Current Obesity Reports

, Volume 6, Issue 4, pp 362–370 | Cite as

Spontaneous Physical Activity Defends Against Obesity

  • Catherine M. Kotz
  • Claudio E. Perez-Leighton
  • Jennifer A. Teske
  • Charles J. Billington
Metabolism (CJ Billington, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Metabolism


Purpose of Review

Spontaneous physical activity (SPA) is a physical activity not motivated by a rewarding goal, such as that associated with food-seeking or wheel-running behavior. SPA is often thought of as only “fidgeting,” but that is a mischaracterization, since fidgety behavior can be linked to stereotypies in neurodegenerative disease and other movement disorders. Instead, SPA should be thought of as all physical activity behavior that emanates from an unconscious drive for movement.

Recent Findings

An example of this may be restless behavior, which can include fidgeting and gesticulating, frequent sit-to-stand movement, and more time spent standing and moving. All physical activity burns calories, and as such, SPA could be manipulated as a means to burn calories, and defend against weight gain and reduce excess adiposity.


In this review, we discuss human and animal literature on the use of SPA in reducing weight gain, the neuromodulators that could be targeted to this end, and future directions in this field.


Spontaneous physical activity Non-exercise energy expenditure Locomotion Exercise Obesity Food intake Eating behavior Brain Central nervous system Orexin Dynorphin DREADD Optogenetics Human Animal 


Compliance with Ethical Standards

Conflict of Interest

Catherine M. Kotz declares that she has no conflict of interest.

Claudio E. Perez-Leighton declares that he has no conflict of interest.

Jennifer A. Teske declares that she has no conflict of interest.

