Adipocyte1:2,116–120;April/May/June2012;G2012LandesBioscience An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis Shaun F. Morrison,* Christopher J. Madden and Domenico Tupone DepartmentofNeurologicalSurgery;OregonHealth&ScienceUniversity;Portland,ORUSA Non-shivering thermogenesis in as well as the neuroendocrine, metabolic brown adipose tissue (BAT) plays and autonomic variables engaged during an important role in thermoregulatory thesestates.5-8Lossoforexinneuronsfrom cold-defense and, through its metabolic the PeF-LH leads to the disordered sleep consumption of energy reserves to pro- patterns ofnarcolepsy and is often accom- duce heat, can affect the long-term panied by lethargy and impairments regulation of adiposity. An orexinergic in metabolic homeostasis, including a pathway from the perifornical lateral high risk for obesity9,10 and for altered hypothalamus (PeF/LH) to the rostral thermoregulation.11 raphe pallidus (rRPa) has been demon- Brownadiposetissue(BAT)isaunique strated to increase the gain of the mammalian metabolic furnace that is excitatory drives to medullary sympathe- underthedirectcontrolofthesympathetic tic premotor neurons controlling BAT nervous system12 and produces heat sympathetic outflow and BAT thermo- through the uncoupling of its mitochon- genesis. With this background, we con- drial oxidative phosphorylation.13 BAT sider neural mechanisms that could thermogenesis plays a significant role in underlie orexin’s modulation of the the maintenance of body temperature and excitabilityofBATsympatheticpremotor BAT energy consumption contributes to neuronsinrRPaandthepotentialroleof bodyweight regulation, theimportanceof altered BAT thermogenesis in patho- which has been recently reinforced with Keywords: endocannabinoid, narcolepsy, logical conditions associated with the the demonstration of metabolically sig- obesity, stress, ultradian rhythm absence of the central orexin system. nificant BAT depots in humans and the Overall, these new data enhance our discovery of a reduced BAT activity in Abbreviations:BAT,brownadiposetissue; understanding of the role of central obese persons.14-16 Since mammalian, NMDA,n-methyl-D-aspartate; orexin in regulating body temperature including human, BAT thermogenesis PeF/LH,perifornicallateralhypothalamus; and energy homeostasis and provide contributestothermoregulatoryandmeta- rRPa,rostral raphe pallidus; further insight into the neurochemical bolichomeostasisandisalteredduringthe SNA,sympatheticnerve activity regulation of BAT thermogenesis and behavioral and state changes with which metabolism. changes in orexin are also associated, a Submitted: 01/03/12 connectionbetweentheorexinsystemand Revised: 02/14/12 the central circuits that influence the Accepted: 02/16/12 sympathetic outflow to BAT has been Introduction sought. http://dx.doi.org/10.4161/adip.19736 *Correspondenceto:ShaunF.Morrison; Orexins (hypocretins) are neuropeptides EstablishingaConnection Email:[email protected] synthesized by neurons in the perifornical betweenOrexinNeurotransmission region of the lateral hypothalamus andCentralRegulationofBAT Commentaryto:TuponeD,MaddenCJ,CanoG, (PeF-LH)1,2 that have widespread projec- MorrisonSF.Anorexinergicprojectionfrom perifornicalhypothalamustoraphepallidus tions that position the orexin system to In the study by Tupone and colleagues,17 increasesratbrownadiposetissuethermogenesis. influence a variety of behaviors and anatomical tracing and orexin immuno- JNeurosci2011;31:15944–55;PMID:22049437; physiological functions including sleep- histochemical localization were com- http://dx.doi.org/10.1523/JNEUROSCI.3909-11.2011 wake states and stress-arousal responses,3,4 bined with in vivo electrophysiological 116 Adipocyte Volume1Issue2 COMMENTARY techniques to elucidate a central neural sympathetic premotor neurons due to could act at orexin receptors on presynap- pathway through which orexin neurons their excitatory inputs is augmented with tic terminals (Fig.1A) to reduce GABA influence BAT thermogenesis and energy respect to that in the absence of orexin. release or increase glutamate release onto expenditure in rats. Viral retrograde trac- On the other hand, if the excitatory drive BAT sympathetic