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Exp Clin Endocrinol Diabetes 2013; 121(08): 466-474
DOI: 10.1055/s-0033-1349123
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Effect of Streptozotocin-induced Diabetes on Clock Gene Expression in Tissues Inside and Outside the Blood-brain Barrier in Rat

D. Šoltésová
1   Department of Animal Physiology and Ethology, Comenius University in Bratislava, Bratislava, Slovak Republic
,
J. Monošíková
1   Department of Animal Physiology and Ethology, Comenius University in Bratislava, Bratislava, Slovak Republic
,
L. Koyšová
1   Department of Animal Physiology and Ethology, Comenius University in Bratislava, Bratislava, Slovak Republic
,
A. Veselá
1   Department of Animal Physiology and Ethology, Comenius University in Bratislava, Bratislava, Slovak Republic
,
B. Mravec
2   Institute of Pathophysiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovak Republic
3   Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
,
I. Herichová
1   Department of Animal Physiology and Ethology, Comenius University in Bratislava, Bratislava, Slovak Republic
› Author Affiliations
Further Information

Publication History

received 01 March 2013
first decision 04 June 2013

accepted 12 June 2013

Publication Date:
17 July 2013 (online)

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Abstract

The circadian system allows organisms to remain synchronized with rhythmic environmental changes with a 24-h period. The molecular mechanism of circadian oscillations is based on the rhythmic expression of clock genes organized in feedback loops. Alterations in the circadian system contribute to the development of several pathological conditions including diabetes, but the exact mechanisms responsible for such alterations are not known. Therefore, we employed streptozotocin-induced diabetes to elucidate the influence of metabolic changes on clock gene (clock, npas2, per2) expression in peripheral oscillators in tissues inside (frontal cortex, cerebellum) and outside (heart, kidney) the blood–brain barrier. Diabetes was induced by streptozotocin injection. Seventeen days later, sampling was performed during a 24-h cycle. Gene expression was measured using real-time PCR. We observed a phase advance in rhythmic clock gene expression in the heart and kidney of diabetic rats. The study also focused on the possible role of npas2 in locomotor activity regulation in diabetic animals. The most pronounced changes were observed in the frontal cortex, which displayed up-regulation of npas2 expression. A change in locomotor activity was observed in diabetic rats during the dark phase of the 24-h cycle. We suggest that the altered function of the frontal cortex induced by diabetes might contribute to the modified behavior of diabetic rats.