Charles J. Billington has received compensation from Novo Nordisk, EnteroMedics, and Optum Health for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors. All studies (Fig. 1) and those cited by the authors in this review had local Institutional Animal Care and Use Committee approval.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bouchard C. Gene-environment interactions in the etiology of obesity: defining the fundamentals. Obesity. 2008;16(Suppl 3):S5–S10. Scholar
  2. 2.
    Lindgren CM, McCarthy MI. Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract Endocrinol Metab. 2008;4(3):156–63. Scholar
  3. 3.
    Crocker MK, Yanovski JA. Pediatric obesity: etiology and treatment. Endocrinol Metab Clin N Am. 2009;38(3):525–48. Scholar
  4. 4.
    Blundell JE, Stubbs RJ, Golding C, Croden F, Alam R, Whybrow S, et al. Resistance and susceptibility to weight gain: individual variability in response to a high-fat diet. Physiol Behav. 2005;86(5):614–22. Scholar
  5. 5.
    Levine JA, Eberhardt NL, Jensen MD. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science. 1999;283(5399):212–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, et al. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension. J Hypertens. 2012;30(6):1047–55. Scholar
  7. 7.
    Zurlo F, Ferraro RT, Fontvielle AM, Rising R, Bogardus C, Ravussin E. Spontaneous physical activity and obesity: cross-sectional and longitudinal studies in Pima Indians. Am J Phys. 1992;263(2 Pt 1):E296–300.Google Scholar
  8. 8.
    Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest. 1986;78(6):1568–78. Scholar
  9. 9.
    Vanltallie TB. Resistance to weight gain during overfeeding: a NEAT explanation. Nutr Rev. 2001;59(2):48–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Garland T Jr, Schutz H, Chappell MA, Keeney BK, Meek TH, Copes LE, et al. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J Exp Biol. 2011;214(Pt 2):206–29. Scholar
  11. 11.
    Kotz CM, Levine JA. Role of nonexercise activity thermogenesis (NEAT) in obesity. Minn Med. 2005;88(9):54–7.PubMedGoogle Scholar
  12. 12.
    Levine JA, Vander Weg MW, Hill JO, Klesges RC. Non-exercise activity thermogenesis: the crouching tiger hidden dragon of societal weight gain. Arterioscler Thromb Vasc Biol. 2006;26(4):729–36. Scholar
  13. 13.
    Levine JA, Lanningham-Foster LM, McCrady SK, Krizan AC, Olson LR, Kane PH, et al. Interindividual variation in posture allocation: possible role in human obesity. Science. 2005;307(5709):584–6. Scholar
  14. 14.
    Teske JA, Billington CJ, Kotz CM. Neuropeptidergic mediators of spontaneous physical activity and non-exercise activity thermogenesis. Neuroendocrinology. 2008;87(2):71–90. Scholar
  15. 15.
    Nixon JP, Kotz CM, Novak CM, Billington CJ, Teske JA. Neuropeptides controlling energy balance: orexins and neuromedins. Handb Exp Pharmacol. 2012;209:77–109. Scholar
  16. 16.
    Shook RP, Hand GA, Drenowatz C, Hebert JR, Paluch AE, Blundell JE, et al. Low levels of physical activity are associated with dysregulation of energy intake and fat mass gain over 1 year. Am J Clin Nutr. 2015;102(6):1332–8. Scholar
  17. 17.
    Uemura H, Katsuura-Kamano S, Yamaguchi M, Nakamoto M, Hiyoshi M, Arisawa K. Abundant daily non-sedentary activity is associated with reduced prevalence of metabolic syndrome and insulin resistance. J Endocrinol Investig. 2013;36(11):1069–75. Scholar
  18. 18.
    Piaggi P, Thearle MS, Krakoff J, Votruba SB. Higher daily energy expenditure and respiratory quotient, rather than fat-free mass, independently determine greater ad libitum overeating. J Clin Endocrinol Metab. 2015;100(8):3011–20. Scholar
  19. 19.
    Drenowatz C, Hill JO, Peters JC, Soriano-Maldonado A, Blair SN. The association of change in physical activity and body weight in the regulation of total energy expenditure. Eur J Clin Nutr. 2017;71(3):377–82. Scholar
  20. 20.
    Piaggi P, Thearle MS, Bogardus C, Krakoff J. Lower energy expenditure predicts long-term increases in weight and fat mass. J Clin Endocrinol Metab. 2013;98(4):E703–7. Scholar
  21. 21.