premotor neurons in ingfromBATandcholeratoxinretrograde to BAT sympathetic premotor neurons is rRPa. In this regard, orexin increased the tracing from the rostral raphe pallidus low (or the inhibitory inputs are suffi- frequencyofglutamatergicminiaturepost- (rRPa) indicated that a population of cientlyhigh),asinthecaseofawarmcore synaptic potentials in the presence of orexin neurons in the PeF-LH is synapti- temperature greater than ~37°C, then TTX.22 Interestingly, orexin release in cally connected to BAT via a direct orexin in rRPa is not capable of augment- rRPa could increase BAT sympathetic projection from the PeF-LH to the rRPa. ing the discharge of BAT sympathetic premotor neuron activity by reducing The connection from PeF-LH to neurons premotor neurons to a level that results in GABA release through an endocannabi- intherRPaisimportantbecausetherRPa activity on the sympathetic nerve to BAT. noid-mediated retrograde neurotransmis- contains sympathetic premotor neurons The findings that cooling-evoked (i.e., sion(Fig.1C)asdemonstratedtomediate whose excitatory drive to BAT sympathe- thermoregulatory) sympathetic outflow to orexin’s antinociceptive effect within the tic preganglionic neurons in the thoracic BAT is dependent on glutamate receptor periaqueductal gray.26 Orexin could pre- spinal cord determines the sympathetic activation in the rRPa18 and that blockade synaptically potentiate glutamate release outflow to BAT and, in turn, the level of oflocalGABA receptorsintherRPawith onto BAT sympathetic premotor neurons A BAT metabolism and thermogenesis. bicucullineelicitsapotentincreaseinBAT in the rRPa, similar to mechanisms In anesthetized, paralyzed and artifi- SNA19 suggest basic mechanisms that suggested for the potentiation of masseter cially ventilated rats whose core tempera- could each contribute to the ability of muscle tone with microinjection of orexin turewasmaintainedbelow37°C,suchthat orexin in the rRPa to increase the gain of intothetrigeminalnucleus.27However,in there was a low level of ongoing BAT the excitatory drive to BAT sympathetic thelatterexperiments,asinours,ifthereis sympathetic nerve activity (SNA), nano- premotor neurons and thereby facilitate astrongdependenceonglutamatereceptor injection of orexin-A into the rRPa ongoing sympathetic activity to BAT and activation for excitatory transmission produced large and sustained increases in BAT thermogenesis. through the nucleus in which orexin is BAT sympathetic outflow, in BAT ther- First, orexin could bind to orexin being injected, identifying a presynaptic, mogenesis and in heart rate. Activation of receptors on sympathetic premotor neu- orexin receptor-mediated mechanism for neuronsinthePeF-LHwithnanoinjection rons (Fig.1B), including serotonergic glutamate release would require in vitro of n-methyl-D-aspartate (NMDA) also neurons,20,21 in rRPa to alter their respon- approachesratherthansimplydemonstrat- markedly enhanced BAT SNA and BAT siveness to excitatory synaptic inputs. ing a reduction in the excitatory effects of thermogenesis over a long time course. In Orexin has a potent effect at postsynaptic orexin by glutamate receptor blockade contrast, in rats that were warmed slightly receptors, acting through G-protein in vivo. to core temperatures at which the BAT coupled receptors to increase cytosolic sympathetic nerve was quiescent, neither calcium levels22 and orexin receptors have Potential Physiological Sequelae nanoinjectionoforexininrRPanordirect, been localized on neurons in the rRPa,23 of the Central Orexin Influence NMDA-mediated activation of PeF-LH but there has been no further charac- on BAT Thermogenesis neurons, including those containing terization of the medullary neurons orexin, increased BAT SNA or BAT expressing the orexin receptor. We have Orexinmayplayaroleintheregulationof temperature. These results indicate the demonstrated that activation of serotoner- the ultradian rhythm of BAT thermo- ability of orexin released from the termi- gic receptors in the spinal cord increases genesis28,29 which is characterized in nals of orexin neurons in PeF-LH directly thegainofthespinalthermogenicnetwork rodents by increases in BAT temperature into the rRPa to