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Role of orexin-A in the ventrolateral preoptic area on components of total energy expenditure

International Journal of Obesity volume 41, pages 1256–1262 (2017)Cite this article

Subjects

Abstract

Background:

Identifying whether components of total energy expenditure (EE) are affected by orexin receptor (OXR1 and OXR2) stimulation or antagonism with dual orexin receptor antagonists (DORAs) has relevance for obesity treatment. Orexin receptor stimulation reduces weight gain by increasing total EE and EE during spontaneous physical activity (SPA).

Objective:

The purpose of this study was to determine if a DORA (TCS-1102) in the ventrolateral preoptic area (VLPO) reduced orexin-A-induced arousal, SPA, total EE and EE during sleep, rest, wake and SPA and whether the DORA alone reduced total EE and its components. We hypothesized that: (1) a DORA would reduce orexin-A induced increases in arousal, SPA, components of total EE, reductions in sleep and the EE during sleep and (2) the DORA alone would reduce baseline (non-stimulated) SPA and total EE.

Subjects/Methods:

Sleep, wakefulness, SPA and EE were determined after microinjection of the DORA (TCS-1102) and orexin-A in the VLPO of male Sprague–Dawley rats with a unilateral cannula targeted towards the VLPO. Individual components of total EE were determined based on time-stamped data.

Results:

The DORA reduced orexin-A-induced increases in arousal, SPA, total EE and EE during SPA, wake, rest and sleep 1 h post injection (P<0.05). Orexin-A significantly reduced sleep and significantly increased EE during sleep 1 h post injection (P<0.05). Furthermore, the DORA alone significantly reduced total EE, EE during sleep (NREM and REM) and resting EE 2 h post injection (P<0.05).

Conclusions:

These data suggest that orexin-A reduces weight gain by stimulating total EE through increases in EE during SPA, rest and sleep. Residual effects of the DORA alone include decreases in total EE and EE during sleep and rest, which may promote weight gain.

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References

  1. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95: 322–327.

    Article  CAS  Google Scholar 

  2. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 1–696.

    Article  Google Scholar 

  3. Li J, Hu Z, de Lcea L . The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol 2014; 171: 332–350.

    Article  CAS  Google Scholar 

  4. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365–376.

    Article  CAS  Google Scholar 

  5. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 437–451.

    Article  CAS  Google Scholar 

  6. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469–474.

    Article  CAS  Google Scholar 

  7. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E . Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39–40.

    Article  CAS  Google Scholar 

  8. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001; 30: 345–354.

    Article  CAS  Google Scholar 

  9. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 1999; 96: 10911–10916.

    Article  CAS  Google Scholar 

  10. Piper DC, Upton N, Smith MI, Hunter AJ . The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci 2000; 12: 726–730.

    Article  CAS  Google Scholar 

  11. Kotz CM, Teske JA, Billington CJ . Neuroregulation of nonexercise activity thermogenesis and obesity resistance. Am J Physiol Regul Integr Comp Physiol 2008; 294: R699–R710.

    Article  CAS  Google Scholar 

  12. Lubkin M, Stricker-Krongrad A . Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 1998; 253: 241–245.

    Article  CAS  Google Scholar 

  13. Sweet DC, Levine AS, Billington CJ, Kotz CM . Feeding response to central orexins. Brain Res 1999; 821: 535–538.

    Article  CAS  Google Scholar 

  14. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007; 13: 150–155.

    Article  CAS  Google Scholar 

  15. Winrow CJ, Tanis KQ, Reiss DR, Rigby AM, Uslaner JM, Uebele VN et al. Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure. Neuropharmacology 2010; 58: 185–194.

    Article  CAS  Google Scholar 

  16. Mang GM, Dürst T, Bürki H, Imobersteg S, Abramowski D, Schuepbach E et al. The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 2012; 35: 1625–1635.

    Article  Google Scholar 

  17. Sherin JE, Shiromani PJ, McCarley RW, Saper CB . Activation of ventrolateral preoptic neurons during sleep. Science 1996; 271: 216–219.

    Article  CAS  Google Scholar 

  18. Szymusiak R, Alam N, Steininger TL, McGinty D . Sleep-waking discharge patterns of ventrolateral preoptic/anterior hypothalamic neurons in rats. Brain Res 1998; 803: 178–188.

    Article  CAS  Google Scholar 

  19. Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y et al. Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 2005; 46: 297–308.

    Article  CAS  Google Scholar 

  20. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6–25.

    Article  CAS  Google Scholar 

  21. Mavanji V, Teske JA, Billington CJ, Kotz CM . Elevated sleep quality and orexin receptor mRNA in obesity-resistant rats. Int J Obes (Lond) 2010; 34: 1576–1588.

