Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 291; no. 4; pp. R889 - R899
• Main Authors: Teske, J. A, Levine, A. S, Kuskowski, M, Levine, J. A, Kotz, C. M
• Format: Journal Article
• Language: English
• Published: United States 01.10.2006
• Subjects: Age Factors; Animals; Energy Intake - drug effects; Energy Intake - physiology; Hypothalamus - physiology; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - pharmacology; Male; Motor Activity - physiology; Neuropeptides - metabolism; Neuropeptides - pharmacology; Obesity - metabolism; Obesity - physiopathology; Orexin Receptors; Orexins; Phenotype; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide - genetics; Receptors, Neuropeptide - metabolism; RNA, Messenger - metabolism; Signal Transduction - physiology; Species Specificity
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00536.2005

1 Department of Food Science and Nutrition, University of Minnesota, Saint Paul; 2 Departments of Medicine, Psychology, and Psychiatry, University of Minnesota, Minneapolis; 3 Minnesota Obesity Center; 4 Veterans Affairs Medical Center, Minneapolis; and 5 Mayo Clinic Rochester, Endocrine Research Unit, Rochester, Minnesota Submitted 21 July 2005 ; accepted in final form 23 May 2006 Selectively-bred obesity-resistant [diet resistant (DR)] rats weigh less than obesity-prone [diet-induced obese (DIO)] rats, despite comparable daily caloric intake, suggesting phenotypic energy expenditure differences. Human data suggest that obesity is maintained by reduced ambulatory or spontaneous physical activity (SPA). The neuropeptide orexin A robustly stimulates SPA. We hypothesized that DR rats have greater: 1 ) basal SPA, 2 ) orexin A-induced SPA, and 3 ) preproorexin, orexin 1 and 2 receptor (OX1R and OX2R) mRNA, compared with DIO rats. A group of age-matched out-bred Sprague-Dawley rats were used as additional controls for the behavioral studies. DIO, DR, and Sprague-Dawley rats with dorsal-rostral lateral hypothalamic (rLHa) cannulas were injected with orexin A (0, 31.25, 62.5, 125, 250, and 500 pmol/0.5 µl). SPA and food intake were measured for 2 h after injection. Preproorexin, OX1R and OX2R mRNA in the rLHa, and whole hypothalamus were measured by real-time RT-PCR. Orexin A significantly stimulated feeding in all rats. Orexin A-induced SPA was significantly greater in DR and Sprague-Dawley rats than in DIO rats. Two-mo-old DR rats had significantly greater rLHa OX1R and OX2R mRNA than DIO rats but comparable preproorexin levels. Eight-mo-old DR rats had elevated OX1R and OX2R mRNA compared with DIO rats, although this increase was significant for OX2R only at this age. Thus DR rats show elevated basal and orexin A-induced SPA associated with increased OX1R and OX2R gene expression, suggesting that differences in orexin A signaling through OX1R and OX2R may mediate DIO and DR phenotypes. hypocretin; lateral hypothalamus; locomotor activity; diet-induced obesity Address for reprint requests and other correspondence: C. Kotz, Veterans Affairs Medical Center, GRECC (11G), One Veterans Dr., Minneapolis, MN 55417 (e-mail: kotzx004{at}umn.edu )