    Ahmad S, Rukh G, Varga TV, Ali A, Kurbasic A, Shungin D, et al. Gene x physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry. PLoS Genet. 2013;9(7):e1003607. Scholar
  22. 22.
    Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, O’Connell JR, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008;168(16):1791–7. Scholar
  23. 23.
    Hao YY, Yuan HW, Fang PH, Zhang Y, Liao YX, Shen C, et al. Plasma orexin-A level associated with physical activity in obese people. Eat Weight Disord. 2017;22(1):69–77. Scholar
  24. 24.
    Nicklas BJ, Gaukstern JE, Beavers KM, Newman JC, Leng X, Rejeski WJ. Self-monitoring of spontaneous physical activity and sedentary behavior to prevent weight regain in older adults. Obesity (Silver Spring). 2014;22(6):1406–12. Scholar
  25. 25.
    Elbelt U, Schuetz T, Knoll N, Burkert S. Self-directed weight loss strategies: energy expenditure due to physical activity is not increased to achieve intended weight loss. Nutrients. 2015;7(7):5868–88. Scholar
  26. 26.
    Schmidt SL, Harmon KA, Sharp TA, Kealey EH, Bessesen DH. The effects of overfeeding on spontaneous physical activity in obesity prone and obesity resistant humans. Obesity (Silver Spring). 2012;20(11):2186–93. Scholar
  27. 27.
    • Villablanca PA, Alegria JR, Mookadam F, Holmes DR Jr, Wright RS, Levine JA. Nonexercise activity thermogenesis in obesity management. Mayo Clin Proc. 2015;90(4):509–19. This paper reviews the available methodologies for changing spontaneous physical activity and the associated non-exercise thermogenesis as part of weight management strategies. CrossRefPubMedGoogle Scholar
  28. 28.
    Koepp GA, Moore G, Levine JA. An under-the-table leg-movement apparatus and changes in energy expenditure. Front Physiol. 2017;8:318. Scholar
  29. 29.
    Koepp GA, Moore GK, Levine JA. Chair-based fidgeting and energy expenditure. BMJ Open Sport Exerc Med. 2016;2(1):e000152. Scholar
  30. 30.
    Dutta N, Koepp GA, Stovitz SD, Levine JA, Pereira MA. Using sit-stand workstations to decrease sedentary time in office workers: a randomized crossover trial. Int J Environ Res Public Health. 2014;11(7):6653–65. Scholar
  31. 31.
    Thompson WG, Koepp GA, Levine JA. Increasing physician activity with treadmill desks. Work. 2014;48(1):47–51. Scholar
  32. 32.
    Koepp GA, Manohar CU, McCrady-Spitzer SK, Ben-Ner A, Hamann DJ, Runge CF, et al. Treadmill desks: a 1-year prospective trial. Obesity. 2013;21(4):705–11. Scholar
  33. 33.
    McCrady-Spitzer SK, Manohar CU, Koepp GA, Levine JA. Low-cost and scalable classroom equipment to promote physical activity and improve education. J Phys Act Health. 2015;12(9):1259–63. Scholar
  34. 34.
    Melanson EL. The effect of exercise on non-exercise physical activity and sedentary behavior in adults. Obes Rev. 2017;18(Suppl 1):40–9. Scholar
  35. 35.
    Washburn RA, Lambourne K, Szabo AN, Herrmann SD, Honas JJ, Donnelly JE. Does increased prescribed exercise alter non-exercise physical activity/energy expenditure in healthy adults? A systematic review. Clin Obes. 2014;4(1):1–20. Scholar
  36. 36.
    Westerterp KR. Control of energy expenditure in humans. Eur J Clin Nutr. 2017;71(3):340–4. Scholar
  37. 37.
    Gomersall SR, Rowlands AV, English C, Maher C, Olds TS. The ActivityStat hypothesis: the concept, the evidence and the methodologies. Sports Med. 2013;43(2):135–49. Scholar
  38. 38.
    Mathot KJ, Dingemanse NJ. Energetics and behavior: unrequited needs and new directions. Trends Ecol Evol. 2015;30(4):199–206. Scholar
  39. 39.
    Pontzer H. Constrained Total energy expenditure and the evolutionary biology of energy balance. Exerc Sport Sci Rev. 2015;43(3):110–6. Scholar
  40. 40.
    Ravussin E, Peterson CM. Physical activity and the missing calories. Exerc Sport Sci Rev. 2015;43(3):107–8. Scholar
  41. 41.
    Gomersall SR, Maher C, English C, Rowlands AV, Dollman J, Norton K, et al. Testing the activitystat hypothesis: a randomised controlled trial. BMC Public Health. 2016;16:900. Scholar
  42. 42.
    Snitker S, Tataranni PA, Ravussin E. Spontaneous physical activity in a respiratory chamber is correlated to habitual physical activity. Int J Obes Relat Metab Disord. 2001;25(10):1481–6. Scholar
