Mechanisms underlying obesity resistance associated with high spontaneous physical activity

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Obesity resistance due to elevated orexin signaling is accompanied by high levels of spontaneous physical activity (SPA). The behavioral and neural mechanisms underlying this observation have not been fully worked out. We determined the contribution of hypothalamic orexin receptors (OXRs) to SPA stimulated by orexin A (OXA), whether OXA-stimulated SPA was secondary to arousal and whether voluntary wheel running led to compensations in 24-h SPA. We further tested whether orexin action on dopamine one receptors (DA1R) in the substantia nigra (SN) plays an important role in the generation of SPA. To test this, SPA response was determined in lean and obese rats with cannulae targeted toward the rostral lateral hypothalamus (rLH) or SN. Sleep/wake states were also measured in rats with rLH cannula and electroencephalogram/electromyogram radiotelemetry transmitters. SPA in lean rats was more sensitive to antagonism of the OX1R and in the early response to the orexin 2 agonist. OXA increased arousal equally in lean and obese rodents, which is discordant from the greater SPA response in lean rats. Obesity-resistant rats ran more and wheel running was directly related to 24-h SPA levels. The OX1R antagonist, SB-334867-A, and the DA1R antagonist, SCH3390, in SN more effectively reduced SPA stimulated by OXA in obesity-resistant rats. These data suggest OXA-stimulated SPA is not secondary to enhanced arousal, propensity for SPA parallels inclination to run and that orexin action on dopaminergic neurons in SN may participate in the mediation of SPA and running wheel activity.

Original languageEnglish (US)
Pages (from-to)91-100
Number of pages10
StatePublished - Jan 3 2014

Bibliographical note

Funding Information:
Funding for this research and publication was supported by an ACSM Foundation Research Grant from the American College of Sports Medicine Foundation, University of Minnesota Doctoral Dissertation Fellowship, Minnesota Partnership for Biotechnology and Genomics, Department of Veterans Affairs (F7212W to JAT) and the National Institutes of Health (NIDDK R01DK078985 to CMK).

Copyright 2014 Elsevier B.V., All rights reserved.


  • Diet-induced obesity
  • Hypocretin
  • Lateral hypothalamus
  • Locomotor activity
  • Reward


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