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

J. A. Teske, A. S. Levine, M. Kuskowski, J. A. Levine, C. M. Kotz
2006 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  
lectively-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
more » ... 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 l). 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-moold 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. OUT-BRED MALE SPRAGUE-DAWLEY rats fed a high-energy diet display divergent body weight gain patterns. Approximately half of the rats become obese [diet induced obese (DIO)] while the other half remain lean [diet resistant (DR)]. DIO and DR rats can be prospectively identified before exposure to a highenergy diet based on sympathetic activation (32) and monoaminergic function (13, 24, 26) , suggesting that differences in the propensity toward weight gain are due to differences in CNS function. To better understand the mechanism underlying the propensity or resistance to weight gain observed in the out-bred DIO and DR rats, Sprague-Dawley rats fed a high-fat diet were selectively bred for their weight gain. This selective breeding scheme produced two substrains of Sprague-Dawley
doi:10.1152/ajpregu.00536.2005 pmid:16763079 fatcat:khzhbx4n7ff6hfdjlp2gqfprxm