  43. 43.
    •• Teske JA, Perez-Leighton CE, Billington CJ, Kotz CM. Methodological considerations for measuring spontaneous physical activity in rodents. Am j physiol Regul integr comp physiol. 2014;306(10):R714–21. This paper shows that different methods of measuring SPA (e.g., timing of measurement, housing) can yield different absolute numbers and may alter data interpretation. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Cacioppo JT, Cacioppo S, Capitanio JP, Cole SW. The neuroendocrinology of social isolation. Annu Rev Psychol. 2015;66:733–67. Scholar
  45. 45.
    Bunney PE, Zink AN, Holm AA, Billington CJ, Kotz CM. Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. Physiol Behav. 2017;176:139–48. Scholar
  46. 46.
    Coborn JE, DePorter DP, Mavanji V, Sinton CM, Kotz CM, Billington CJ, et al. Role of orexin-A in the ventrolateral preoptic area on components of total energy expenditure. Int J Obes. 2017;41(8):1256–62. Scholar
  47. 47.
    Dulloo AG, Miles-Chan JL, Montani JP, Schutz Y. Isometric thermogenesis at rest and during movement: a neglected variable in energy expenditure and obesity predisposition. Obes Rev. 2017;18(Suppl 1):56–64. Scholar
  48. 48.
    Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE. Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Phys. 1997;273(2 Pt 2):R725–30.Google Scholar
  49. 49.
    Teske JA, Levine AS, Kuskowski M, Levine JA, Kotz CM. Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. Am j physiol Regul integr comp physiol. 2006;291(4):R889–99. Scholar
  50. 50.
    Teske JA, Billington CJ, Kuskowski MA, Kotz CM. Spontaneous physical activity protects against fat mass gain. Int J Obes. 2012;36(4):603–13. Scholar
  51. 51.
    Perez-Leighton CE, Boland K, Billington C, Kotz CM. High and low activity rats: elevated intrinsic physical activity drives resistance to diet-induced obesity in non-bred rats. Obesity (Silver Spring). 2013 Feb;21(2):353-60. doi: 10.1002/oby.20045.
  52. 52.
    Perez-Leighton CE, Grace M, Billington CJ, Kotz CM. Role of spontaneous physical activity in prediction of susceptibility to activity based anorexia in male and female rats. Physiol Behav. 2014;135:104–11. Scholar
  53. 53.
    Smyers ME, Bachir KZ, Britton SL, Koch LG, Novak CM. Physically active rats lose more weight during calorie restriction. Physiol Behav. 2015;139:303–13. Scholar
  54. 54.
    Gac L, Kanaly V, Ramirez V, Teske JA, Pinto MP, Perez-Leighton CE. Behavioral characterization of a model of differential susceptibility to obesity induced by standard and personalized cafeteria diet feeding. Physiol behav. 2015;152(Pt A):315–22. Scholar
  55. 55.
    Moretto TL, Benfato ID, de Carvalho FP, Barthichoto M, Le Sueur-Maluf L, de Oliveira CAM. The effects of calorie-matched high-fat diet consumption on spontaneous physical activity and development of obesity. Life Sci. 2017;179:30–6. Scholar
  56. 56.
    Sadowska J, Gebczynski AK, Konarzewski M. Selection for high aerobic capacity has no protective effect against obesity in laboratory mice. Physiol Behav. 2017;175:130–6. Scholar
  57. 57.
    Sadowska J, Gebczynski AK, Konarzewski M. Metabolic risk factors in mice divergently selected for BMR fed high fat and high carb diets. PLoS One. 2017;12(2):e0172892. Scholar
  58. 58.
    Acosta W, Meek TH, Schutz H, Dlugosz EM, Vu KT, Garland T Jr. Effects of early-onset voluntary exercise on adult physical activity and associated phenotypes in mice. Physiol Behav. 2015;149:279–86. Scholar
  59. 59.
    Copes LE, Schutz H, Dlugosz EM, Acosta W, Chappell MA, Garland T Jr. Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: results from an artificial selection experiment. Physiol Behav. 2015;149:86–94. Scholar
  60. 60.
    de Carvalho FP, Benfato ID, Moretto TL, Barthichoto M, de Oliveira CA. Voluntary running decreases nonexercise activity in lean and diet-induced obese mice. Physiol Behav. 2016;165:249–56. Scholar
  61. 61.
