title: Mechanisms underlying obesity resistance associated with high spontaneous physical activity.
abstract: 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.
authors.affiliation: Department of Nutritional Sciences, University of Arizona and Southern Arizona, VA Health Care System, Tucson, AZ, USA; Minneapolis VA Health Care System, Minneapolis, MN 55417, USA; Minnesota Obesity Center, 1334 Eckles Avenue, Saint Paul, MN 55108, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, Saint Paul, MN 55108, USA. Electronic address: teskeja@email.arizona.edu.
authors.forename: J A
authors.initials: JA
authors.lastname: Teske
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, MN 55417, USA; Minnesota Obesity Center, 1334 Eckles Avenue, Saint Paul, MN 55108, USA; Department of Medicine, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, Saint Paul, MN 55108, USA. Electronic address: billi005@umn.edu.
authors.forename: C J
authors.initials: CJ
authors.lastname: Billington
authors.affiliation: Minneapolis VA Health Care System, Minneapolis, MN 55417, USA; Minnesota Obesity Center, 1334 Eckles Avenue, Saint Paul, MN 55108, USA; Geriatric Research, Education and Clinical Center, One Veterans Drive, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, Saint Paul, MN 55108, USA. Electronic address: kotzx004@umn.edu.
authors.forename: C M
authors.initials: CM
authors.lastname: Kotz
mesh_terms: D000367:Age Factors; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D004576:Electromyography; D005133:Eye Movements / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009287:Naphthyridines; D009479:Neuropeptides / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001552:Benzazepines; D001583:Benzoxazoles; D018492:Dopamine Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D000068797:Orexins; C534628:SCH 23390; D014508:Urea
keywords: ANOVA; AW; DA1R; EEG; EMG; OP; OR; OXA; OXR; REM; SN; SPA; SWS; active wake; analysis of variance; diet-induced obesity; dopamine one receptor; electroencephalogram; electromyogram; hypocretin; lateral hypothalamus; locomotor activity; obesity prone; obesity resistant; orexin A; orexin receptor; rLH; rapid eye movement; reward; rostral lateral hypothalamus; slow wave sleep; spontaneous physical activity; substantia nigra