Key words

frontal cortex - heart - cerebellum - per2 - npas2 - locomotor activity
 

  • References

  • 1 Aschoff J. Handbook of behavioral neurobiology: IV. Biological rhythms. New York: Plenum Press; 1981: 25-60
    CrossrefGoogle Scholar
  • 2 Challet E. Interactions between light, mealtime and calorie restriction to control daily timing in mammals. J Comp Physiol B 2010; 180: 631-644
    CrossrefPubMedGoogle Scholar
  • 3 Barnard AR, Nolan PM. When clocks go bad: neurobehavioural consequences of disrupted circadian timing. PLoS Genet 2008; 4: e1000040
    CrossrefPubMedGoogle Scholar
  • 4 Laposky AD, Bass J, Kohsaka A et al. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett 2008; 582: 142-151
    CrossrefPubMedGoogle Scholar
  • 5 Hashiramoto A, Yamane T, Tsumiyama K et al. Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-alpha. J Immunol 2010; 184: 1560-1565
    CrossrefPubMedGoogle Scholar
  • 6 Sumová A, Trávnícková Z, Peters R et al. The rat suprachiasmatic nucleus is a clock for all seasons. Proc Natl Acad Sci USA 1995; 92: 7754-7758
    CrossrefPubMedGoogle Scholar
  • 7 Zylka MJ, Shearman LP, Weaver DR et al. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 1998; 20: 1103-1110
    CrossrefPubMedGoogle Scholar
  • 8 Balsalobre A, Brown SA, Marcacci L et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 2000; 289: 2344-2347
    CrossrefPubMedGoogle Scholar
  • 9 Damiola F, Le Minh N, Preitner N et al. Restricted feeding uncouples circadian oscillator in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 2000; 14: 2950-2961
    CrossrefPubMedGoogle Scholar
  • 10 Shearman LP, Sriram S, Weaver DR et al. Interacting molecular loops in the mammalian circadian clock. Science 2000; 288: 1013-1019
    CrossrefPubMedGoogle Scholar
  • 11 Albrecht U, Zheng B, Larkin D et al. mPer1 and mPer2 are essential for normal resetting of the circadian clock. J Biol Rhythms 2001; 16: 100-104
    CrossrefPubMedGoogle Scholar
  • 12 Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002; 418: 935-941
    CrossrefPubMedGoogle Scholar
  • 13 Albrecht U. Orchestration of gene expression and physiology by the circadian clock. J Physiol Paris 2006; 100: 243-251
    CrossrefPubMedGoogle Scholar
  • 14 Ko CH, Takahashi JS. Molecular components of the mammalian circadian clock. Hum Mol Genet 2006; 15: R271-R277
    CrossrefPubMedGoogle Scholar
  • 15 DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci 2007; 5: 543-545
    PubMedGoogle Scholar
  • 16 Shi S, Hida A, McGuinness OP et al. Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2. Curr Biol 2010; 20: 316-321
    CrossrefPubMedGoogle Scholar
  • 17 Zhou YD, Barnard M, Tian H et al. Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system. Proc Natl Acad Sci USA 1997; 94: 713-718
    CrossrefPubMedGoogle Scholar
  • 18 Reick M, Garcia JA, Dudley C et al. NPAS2: An analog of clock operative in mammalian forebrain. Science 2001; 293: 506-509
    CrossrefPubMedGoogle Scholar
  • 19 Dudley CA, Erbel-Sieler C, Estill SJ et al. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 2003; 301: 379-383
    CrossrefPubMedGoogle Scholar
  • 20 Wu X, Wiater MF, Ritter S. NPAS2 deletion impairs responses to restricted feeding but not to metabolic challenges. Physiol Behav 2010; 99: 466-471
    CrossrefPubMedGoogle Scholar
  • 21 Kohsaka A, Laposky AD, Ramsey KM et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 2007; 6: 414-421
    CrossrefPubMedGoogle Scholar
  • 22 Oishi K, Uchida D, Ohkura N et al. Ketogenic diet disrupts the circadian clock and increases hypofibrinolytic risk by inducing expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2009; 29: 1571-1577
    CrossrefPubMedGoogle Scholar
  • 23 Challet E, Losee-Olson S, Turek FW. Reduced glucose availability attenuates circadian responses to light in mice. Am J Physiol 1999; 276: 1063-1070
    PubMedGoogle Scholar
  • 24 Hirota T, Okano T, Kokame K et al. Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured rat-1 fibroblasts. J Biol Chem 2002; 277: 44244-44251
