprotein lipase activity in heart and adipose tissue in rats fed a high and low fat diet. J. Nutr. 107, 199–212 (1977).

    CAS  PubMed  Google Scholar 

  118. Arasaradnam, M. P., Morgan, L., Wright, J. & Gama, R. Diurnal variation in lipoprotein lipase activity. Ann. Clin. Biochem. 39, 136–139 (2002).

    CAS  PubMed  Google Scholar 

  119. Zvonic, S. F. Z., Floyd, Z. E., Mynatt, R. L. & Gimble, J. M. Circadian rhythms and the regulation of metabolic tissue function and energy homeostasis. Obesity 15, 539–543 (2006).

    Google Scholar 

  120. Cermakian, N. & Boivin, D. B. The regulation of central and peripheral circadian clocks in humans. Obes. Rev. 10 (Suppl. 2), 25–36 (2009).

    CAS  PubMed  Google Scholar 

  121. Johnston, J. D., Frost, G. & Otway, D. T. Adipose tissue, adipocytes and the circadian timing system. Obes. Rev. 10 (Suppl. 2), 52–60 (2009).

    PubMed  Google Scholar 

  122. Sutton, G. M., Centanni, A. V. & Butler, A. A. Protein malnutrition during pregnancy in C57BL/6J mice results in offspring with altered circadian physiology before obesity. Endocrinology 151, 1570–1580 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Oishi, K., Kasamatsu, M. & Ishida, N. Gene- and tissue-specific alterations of circadian clock gene expression in streptozotocin-induced diabetic mice under restricted feeding. Biochem. Biophys. Res. Commun. 317, 330–334 (2004).

    CAS  PubMed  Google Scholar 

  124. Oishi, K. et al. Tissue-specific augmentation of circadian PAI-1 expression in mice with streptozotocin-induced diabetes. Thromb. Res. 114, 129–135 (2004).

    CAS  PubMed  Google Scholar 

  125. Young, M. E., Wilson, C. R., Razeghi, P., Guthrie, P. H. & Taegtmeyer, H. Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. J. Mol. Cell. Cardiol. 34, 223–231 (2002).

    CAS  PubMed  Google Scholar 

  126. Antoch, M. P. & Kondratov, R. V. Circadian proteins and genotoxic stress response. Circ. Res. 106, 68–78 (2010).

    CAS  PubMed  Google Scholar 

  127. Kondratov, R. V. & Antoch, M. P. Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends Cell Biol. 17, 311–317 (2007).

    CAS  PubMed  Google Scholar 

  128. Froy, O. Cytochrome P450 and the biological clock in mammals. Curr. Drug Metab. 10, 104–115 (2009).

    CAS  PubMed  Google Scholar 

  129. Scott, E. M., Carter, A. M. & Grant, P. J. Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int. J. Obes. (Lond.) 32, 658–662 (2008).

    CAS  Google Scholar 

  130. Sookoian, S. et al. Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am. J. Clin. Nutr. 87, 1606–1615 (2008).

    CAS  PubMed  Google Scholar 

  131. Garaulet, M. et al. Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors in overweight subjects (GOLDN population). Eur. J. Hum. Genet. 18, 364–369 (2010).

    CAS  PubMed  Google Scholar 

  132. Garaulet, M. et al. CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet. Int. J. Obes. (Lond.) 34, 516–523 (2010).

    CAS  Google Scholar 

  133. Woon, P. Y. et al. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc. Natl Acad. Sci. USA 104, 14412–14417 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Garaulet, M. et al. PERIOD2 variants are associated with abdominal obesity, psycho-behavioral factors, and attrition in the dietary treatment of obesity. J. Am. Diet Assoc. 110, 917–921 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Andersson, E. A. et al. MTNR1B G24E variant associates with BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans. Diabetes 59, 1539–1548 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Prokopenko, I. et al. Variants in MTNR1B influence fasting glucose levels. Nat. Genet. 41, 77–81 (2009).

    CAS  PubMed  Google Scholar 

  137. Bouatia-Naji, N. et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat. Genet. 41, 89–94 (2009).

    CAS  PubMed  Google Scholar 

  138. Chen, J. J. & London, I. M. Hemin enhances the differentiation of mouse 3T3 cells to adipocytes. Cell 26, 117–122 (1981).