    Article  CAS  Google Scholar 

  22. Methippara MM, Alam MN, Szymusiak R, McGinty D . Effects of lateral preoptic area application of orexin-A on sleep–wakefulness. Neuroreport 2000; 11: 3423–3426.

    Article  CAS  Google Scholar 

  23. Levine JA, Eberhardt NL, Jensen MD . Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 1999; 283: 212–214.

    Article  CAS  Google Scholar 

  24. Mavanji V, Perez-Leighton CE, Kotz CM, Billington CJ, Parthasarathy S, Sinton CM et al. Promotion of wakefulness and energy expenditure by orexin A in the ventrolateral preoptic area. Sleep 2015; 38: 1361–1370.

    Article  Google Scholar 

  25. Paxinos G, Watson C, Pennisi M, Bregma Topple A . lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 1985; 13: 139–143.

    Article  CAS  Google Scholar 

  26. O'Hare E, Cleary J, Weldon DT, Pomonis JD, Billington CJ, Levine AS . Intrahypothalamic discriminative stimulus effects of neuropeptide Y. Pharmacol Biochem Behav 1998; 59: 375–378.

    Article  CAS  Google Scholar 

  27. Teske JA, Billington CJ, Kotz CM . Mechanisms underlying obesity resistance associated with high spontaneous physical activity. Neuroscience 2014; 256: 91–100.

    Article  CAS  Google Scholar 

  28. Nicholson C . Diffusion from an injected volume of a substance in brain tissue with arbitrary volume fraction and tortuosity. Brain Res 1985; 333: 325–329.

    Article  CAS  Google Scholar 

  29. Kaiyala KJ, Morton GJ, Thaler JP, Meek TH, Tylee T, Ogimoto K et al. Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice. PLoS One 2012; 7: e41473.

    Article  CAS  Google Scholar 

  30. Weir JB . New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 1949; 109: 1–9.

    Article  Google Scholar 

  31. Parrish JB, Teske JA . Acute partial sleep deprivation due to environmental noise increases weight gain by reducing energy expenditure in rodents. Obesity (Silver Spring, MD) 2017; 25: 141–146.

    Article  Google Scholar 

  32. Teske JA, Billington CJ, Kuskowski MA, Kotz CM . Spontaneous physical activity protects against fat mass gain. Int J Obes (Lond) 2012; 36: 603–613.

    Article  CAS  Google Scholar 

  33. Kotz CM, Teske JA, Levine JA, Wang C . Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 2002; 104: 27–32.

    Article  CAS  Google Scholar 

  34. Kotz C, Nixon J, Butterick T, Perez-Leighton C, Teske J, Billington C . Brain orexin promotes obesity resistance. Ann NY Acad Sci 2012; 1264: 72–86.

    Article  CAS  Google Scholar 

  35. Winrow CJ, Renger JJ . Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 2014; 171: 283–293.

    Article  CAS  Google Scholar 

  36. Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 2001; 98: 9965–9970.

    Article  CAS  Google Scholar 

  37. Kiwaki K, Kotz CM, Wang C, Lanningham-Foster L, Levine JA, Orexin A . (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats. Am J Physiol Endocrinol Metab 2004; 286: E551–E559.

    Article  CAS  Google Scholar 

  38. Novak CM, Kotz CM, Levine JA . Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats. Am J Physiol Endocrinol Metab 2006; 290: E396–E403.

    Article  CAS  Google Scholar 

  39. Yoshimichi G, Yoshimatsu H, Masaki T, Sakata T . Orexin-A regulates body temperature in coordination with arousal status. Exp Biol Med (Maywood) 2001; 226: 468–476.

    Article  CAS  Google Scholar 

  40. Tupone D, Madden CJ, Cano G, Morrison SF . An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci 2011; 31: 15944–15955.

    Article  CAS  Google Scholar 

  41. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H . Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 1999; 277 (Part 2): R1780–R1785.

    CAS  PubMed  Google Scholar 

  42. Novak CM, Levine JA . Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity (Silver Spring, MD) 2009; 17: 1493–1498.

    Article  CAS  Google Scholar 

  43. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K et al. Orexin receptor antagonism for treatment of insomnia: a randomized clinical trial of suvorexant. Neurology 2012; 79: 2265–2274.

    Article  CAS  Google Scholar 

  44. Ramirez AD, Gotter AL, Fox SV, Tannenbaum PL, Yao L, Tye SJ et al. Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators. Front Neurosci 2013; 7: 254.

    Article  Google Scholar 

  45. Ravussin E, Burnand B, Schutz Y, Jequier E . Twenty-four-hour energy expenditure and resting metabolic rate in obese, moderately obese, and control subjects. Am J Clin Nutr 1982; 35: 566–573.

    Article  CAS  Google Scholar 

  46. Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 2002; 290: 1237–1245.

