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NCB5OR Deficiency in the Cerebellum and Midbrain Leads to Dehydration and Alterations in Thirst Response, Fasted Feeding Behavior, and Voluntary Exercise in Mice

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Abstract

Cytosolic NADH­cytochrome­b5­oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity. It has been established that lesion to or removal of the cerebellum leads to changes in nutrient organization, visceral response, feeding behavior, and body weight. This study assessed whether loss of NCB5OR in the cerebellum and midbrain altered feeding or metabolic activity and had an effect on serum T3, cortisol, prolactin, and leptin levels. Metabolic cage data revealed that 16 week old male CKO mice had elevated respiratory quotients and decreased respiratory water expulsion, decreased voluntary exercise, and altered feeding and drinking behavior compared to wild-type littermate controls. Most notably, male CKO mice displayed higher consumption of food during refeeding after a 48­h fast. Echo MRI revealed normal body composition but decreased total water content and hydration ratios in CKO mice. Increased serum osmolality measurements confirmed the dehydration status of male CKO mice. Serum leptin levels were significantly elevated in male CKO mice while prolactin, T3, and cortisol levels remain unchanged relative to wild-type controls, consistent with elevated transcript levels for leptin receptors (short form) in the male CKO mouse cerebellum. Taken together, these findings suggest altered feeding response post starvation as a result of NCB5OR deficiency in the cerebellum.

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References

  1. Stroh M, Swerdlow RH, Zhu H. Common defects of mitochondria and iron in neurodegeneration and diabetes (MIND): a paradigm worth exploring. Biochem Pharmacol. 2014;88(4):573–83.

    Article  CAS  PubMed  Google Scholar 

  2. Zhu H, Qiu H, Yoon HW, Huang S, Bunn HF. Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells. Proc Natl Acad Sci U S A. 1999;96(26):14742–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhu H, et al. NCB5OR is a novel soluble NAD(P)H reductase localized in the endoplasmic reticulum. J Biol Chem. 2004;279(29):30316–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kalman FS, et al. Natural mutations lead to enhanced proteasomal degradation of human Ncb5or, a novel flavoheme reductase. Biochimie. 2013;95(7):1403–10.

    Article  CAS  PubMed  Google Scholar 

  5. Zhu H, Wang WF, Wang HP, Xu M, E L, Swerdlow RH. Impaired iron metabolism in monogenic Ncb5or diabetes. Diabetes. 2013;62:556–87. (Abstract)

    Article  Google Scholar 

  6. Xu M, et al. Ncb5or deficiency increases fatty acid catabolism and oxidative stress. J Biol Chem. 2011;286(13):11141–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guo Y, et al. Beta-cell injury in Ncb5or-null mice is exacerbated by consumption of a high-fat diet. Eur J Lipid Sci Technol. 2012;114(3):233–43.

    Article  CAS  PubMed  Google Scholar 

  8. Larade K, et al. Loss of Ncb5or results in impaired fatty acid desaturation, lipoatrophy, and diabetes. J Biol Chem. 2008;283(43):29285–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Xie J, et al. Absence of a reductase, NCB5OR, causes insulin-deficient diabetes. Proc Natl Acad Sci U S A. 2004;101(29):10750–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stroh MA, Winter MK, Swerdlow RH, McCarson KE, Zhu H. Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice. Metab Brain Dis. 2016;31:951–64.

    Article  CAS  PubMed  Google Scholar 

  11. Mendoza J, Pevet P, Felder-Schmittbuhl MP, Bailly Y, Challet E. The cerebellum harbors a circadian oscillator involved in food anticipation. J Neurosci. 2010;30(5):1894–904.

    Article  CAS  PubMed  Google Scholar 

  12. Zhu JN, Wang JJ. The cerebellum in feeding control: possible function and mechanism. Cell Mol Neurobiol. 2008;28(4):469–78.

    Article  PubMed  Google Scholar 

  13. Kim JG, Jung HS, Kim KJ, Min SS, Yoon BJ. Basal blood corticosterone level is correlated with susceptibility to chronic restraint stress in mice. Neurosci Lett. 2013;555:137–42.

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura K, et al. Effect of food-restriction stress on immune response in mice. J Neuroimmunol. 1990;30(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  15. Gong S, et al. Dynamics and correlation of serum cortisol and corticosterone under different physiological or stressful conditions in mice. PLoS One. 2015;10(2):e0117503.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dietrichs E, Haines DE, Roste GK, Roste LS. Hypothalamocerebellar and cerebellohypothalamic projections—circuits for regulating nonsomatic cerebellar activity? Histol Histopathol. 1994;9(3):603–14.

    CAS  PubMed  Google Scholar 

  17. Haines DE, Dietrichs E, Mihailoff GA, McDonald EF. The cerebellar-hypothalamic axis: basic circuits and clinical observations. Int Rev Neurobiol. 1997;41:83–107.