    CrossrefPubMedGoogle Scholar
  • 25 Iwanaga H, Yano M, Miki H et al. Per2 gene expressions in the suprachiasmatic nucleus and liver differentially respond to nutrition factors in rats. JPEN J Parenter Enteral Nutr 2005; 29: 157-161
    CrossrefPubMedGoogle Scholar
  • 26 Yamanouchi S, Shimazoe T, Nagata S et al. Decreased level of light-induced Fos expression in the suprachiasmatic nucleus of diabetic rats. Neurosci Lett 1997; 227: 103-106
    CrossrefPubMedGoogle Scholar
  • 27 Brown MJ, Sumner AJ, Greene AG et al. Distal neuropathy in experimental diabetes mellitus Ann. Neurol 1980; 8: 168-178
    PubMedGoogle Scholar
  • 28 Baydas G, Nedzvetskii VS, Nerush PA et al. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003; 73: 1907-1916
    CrossrefPubMedGoogle Scholar
  • 29 Hoybergs YM, Biermans RL, Meert TF. The impact of bodyweight and body condition on behavioral testing for painful diabetic neuropathy in the streptozotocin rat model. Neurosci Lett 2008; 436: 13-18
    CrossrefPubMedGoogle Scholar
  • 30 Joghataie MT, Roghani M, Jalali MR et al. Dendritic spine changes in medial prefrontal cortex of male diabetic rats using Golgi-impregnation method. Arch Iran med 2007; 10: 54-58
    PubMedGoogle Scholar
  • 31 Shimazoe T, Ishida J, Maetani M et al. Entrainment function in the suprachiasmatic nucleus of streptozotocin-induced diabetic rats. Jpn J Pharmacol 2000; 83: 355-358
    CrossrefPubMedGoogle Scholar
  • 32 Rerup CC. Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 1970; 22: 485-518
    PubMedGoogle Scholar
  • 33 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate phenol-chloroform extraction. Anal Biochem 1987; 162: 156-159
    PubMedGoogle Scholar
  • 34 Nelson W, Tong YL, Lee JK et al. Methods for cosinor-rhythmometry. Chronobiologia 1979; 6: 305-323
    PubMedGoogle Scholar
  • 35 Klemfuss H, Clopton PL. Seeking tau: a comparison of six methods. J Interdiscip Cycle Res 1993; 24: 1-16
    CrossrefPubMedGoogle Scholar
  • 36 Warnecke M, Oster H, Revelli JP et al. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception. Genes Dev 2005; 19: 614-625
    CrossrefPubMedGoogle Scholar
  • 37 Rath MF, Rohde K, Fahrenkrug J et al. Circadian clock components in the rat neocortex: daily dynamics, localization and regulation. Brain Struct Funct 2012; [Epub ahead of print]
    PubMedGoogle Scholar
  • 38 Silver IA, Erecińska M. Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J Neurosci 1994; 14: 5068-5076
    PubMedGoogle Scholar
  • 39 Jacob RJ, Fan X, Evans ML et al. Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no evidence for protective adaptation by the blood brain barrier. Metabolism 2002; 51: 1522-1524
    CrossrefPubMedGoogle Scholar
  • 40 Puchowicz MA, Xu K, Magness D et al. Comparison of glucose influx and blood flow in retina and brain of diabetic rats. J Cereb Blood Flow Metab 2004; 24: 449-457
    CrossrefPubMedGoogle Scholar
  • 41 Rutter J, Reick M, Wu LC et al. Reglutaion of Clock and NPAS2 DNA Binding by the Redox State of NAD Cofactors. Science 2001; 293: 510-514
    CrossrefPubMedGoogle Scholar
  • 42 Pardini L, Kaeffer B. Feeding and circadian clocks. Reprod Nutr Dev 2006; 5: 463-480
    PubMedGoogle Scholar
  • 43 Mizuno Y, Oomura Y. Glucose responding neurons in the nucleus tractus solitarius of the rat, in vitro study. Brain Res 1984; 307: 109-116
    CrossrefPubMedGoogle Scholar
  • 44 Silver IA, Erecinska M. Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons. J Neurophysiol 1998; 79: 1733-1745
    PubMedGoogle Scholar
  • 45 Routh VH. Glucose sensing neurons in the ventromedial hypothalamus. Sensors 2010; 10: 9002-9025
    CrossrefPubMedGoogle Scholar
  • 46 Thorens B. Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obes Metab 2011; (Suppl. 01) 82-88
    PubMedGoogle Scholar
  • 47 Velasco A, Huerta I, Marin B. Plasma corticosterone, motor activity and metabolic circadian patterns in streptozotocin-induced diabetic rats. Chronobiol Int 1988; 5: 127-135
    CrossrefPubMedGoogle Scholar
