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 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 rats that displayed divergent body weight gain patterns despite comparable caloric intake following chow feeding (29, 47), suggesting that differences in energy expenditure primarily underlie phenotypic differences in body weight gain patterns. It has been demonstrated that lean individuals spent more time standing and ambulating than obese individuals, and this amount of time remained fixed independent of body weight despite overfeeding lean or underfeeding mildly obese individuals (33). Similarly, differences in spontaneous physical activity (SPA) between lean and obese out-...

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High levels of spontaneous physical activity in lean people and the nonexercise activity thermogenesis (NEAT) derived from that activity appear to protect lean people from obesity during caloric challenge, while obesity in humans is characterized by dramatically reduced spontaneous physical activity. We have similarly demonstrated that obesity-resistant rats have significantly greater spontaneous physical activity than obesity-prone rats, and that spontaneous physical activity predicts body weight gain. Although the energetic cost of activity varies between types of activity and may be regulated, individual level of spontaneous physical activity is important in determining propensity for obesity. We review the current status of knowledge about the brain mechanisms involved in controlling the level of spontaneous physical activity and the NEAT so generated. Focus is on potential neural mediators of spontaneous physical activity and NEAT, including orexin A (also known as hypocretin 1), agouti-related protein, ghrelin, and neuromedin U, in addition to brief mention of neuropeptide Y, corticotrophin releasing hormone, cholecystokinin, estrogen, leptin, and dopamine effects on spontaneous physical activity. We further review evidence that strain differences in orexin stimulation pathways for spontaneous physical activity and NEAT appear to track with the body weight phenotype, thus providing a potential mechanistic explanation for reduced activity and weight gain.

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These data show the ventrolateral preoptic area is a site of action for orexin-A, which may promote negative energy balance by modulating sleep/wakefulness and stimulating spontaneous physical activity and energy expenditure.