    Article  CAS  PubMed  Google Scholar 

  18. Zhu JN, Yung WH, Kwok-Chong Chow B, Chan YS, Wang JJ. The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration. Brain Res Rev. 2006;52(1):93–106.

    Article  PubMed  Google Scholar 

  19. Hoche F, Guell X, Sherman JC, Vangel MG, & Schmahmann JD. Cerebellar contribution to social cognition. Cerebellum. 2016;15(6):732–743.

  20. Korenaga K, et al. Clinical usefulness of non-protein respiratory quotient measurement in non-alcoholic fatty liver disease. Hepatol Res. 2013;43(12):1284–94.

    Article  PubMed  Google Scholar 

  21. Nakaya Y, et al. Respiratory quotient in patients with non-insulin-dependent diabetes mellitus treated with insulin and oral hypoglycemic agents. Ann Nutr Metab. 1998;42(6):333–40.

    Article  CAS  PubMed  Google Scholar 

  22. Antunes-Rodrigues J, de Castro M, Elias LL, Valenca MM, McCann SM. Neuroendocrine control of body fluid metabolism. Physiol Rev. 2004;84(1):169–208.

    Article  CAS  PubMed  Google Scholar 

  23. Franci CR, Kozlowski GP, McCann SM. Water intake in rats subjected to hypothalamic immunoneutralization of angiotensin II, atrial natriuretic peptide, vasopressin, or oxytocin. Proc Natl Acad Sci U S A. 1989;86(8):2952–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Daniels D. Angiotensin II (de)sensitization: fluid intake studies with implications for cardiovascular control. Physiol Behav. 2016.

  25. Thornton SN. Angiotensin inhibition and longevity: a question of hydration. Pflugers Archiv-Eur J Physiol. 2011;461(3):317–24.

    Article  CAS  Google Scholar 

  26. Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C. Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Front Neuroendocrinol. 1997;18(4):383–439.

    Article  CAS  PubMed  Google Scholar 

  27. Huang Z, et al. Immunohistochemical detection of angiotensin II receptors in mouse cerebellum and adrenal gland using “in vivo cryotechnique”. Histochem Cell Biol. 2013;140(4):477–90.

    Article  CAS  PubMed  Google Scholar 

  28. Parsons LM, et al. Neuroimaging evidence implicating cerebellum in support of sensory/cognitive processes associated with thirst. Proc Natl Acad Sci U S A. 2000;97(5):2332–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wen YQ, Zhu JN, Zhang YP, Wang JJ. Cerebellar interpositus nuclear inputs impinge on paraventricular neurons of the hypothalamus in rats. Neurosci Lett. 2004;370(1):25–9.

    Article  CAS  PubMed  Google Scholar 

  30. Santollo J, Daniels D. Control of fluid intake by estrogens in the female rat: role of the hypothalamus. Front Syst Neurosci. 2015;9:25.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Santollo J, Daniels D. Multiple estrogen receptor subtypes influence ingestive behavior in female rodents. Physiol Behav. 2015;152(Pt B):431–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xue B, Johnson AK, Hay M. Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen. Am J Physiol Regul Integr Comp Physiol. 2013;305(5):R459–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Keller U, Szinnai G, Bilz S, Berneis K. Effects of changes in hydration on protein, glucose and lipid metabolism in man: impact on health. Eur J Clin Nutr. 2003;57(Suppl 2):S69–74.

    Article  CAS  PubMed  Google Scholar 

  34. Kalra B, Gefen E. Scorpions regulate their energy metabolism towards increased carbohydrate oxidation in response to dehydration. Comp Biochem Physiol A Mol Integr Physiol. 2012;162(4):372–7.

    Article  CAS  PubMed  Google Scholar 

  35. Logan-Sprenger HM, Heigenhauser GJ, Jones GL, Spriet LL. The effect of dehydration on muscle metabolism and time trial performance during prolonged cycling in males. Physiol Rep. 2015;3(8)

  36. Diaz-Munoz M, Vazquez-Martinez O, Aguilar-Roblero R, Escobar C. Anticipatory changes in liver metabolism and entrainment of insulin, glucagon, and corticosterone in food-restricted rats. Am J Physiol Regul Integr Comp Physiol. 2000;279(6):R2048–56.

    Article  CAS  PubMed  Google Scholar 

  37. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763–70.

    Article  CAS  PubMed  Google Scholar 

  38. van Swieten MMH, Pandit R, Adan RAH, van der Plasse G. The neuroanatomical function of leptin in the hypothalamus. J Chem Neuroanat. 2014;61-62:207–20.

    Article  PubMed  Google Scholar 

  39. Bennett PA, et al. Differential expression and regulation of leptin receptor isoforms in the rat brain: effects of fasting and oestrogen. Neuroendocrinology. 1998;67(1):29–36.

    Article  CAS  PubMed  Google Scholar 

  40. Burguera B, et al. The long form of the leptin receptor (OB-Rb) is widely expressed in the human brain. Neuroendocrinology. 2000;71(3):187–95.

