Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats

Abstract

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...

Sex‐dependent differences in voluntary physical activity

“…Rodents models, such as transgenic mice, those with pharmacologically-induced neural lesions, and those selectively bred to engage in high or low amount of wheel running or other PA, have helped elucidate the brain regions and molecular mechanisms regulating PA. Because of the strong conservation in brain structure and physiology between rodents and humans (Howdeshell 2002; Rice and Barone 2000), the same brain areas likely facilitate PA in humans. The brain regions in rodents that are essential in modulating this behavior include the striatum, NAc, hypothalamus, amygdala, hippocampus, prefrontal cortex, locus coeruleus, cerebellum, and pons (Ambrogi Lorenzini et al 1991; Andrzejewski et al 2004; Basso and Morrell 2015; Beninger et al 2009; Bronikowski et al 2004; Cahill et al 2015; Dubreucq et al 2010; Kolb et al 2013; Korczynski and Fonberg 1979; Monroe et al 2014; Nonneman and Corwin 1981; Rhodes et al 2003; Roberts et al 2014; Ruegsegger et al 2016; Ruegsegger et al 2015; Tarr et al 2004; Teske et al 2013; Werme et al 2002; Yim and Mogenson 1989). The currently known identified genes and pathways in the brain that are particularly important in stimulating or suppressing this behavioral response include Fos/DeltaFosB (Correa et al 2016; Rhodes et al 2003; Werme et al 2002), CB1 receptors (Dubreucq et al 2010), NMDA receptor (Andrzejewski et al 2004; Yim and Mogenson 1989), dopaminergic (Monroe et al 2014; Roberts et al 2013; Roberts et al 2012; Waters et al 2013; Yang et al 2012)(Park et al Physiology & Behavior, Resubmitted )(Correa et al 2016), opioid (Ruegsegger et al 2015), and leptin (Matheny et al 2009; Ruegsegger et al 2016) signaling pathways.…”

“…Sexually dimorphic responses are observed in the HR lines with speed varying in females; whereas speed and time differ in HR males relative to control lines (Garland et al 2011). Testing of obesity-resistant (OR) and Sprague-Dawley rats reveals the locus coerulus (LC) is a primary brain region modulating orexin-induced spontaneous PA in the former group of rats (Teske et al 2013). Mice with lesions in the dorsal medial habenula (dMHB) exhibit compromised performance in motivational-based locomotor behaviors, including voluntary wheel running and the accelerated rotorod but show mild impairments in gait and balance and exhibit normal basal activity (Hsu and Wang 2014).…”

Spontaneous Physical Activity Defends Against Obesity

“…Orexin-dependent modulation of SPA and NEAT involves OXR subtypes in several brain areas [87–89], including the rostral LH [90, 88], dorsal raphe nucleus, substantia nigra, ventral lateral preoptic area and locus coeruleus [91]. Orexin A in rostral LH increases NEAT [90, 88, 92], and repeated injection reduces adiposity [93].…”

Translational Science: How experimental research has contributed to the understanding of spontaneous Physical Activity and Energy Homeostasis

“…Orexin neurons are concentrated in the lateral hypothalamus (LH), perifornical area, and dorsomedial hypothalamus 42,50 . Some studies in rodents suggest the effect of orexin A on SPA is more relevant to energy balance than its role on the control of food intake 51 . Orexin A infusion in LC promotes SPA but not food intake, suggesting its signaling in LC promotes negative energy balance and reduction of adiposity 51 .…”

“…Some studies in rodents suggest the effect of orexin A on SPA is more relevant to energy balance than its role on the control of food intake 51 . Orexin A infusion in LC promotes SPA but not food intake, suggesting its signaling in LC promotes negative energy balance and reduction of adiposity 51 . In another study by Teske et al 52 , it was shown that orexin projections from the LH stimulates orexin and dopamine signaling in the SN and promotes SPA.…”