Reviews in Endocrine and Metabolic Disorders

, Volume 14, Issue 4, pp 357–364 | Cite as

Orexin: Pathways to obesity resistance?

  • Tammy A. Butterick
  • Charles J. Billington
  • Catherine M. Kotz
  • Joshua P. Nixon


Obesity has increased in prevalence worldwide, attributed in part to the influences of an obesity-promoting environment and genetic factors. While obesity and overweight increasingly seem to be the norm, there remain individuals who resist obesity. We present here an overview of data supporting the idea that hypothalamic neuropeptide orexin A (OXA; hypocretin 1) may be a key component of brain mechanisms underlying obesity resistance. Prior work with models of obesity and obesity resistance in rodents has shown that increased orexin and/or orexin sensitivity is correlated with elevated spontaneous physical activity (SPA), and that orexin-induced SPA contributes to obesity resistance via increased non-exercise activity thermogenesis (NEAT). However, central hypothalamic orexin signaling mechanisms that regulate SPA remain undefined. Our ongoing studies and work of others support the hypothesis that one such mechanism may be upregulation of a hypoxia-inducible factor 1 alpha (HIF-1α)-dependent pathway, suggesting that orexin may promote obesity resistance both by increasing SPA and by influencing the metabolic state of orexin-responsive hypothalamic neurons. We discuss potential mechanisms based on both animal and in vitro pharmacological studies, in the context of elucidating potential molecular targets for obesity prevention and therapy.


Orexin (hypocretin) Hypothalamus Obesity Spontaneous physical activity 



Diet-induced obese




Extracellular receptor kinase 1 and 2


Factor inhibiting HIF




High caloric restriction


Human embryonic kidney


Hypoxia-inducible factor 1 alpha




Low caloric restriction


Mitogen-activated protein kinase




Non-exercise activity thermogenesis






Orexin/hypocretin 1 receptor


Orexin/hypocretin 2 receptor


Orexin A (Hypocretin 1)


Orexin B (Hypocretin 2)


Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha


Protein kinase A


Protein kinase C


Phospholipase C




Pertussis toxin


Rostral lateral hypothalamic area


Spontaneous physical activity



Authors received support from the US Department of Veterans Affairs Rehabilitation Research and Development, Veterans Affairs grant BX001686, and R01 DK078985.

Conflict of interest

The authors declared that they have no any potential conflict of interest relevant to this article.


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Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Tammy A. Butterick
    • 1
    • 2
  • Charles J. Billington
    • 2
    • 3
    • 4
  • Catherine M. Kotz
    • 1
    • 2
  • Joshua P. Nixon
    • 1
    • 2
  1. 1.Department of Veterans AffairsMinneapolis Veterans Affairs Health Care SystemMinneapolisUSA
  2. 2.Department of Food Science and NutritionSt. PaulUSA
  3. 3.Department of MedicineMinneapolis Veterans Affairs Health Care SystemMinneapolisUSA
  4. 4.Department of MedicineUniversity of Minnesota Medical SchoolMinneapolisUSA

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