    Article  CAS  PubMed  Google Scholar 

  41. Guan XM, Hess JF, Yu H, Hey PJ, Vander Ploeg LHT. Differential expression of mRNA for leptin receptor isoforms in the rat brain. Mol Cell Endocrinol. 1997;133(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  42. Berman SM, et al. Effects of leptin deficiency and replacement on cerebellar response to food-related cues. Cerebellum. 2013;12(1):59–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Oldreive CE, Harvey J, Doherty GH. Neurotrophic effects of leptin on cerebellar Purkinje but not granule neurons in vitro. Neurosci Lett. 2008;438(1):17–21.

    Article  CAS  PubMed  Google Scholar 

  44. Fukushima A, et al. Sex differences in feeding behavior in rats: the relationship with neuronal activation in the hypothalamus. Front Neurosci. 2015;9:88.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Forbes S, Herzog H, Cox HM. A role for neuropeptide Y in the gender-specific gastrointestinal, corticosterone and feeding responses to stress. Br J Pharmacol. 2012;166(8):2307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brandebourg TD, Bown JL, Ben-Jonathan N. Prolactin upregulates its receptors and inhibits lipolysis and leptin release in male rat adipose tissue. Biochem Biophys Res Commun. 2007;357(2):408–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fitzgerald P, Dinan TG. Prolactin and dopamine: what is the connection? A review article. J Psychopharmacol. 2008;22(2 Suppl):12–9.

    Article  PubMed  Google Scholar 

  48. Sirotkin AV, et al. Effects of chronic food restriction and treatments with leptin or ghrelin on different reproductive parameters of male rats. Peptides. 2008;29(8):1362–8.

    Article  CAS  PubMed  Google Scholar 

  49. Watanobe H, Schioth HB, Suda T. Stimulation of prolactin secretion by chronic, but not acute, administration of leptin in the rat. Brain Res. 2000;887(2):426–31.

    Article  CAS  PubMed  Google Scholar 

  50. DiLeone RJ. The influence of leptin on the dopamine system and implications for ingestive behavior. Int J Obes. 2009;33:S25–9.

    Article  CAS  Google Scholar 

  51. Fernandes MF, et al. Leptin suppresses the rewarding effects of running via STAT3 signaling in dopamine neurons. Cell Metab. 2015;22(4):741–9.

    Article  CAS  PubMed  Google Scholar 

  52. Ikai Y, Takada M, Shinonaga Y, Mizuno N. Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei. Neuroscience. 1992;51(3):719–28.

    Article  CAS  PubMed  Google Scholar 

  53. Kim KS, et al. Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors. J Biol Chem. 2010;285(12):8905–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cuevas S, Yang Y, Upadhyay K, Armando I, & Jose P (2014) Dopamine D2 receptors regulate leptin and IL-6 in 3T3 L1 adipocytes. Faseb J 28(1), 1107.5.

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Acknowledgements

Authors would like to thank Dr. Jennifer Knapp at University of Kansas Medical Center (KUMC) for assistance with the alternative statistical analysis and Pearson correlation analysis. Authors acknowledge Dr. WenFang Wang (KUMC) for preparing the Ncb5or-floxed line for crossing and Dr. Alexandra Joyner at Memorial Sloan-Kettering Cancer Center for providing the En1-cre driver.

Funding

This project was supported by the School of Health Professions research funds (H.Z.) and the Kansas Intellectual and Developmental Disabilities Research Center (NIH HD002528 and HD090216) at KUMC. M.A.S was supported by a Ruth L. Kirschstein National Research Service Award (NIH T32 HD057850, PI: R. Nudo). J.P.T was supported by NIH DK-088940 and VA Merit Review I01 RX000123.

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  1. Matthew A. Stroh

    Present address: Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA

Authors and Affiliations

  1. Landon Center on Aging, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Matthew A. Stroh

  2. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Matthew A. Stroh & Hao Zhu

  3. Neuroscience Graduate Program, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Matthew A. Stroh & Hao Zhu

  4. Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Michelle K. Winter & Kenneth E. McCarson

  5. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    Kenneth E. McCarson

  6. Department of Molecular Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    John P. Thyfault

  7. Research Service, Kansas City VA Medical Center, Kansas City, MO, 64128, USA

    John P. Thyfault

  8. Department of Clinical Laboratory Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd., MSN 4048G-Eaton, Kansas City, KS, 66160, USA

    Hao Zhu

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Correspondence to Hao Zhu.

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Stroh, M.A., Winter, M.K., McCarson, K.E. et al. NCB5OR Deficiency in the Cerebellum and Midbrain Leads to Dehydration and Alterations in Thirst Response, Fasted Feeding Behavior, and Voluntary Exercise in Mice. Cerebellum 17, 152–164 (2018). https://doi.org/10.1007/s12311-017-0880-7

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