    Scariot PP, Manchado-Gobatto Fde B, Torsoni AS, dos Reis IG, Beck WR, Gobatto CA. Continuous aerobic training in individualized intensity avoids spontaneous physical activity decline and improves MCT1 expression in oxidative muscle of swimming rats. Front Physiol. 2016;7:132. Scholar
  62. 62.
    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 U S A. 1998;95(1):322–7.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    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(4):573–85.CrossRefPubMedGoogle Scholar
  64. 64.
    Kotz C, Nixon J, Butterick T, Perez-Leighton C, Teske J, Billington C. Brain orexin promotes obesity resistance. Ann N Y Acad Sci. 2012;1264:72–86. Scholar
  65. 65.
    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(1):6–25.CrossRefPubMedGoogle Scholar
  66. 66.
    Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 1998;438(1–2):71–5.CrossRefPubMedGoogle Scholar
  67. 67.
    Alam MN, Kumar S, Bashir T, Suntsova N, Methippara MM, Szymusiak R, et al. GABA-mediated control of hypocretin-but not melanin-concentrating hormone-immunoreactive neurones during sleep in rats. J Physiol. 2005;563(Pt 2):569–82. Scholar
  68. 68.
    Karnani MM, Apergis-Schoute J, Adamantidis A, Jensen LT, de Lecea L, Fugger L, et al. Activation of central orexin/hypocretin neurons by dietary amino acids. Neuron. 2011;72(4):616–29. Scholar
  69. 69.
    Williams RH, Alexopoulos H, Jensen LT, Fugger L, Burdakov D. Adaptive sugar sensors in hypothalamic feeding circuits. Proc Natl Acad Sci U S A. 2008;105(33):11975–80. Scholar
  70. 70.
    Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol. 1999;160(3):R7–12.CrossRefPubMedGoogle Scholar
  71. 71.
    Shirasaka T, Miyahara S, Kunitake T, Jin QH, Kato K, Takasaki M, et al. Orexin depolarizes rat hypothalamic paraventricular nucleus neurons. Am j physiol Regul integr comp physiol. 2001;281(4):R1114–8.PubMedGoogle Scholar
  72. 72.
    Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, Barrera JG, et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 2009;10(2):89–98. Scholar
  73. 73.
    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(2):297–308. Scholar
  74. 74.
    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(4):437–51.CrossRefPubMedGoogle Scholar
  75. 75.
    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(2):345–54.CrossRefPubMedGoogle Scholar
  76. 76.
    Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, et al. Fos expression in orexin neurons varies with behavioral state. J neurosci: off j Soc Neurosci. 2001;21(5):1656–62.Google Scholar
  77. 77.
    Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron. 2005;46(5):787–98. Scholar
  78. 78.
    Takahashi K, Lin JS, Sakai K. Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience. 2008;153(3):860–70. Scholar
  79. 79.
    Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, MF W, John J, et al. Release of hypocretin (orexin) during waking and sleep states. J neurosci : off j Soc Neurosci. 2002;22(13):5282–6.Google Scholar
  80. 80.
    Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature. 2007;450(7168):420–4. Scholar
  81. 81.
    Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab. 2009;9(1):64–76. Scholar
  82. 82.
    Perez-Leighton CE, Boland K, Teske JA, Billington C, Kotz CM. Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity. Am J Physiol Endocrinol Metab. 2012;303(7):E865–74. Scholar
  83. 83.
    Espana RA, Reis KM, Valentino RJ, Berridge CW. Organization of hypocretin/orexin efferents to locus coeruleus and basal forebrain arousal-related structures. J Comp Neurol. 2005;481(2):160–78. CrossRefPubMedGoogle Scholar
  84. 84.
    Oldfield BJ, Allen AM, Davern P, Giles ME, Owens NC. Lateral hypothalamic 'command neurons' with axonal projections to regions involved in both feeding and thermogenesis. Eur J Neurosci. 2007;25(8):2404–12. CrossRefPubMedGoogle Scholar
  85. 85.
    Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G. Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behav Brain Res. 2007;183(1):43–51. Scholar
  86. 86.
    Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29(10):571–7. Scholar