  • 48 Shimomura Y, Shimizu H, Takahashi M et al. Changes in ambulatory activity and dopamine turnover in streptozotocin-induced diabetic rats. Endocrinology 1988; 123: 2621-2625
    CrossrefPubMedGoogle Scholar
  • 49 Shimomura Y, Shimizu H, Takahashi M et al. Ambulatory activity in streptozotocin-induced diabetic rats. Physiol Behav 1990; 47: 1153-1155
    CrossrefPubMedGoogle Scholar
  • 50 Howarth FC, Jacobson M, Naseer O et al. Short-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol 2005; 90: 237-245
    CrossrefPubMedGoogle Scholar
  • 51 Howarth FC, Jacobson M, Shafiullah M et al. Long-term effects of streptozotocininduced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol 2005; 90: 827-835
    CrossrefPubMedGoogle Scholar
  • 52 Ramadan W, Dewasmes G, Petitjean M et al. Spontaneous motor activity in fat-fed, streptozotocin-treated rats: a nonobese model of type 2 diabetes. Physiol Behav 2006; 87: 765-772
    CrossrefPubMedGoogle Scholar
  • 53 Kamei J, Saitoh A, Iwamoto Y et al. Effects of diabetes on spontaneous locomotor activity in mice. Neurosci Lett 1994; 178: 69-72
    CrossrefPubMedGoogle Scholar
  • 54 Kamei J, Saitoh A. Evidence for the modulation of spontaneous locomotor activity by higher serum glucose levels and/or spleen-derived factor(s) in diabetic mice. Life Sci 1997; 60: 1699-1708
    CrossrefPubMedGoogle Scholar
  • 55 Stephan FK, Davidson AJ. Glucose, but not fat phase shifts the feeding-entrained circadian clock. Physiol Behav 1998; 65: 277-288
    CrossrefPubMedGoogle Scholar
  • 56 Kraemer S, Danker-Hopfe H, Dorn H et al. Time-of-day variations of indicators of attention: performance, physiologic parameters, and selfassessment of sleepiness. Biol Psychiatry 2000; 48: 1069-1080
    CrossrefPubMedGoogle Scholar
  • 57 Tanji J, Hoshi E. Behavioral planning in the prefrontal cortex. Curr Opin Neurobiol 2001; 11: 164-170
    CrossrefPubMedGoogle Scholar
  • 58 Sylvester CM, Krout KE, Loewy AD. Suprachiasmatic nucleus projection to the medial prefrontal cortex: a viral transneuronal tracing study. Neuroscience 2002; 114: 1071-1080
    CrossrefPubMedGoogle Scholar
  • 59 Phillips CI, Smith VM, Antle MC et al. Neonatal medial frontal cortex lesions disrupt circadian activity patterns. Dev Neurosci 2009; 31: 412-419
    CrossrefPubMedGoogle Scholar
  • 60 Garcia JA, Zhang D, Estill SJ et al. Impaired cued and contextual memory in NPAS2-deficient mice. Science 2000; 288: 2226-2230
    CrossrefPubMedGoogle Scholar
  • 61 Franken P, Dudley A, Estill SJ et al. NPAS2 as a transcriptional regulator of non-rapid eye-movement sleep: Genotype and sex interactions. PNAS 2006; 103: 7118-7123
    CrossrefPubMedGoogle Scholar
  • 62 Howarth FC, Jacobson M, Shafiullah M et al. Long-term effects of streptozotocininduced diabetes on the electrocardiogram, physical activity and body temperature in rats. Exp Physiol 2005; 90: 827-835
    CrossrefPubMedGoogle Scholar
  • 63 Challet E, van Reeth O, Turek FW. Altered circadian responses to light in streptozotocin-induced diabetic mice. Am J Physiol Endocrinol Metab 1999; 277: E232-E237
    PubMedGoogle Scholar
  • 64 da Costa AV, Calábria LK, Nascimento R et al. The streptozotocin- induced rat model of diabetes mellitus evidences significant reduction of myosin-Va expression in the brain. Metab Brain Dis 2011; 26: 247-251
    CrossrefPubMedGoogle Scholar
  • 65 Young ME, Wilson CR, Razeghi P et al. Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. J Mol Cell Cardiol 2002; 34: 223-231
    CrossrefPubMedGoogle Scholar
  • 66 Oishi K, Kasamatsu M, Ishida N. Gene- and tissue-specific alterations of clock gene expression in streptozotocin-induced diabetic mice under restricted feeding. Biochem Biophys Res Commun 2004; 317: 330-334
    CrossrefPubMedGoogle Scholar
  • 67 Herichová I, Zeman M, Stebelová K et al. Effect of streptozotocin-induced diabetes on daily expression of per2 and dbp in the heart and liver and melatonin rhythm in the pineal gland of Wistar rats. Mol Cell Biochem 2005; 270: 223-229
    CrossrefPubMedGoogle Scholar