    CAS  PubMed  Google Scholar 

  139. Hauner, H. et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J. Clin. Invest. 84, 1663–1670 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Kliewer, S. A. et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83, 813–819 (1995).

    CAS  PubMed  Google Scholar 

  141. Forman, B. M. et al. 15-Deoxy-Δ 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812 (1995).

    CAS  PubMed  Google Scholar 

  142. Krey, G. et al. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol. 11, 779–791 (1997).

    CAS  PubMed  Google Scholar 

  143. Schopfer, F. J. et al. Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor gamma ligand. Proc. Natl Acad. Sci. USA 102, 2340–2345 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Wang, N. et al. Vascular PPARγ controls circadian variation in blood pressure and heart rate through Bmal1. Cell Metab. 8, 482–491 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Shirai, H., Oishi, K., Kudo, T., Shibata, S. & Ishida, N. PPARα is a potential therapeutic target of drugs to treat circadian rhythm sleep disorders. Biochem. Biophys. Res. Commun. 357, 679–682 (2007).

    CAS  PubMed  Google Scholar 

  146. Oishi, K., Shirai, H. & Ishida, N. PPARα is involved in photoentrainment of the circadian clock. Neuroreport 19, 487–489 (2008).

    CAS  PubMed  Google Scholar 

  147. Paschos, G. K., Baggs, J. E., Hogenesch, J. B. & FitzGerald, G. A. The role of clock genes in pharmacology. Annu. Rev. Pharmacol. Toxicol. 50, 187–214 (2010).

    CAS  PubMed  Google Scholar 

  148. Iurisci, I. et al. Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor. Cancer Res. 66, 10720–10728 (2006).

    CAS  PubMed  Google Scholar 

  149. Lévi, F. Chronotherapeutics: the relevance of timing in cancer therapy. Cancer Causes Control 17, 611–621 (2006).

    PubMed  Google Scholar 

  150. Lévi, F., Filipski, E., Iurisci, I., Li, X. M. & Innominato, P. Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harb. Symp. Quant. Biol. 72, 465–475 (2007).

    PubMed  Google Scholar 

  151. Shakil, A., Hirabayashi, N. & Toge, T. Circadian variation of 5-fluorouracil and cis-platinum toxicity in mice. Hiroshima J. Med. Sci. 42, 147–154 (1993).

    CAS  PubMed  Google Scholar 

  152. Bailleul, F., Lévi, F., Reinberg, A. & Mathé, G. Interindividual differences in the circadian hematologic time structure of cancer patients. Chronobiol. Int. 3, 47–54 (1986).

    CAS  PubMed  Google Scholar 

  153. Padwal, R. S. & Majumdar, S. R. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 369, 71–77 (2007).

    CAS  PubMed  Google Scholar 

  154. Tam, J. et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J. Clin. Invest. 120, 2953–2966 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Patti, M. E. Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes? J. Clin. Invest. 120, 2646–2648 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Antoch, M. P. & Chernov, M. V. Pharmacological modulators of the circadian clock as potential therapeutic drugs. Mutat. Res. 680, 109–115 (2009).

    CAS  PubMed  Google Scholar 

  157. Hirota, T. & Kay, S. A. High-throughput screening and chemical biology: new approaches for understanding circadian clock mechanisms. Chem. Biol. 16, 921–927 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors wish to thank their colleagues in the Stem Cell Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA, and the Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA, USA, for their comments and input; Ms. Laura Dallam for editorial and administrative assistance; Dr. Xiying Wu for assistance in the preparation of figures; and the Pennington Biomedical Research Foundation for funding.

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J. M. Gimble and A. A. Ptitsyn researched data for the article. J. M. Gimble, G. M. Sutton, B. A. Bunnell and Z. E. Floyd provided substantial contributions to the discussion of the content. J. M. Gimble and B. A. Bunnell wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Jeffrey M. Gimble.

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Gimble, J., Sutton, G., Bunnell, B. et al. Prospective influences of circadian clocks in adipose tissue and metabolism. Nat Rev Endocrinol 7, 98–107 (2011). https://doi.org/10.1038/nrendo.2010.214

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