Teske JA, Perez-Leighton CE, Billington CJ, Kotz CM. Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats. Am J Physiol Regul Integr Comp Physiol 305: R1337-R1345, 2013. First published October 2, 2013; doi:10.1152/ajpregu.00229.2013.-Orexin/hypocretin terminals innervate noradrenergic locus coeruleus (LC) neurons that project to the prefrontral cortex, which may influence spontaneous physical activity (SPA) and energy balance. Obesity-resistant (OR) rats have higher orexin receptors (OXR) mRNA in the LC and other brain regions, as well as lower adiposity compared with obese rats. These findings led us to hypothesize that orexin activity in the LC is relevant for the OR phenotype. We compared OR rats to Sprague-Dawley rats. We predicted that: 1) brain OXR expression pattern is sufficient to differentiate OR from non-bred Sprague-Dawley rats; 2) nonresting energy expenditure (NREE) and orexin A (OXA)-stimulated SPA after injection in LC would be greater in OR rats; and 3) the effect of OXA on SPA would be greater than its effect on feeding. OXR mRNA from 11 brain sites and the SPA and feeding responses to OXA in the LC were determined. Body composition, basal SPA, and EE were determined. Principal component analysis of the OXR expression pattern differentiates OR and Sprague-Dawley rats and suggests the OXR mRNA in the LC is important in defining the OR phenotype. Compared with Sprague-Dawley rats, OR rats had greater SPA and NREE and lower resting EE and adiposity. SPA responsivity to OXA in the LC was greater in OR rats compared with Sprague-Dawley rats. OXA in the LC did not stimulate feeding in OR or Sprague-Dawley rats. These data suggest that the LC is a prominent site modulating OXA-stimulated SPA, which promotes lower adiposity and higher nonresting EE. diet-induced obesity; brain THE HYPOTHALAMIC NEUROPEPTIDE orexin A (10, 42) is crucial for body weight regulation (14). In rodents, orexin A in various brain sites stimulates feeding in a circadian-dependent manner (50), spontaneous physical activity (SPA), and energy expenditure (13,20,42). That orexin A can increase energy intake as well as energy expenditure makes it difficult to reconcile its role in body weight regulation. Evidence suggests the impact of orexin A on SPA is more relevant to energy balance than its effects on feeding. First, orexin A therapy elicits weight loss (33) and leaner body composition (36). Also, mice lacking orexin show obesity caused by reduced physical activity despite hypophagia (14). Second, SPA stimulated by orexin A persists longer than the feeding response. The dose required for the SPA response is lower than that for feeding effects, and the positive effects of orexin A on SPA are distributed among multiple brain sites with different functions (20). While the effect of orexin A on feeding also appears to be distributed in the sense that multiple brain sites contribute to the feeding response to orexin A, we have observed lack of orexin A feeding response in si...