    Article  CAS  Google Scholar 

  47. Takahashi K, Koyama Y, Kayama Y, Yamamoto M . Effects of orexin on the laterodorsal tegmental neurones. Psychiatry Clin Neurosci 2002; 56: 335–336.

    Article  CAS  Google Scholar 

  48. Brown RE, Sergeeva OA, Eriksson KS, Haas HL . Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 2002; 22: 8850–8859.

    Article  CAS  Google Scholar 

  49. Hirota K, Kushikata T, Kudo M, Kudo T, Lambert DG, Matsuki A . Orexin A and B evoke noradrenaline release from rat cerebrocortical slices. Br J Pharmacol 2001; 134: 1461–1466.

    Article  CAS  Google Scholar 

  50. Fadel J, Pasumarthi R, Reznikov LR . Stimulation of cortical acetylcholine release by orexin A. Neuroscience 2005; 130: 541–547.

    Article  CAS  Google Scholar 

  51. Tao R, Ma Z, McKenna JT, Thakkar MM, Winston S, Strecker RE et al. Differential effect of orexins (hypocretins) on serotonin release in the dorsal and median raphe nuclei of freely behaving rats. Neuroscience 2006; 141: 1101–1105.

    Article  CAS  Google Scholar 

  52. Gallopin T, Fort P, Eggermann E, Cauli B, Luppi PH, Rossier J et al. Identification of sleep-promoting neurons in vitro. Nature 2000; 404: 992–995.

    Article  CAS  Google Scholar 

  53. Liu YW, Li J, Ye JH . Histamine regulates activities of neurons in the ventrolateral preoptic nucleus. J Physiol. 2010; 588 (Part 21): 4103–4116.

    Article  CAS  Google Scholar 

  54. Matsuo S, Jang IS, Nabekura J, Akaike N . Alpha 2-adrenoceptor-mediated presynaptic modulation of GABAergic transmission in mechanically dissociated rat ventrolateral preoptic neurons. J Neurophysiol 2003; 89: 1640–1648.

    Article  CAS  Google Scholar 

  55. Saper CB, Chou TC, Scammell TE . The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001; 24: 726–731.

    Article  CAS  Google Scholar 

  56. Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 1999; 96: 748–753.

    Article  CAS  Google Scholar 

  57. Wang J, Osaka T, Inoue S . Energy expenditure by intracerebroventricular administration of orexin to anesthetized rats. Neurosci Lett 2001; 315: 49–52.

    Article  CAS  Google Scholar 

  58. Li A, Hindmarch CC, Nattie EE, Paton JF . Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. J Physiol 2013; 591: 4237–4248.

    Article  CAS  Google Scholar 

  59. Backberg M, Hervieu G, Wilson S, Meister B . Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur J Neurosci 2002; 15: 315–328.

    Article  Google Scholar 

  60. Cui LN, Saeb-Parsy K, Dyball RE . Neurones in the supraoptic nucleus of the rat are regulated by a projection from the suprachiasmatic nucleus. J Physiol 1997; 502 (Part 1): 149–159.

    Article  CAS  Google Scholar 

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Acknowledgements

Funding for this research and publication was supported by a Career Development Award-level 2 (F7212W to JAT) and Merit Award (5I01RX000441-04 to CMK and CJB) from the United States Department of Veterans Affairs Rehabilitation Research and Development Service, the National Institutes of Health-NIDDK (1R01DK100281-01A1 to CMK and CJB and 5P30DK05045619 to CJB), the United States Department of Agriculture (ARZT-1360220-H23-150 and ARZT-1372540-R23-131 to JAT), the University of Arizona Department of Nutritional Sciences DeBell Research Enhancement Award, the National Needs Fellowship (2014-38420-21799) and the University of Arizona College of Agriculture and Life Science Dean's Research Advisory Committee Research Enhancement Award.

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Authors and Affiliations

  1. Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA

    J E Coborn, D P DePorter & J A Teske

  2. Minneapolis VA Health Care System, Minneapolis, MN, USA

    V Mavanji, C M Kotz, C J Billington & J A Teske

  3. Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA

    C M Sinton

  4. Geriatric Research Education and Clinical Center, Minneapolis, MN, USA

    C M Kotz

  5. Minnesota Obesity Center, Saint Paul, MN, USA

    C M Kotz, C J Billington & J A Teske

  6. Department of Food Science and Nutrition, University of Minnesota, Saint Paul, MN, USA

    C M Kotz, C J Billington & J A Teske

  7. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    C J Billington

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  1. J E Coborn
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Correspondence to J A Teske.

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Coborn, J., DePorter, D., Mavanji, V. et al. Role of orexin-A in the ventrolateral preoptic area on components of total energy expenditure. Int J Obes 41, 1256–1262 (2017). https://doi.org/10.1038/ijo.2017.92

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