  87. 87.
    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(4):E551–9. Scholar
  88. 88.
    Kotz CM, Wang C, Teske JA, Thorpe AJ, Novak CM, Kiwaki K, et al. Orexin A mediation of time spent moving in rats: neural mechanisms. Neuroscience. 2006;142(1):29–36. Scholar
  89. 89.
    Thorpe AJ, Kotz CM. Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res. 2005;1050(1–2):156–62. Scholar
  90. 90.
    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(1–3):27–32.CrossRefPubMedGoogle Scholar
  91. 91.
    Teske JA, Perez-Leighton CE, Billington CJ, Kotz CM. Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. Am j physiol Regul integr comp physiol. 2013;305(11):R1337–45. Scholar
  92. 92.
    Teske JA, Billington CJ, Kotz CM. Hypocretin/orexin and energy expenditure. Acta Physiol. 2010;198(3):303–12. Scholar
  93. 93.
    Perez-Leighton CE, Butterick-Peterson TA, Billington CJ, Kotz CM. Role of orexin receptors in obesity: from cellular to behavioral evidence. Int J Obes. 2013;37(2):167–74. Scholar
  94. 94.
    • Perez-Leighton C, Little MR, Grace M, Billington C, Kotz CM. Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high- and low-activity rats. Am j physiol regul integr comp Physiol. 2017;312(3):R338–R46. This paper shows the differential interplay of brain regions in the control of SPA, in high- vs. low-activity rats. Put more simply, the brains of high activity rats may be functionally organized differently than those of low physical activity rats. CrossRefPubMedGoogle Scholar
  95. 95.
    •• Kosse C, Schone C, Bracey E, Burdakov D. Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice. Proc Natl Acad Sci U S A. 2017;114(17):4525–30. This paper shows a link between orexin neurons and another set of neurons that may be important in understanding additional mechanisms by which orexin induces SPA. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    •• Zink AN, Bunney PE, Holm AA, Billington CJ, Kotz CM. Neuromodulation of orexin neurons reduces diet-induced adiposity. International Journal of Obesity. 2017: in press. These studies provide direct evidence that activation of orexin induces SPA and protects against weight gain. Google Scholar
  97. 97.
    Kessler BA, Stanley EM, Frederick-Duus D, Fadel J. Age-related loss of orexin/hypocretin neurons. Neuroscience. 2011;178:82–8. Scholar
  98. 98.
    Pirnik Z, Bundzikova J, Mikkelsen JD, Zelezna B, Maletinska L, Kiss A. Fos expression in hypocretinergic neurons in C57B1/6 male and female mice after long-term consumption of high fat diet. Endocr Regul. 2008;42(4):137–46.PubMedGoogle Scholar
  99. 99.
    Fujiki N, Yoshida Y, Zhang S, Sakurai T, Yanagisawa M, Nishino S. Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Peptides. 2006;27(9):2326–31. Scholar
  100. 100.
    Johren O, Bruggemann N, Dendorfer A, Dominiak P. Gonadal steroids differentially regulate the messenger ribonucleic acid expression of pituitary orexin type 1 receptors and adrenal orexin type 2 receptors. Endocrinology. 2003;144(4):1219–25. Scholar
  101. 101.
    Schmidt FM, Kratzsch J, Gertz HJ, Tittmann M, Jahn I, Pietsch UC, et al. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer’s disease. PLoS One. 2013;8(5):e63136. Scholar
  102. 102.
    Funabashi T, Hagiwara H, Mogi K, Mitsushima D, Shinohara K, Kimura F. Sex differences in the responses of orexin neurons in the lateral hypothalamic area and feeding behavior to fasting. Neurosci Lett. 2009;463(1):31–4. Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Catherine M. Kotz
    • 1
    • 2
  • Claudio E. Perez-Leighton
    • 3
  • Jennifer A. Teske
    • 4
  • Charles J. Billington
    • 5
    • 6
  1. 1.Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisUSA
  2. 2.GRECC, Minneapolis VA Health Care System, GRECCMinneapolisUSA
  3. 3.Facultad de MedicinaUniversidad Andres BelloSantiagoChile
  4. 4.Department of Nutritional SciencesUniversity of ArizonaTucsonUSA
  5. 5.Department of MedicineUniversity of MinnesotaMinneapolisUSA
  6. 6.Minneapolis VA Health Care SystemMinneapolisUSA

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