produce a strong bypotentiatingglutamatergicexcitationof every ~1–2 h during the awake period potentiation of ongoing BAT SNA, BAT sympathetic preganglionic neu- of the ultradian sleep/wake cycle.28,30 BAT thermogenesis and BAT energy rons.24,25 This result raises the interesting Supporting this possibility, the activity of expenditure. possibilitythattheBATexcitatoryeffectof orexinergic neurons and the levels of orexin release in the rRPa could reflect a orexin in the extracellular fluid oscillate Orexin in rRPa Potentiates selective stimulation of local serotonergic with the ultradian sleep/wake cycle, with the Excitatory Drive to BAT BAT sympathetic premotor neurons pro- higherindicesoforexinactivityduringthe Sympathetic Premotor Neurons ducing a spinal serotonergic potentiation waking state31-33 and ventricular admini- of descending glutamatergic drive to BAT stration of orexin increases BAT tempera- The potentiation of BAT SNA by orexin sympathetic preganglionic neurons. ture.34 Although an ultradian rhythm in in the rRPa may be viewed as an increase Postsynaptic effects of orexin could also BAT temperature in orexin-null mice has inthegainoftheexcitatoryinputstoBAT be mediated by orexin receptors on local notbeenassessed,theultradiansleep/wake sympathetic premotor neurons in the interneuronsintherRPaareathat,inturn, cycle of these mice is disrupted, with rRPa—when orexin is released in the affect the activity of BAT sympathetic shorterwakefulnessperiodsthanwild-type rRPa, the level of discharge of BAT premotor neurons. Alternatively, orexin mice.30,35 We postulate that the ultradian www.landesbioscience.com Adipocyte 117 Figure1.Potentialsynapticmechanismsunderlyingtheorexin-evokedincreaseinactivityofsympatheticpremotorneuronsforBATinrostralraphe pallidus(rRPa).(A)OrexincouldbindtopresynapticorexinreceptorstoaugmenttheongoingreleaseofglutamateontoBATsympatheticpremotor neurons(graysphere).(B)OrexincouldactatpostsynapticorexinreceptorsonBATsympatheticpremotorneuronstoincreasetheirexcitability, therebyaugmentingtheirdischargeevokedbyactiveglutamatergicinputs.(C)Orexinbindingtopostsynapticorexinreceptorscouldstimulatesynthesis ofendocannabinoid,whichwouldincreasetheactivityoftheBATsympatheticpremotorneuronsinrRPabyactingretrogradelytoinhibitatonicGABA releasefrompresynapticterminals. increases in BAT temperature are neurotransmission in the rRPa, the degree orexin activity prevents diet-induced mediated by the periodic release of orexin of orexin receptor activation in the rRPa obesity and could contribute to a lean in the rRPa, resulting in increases in the should have a significant influence on the phenotype.46 The excess weight gain in gainoftheBATthermogenicpathwaythat consumption of energy stores in white orexin-null mice is attributable to increases body and brain temperatures. adipose tissue and thus on the regulation impaired thermogenesis in BAT.47 Although the functional implications of of body weight. Althoughthepotentialrolefordiminished orexin’s ability to increase the gain of the Narcolepsy is the neurological disorder BAT activation in the increased incidence thermogenic neurotransmission in the attributable to reduced orexin neurotrans- of obesity in narcoleptic patients has not rRPa remain untested, the close correla- mission36-38 and, although principally been tested, this hypothesis would be tion of BAT thermogenesis and the characterized by altered sleep/wake cycles, consistent with the recent demonstrations resulting increase in body temperature narcolepsyisalsoassociatedwithobesityin of an inverse relationship between the during periods of wakefulness suggests human patients,9,39-43 despite a reduced activity of BAT and body mass index in that BAT thermogenesis may contribute caloricintake44andanormaltotalphysical adult humans14-16 and with the overall toanenhancedmetabolismduringperiods activitycomparedeithertohealthycontrol reduction in BAT energy consumption of wakefulness or arousal that require subjects45 or to patients with idiopathic expected in the absence of orexin.17 enhanced performance. Conversely, low hypersomnia.9 Mice that lack orexin Handlingandavarietyofotherstressful levels of thermogenesis during sleep states neurons also gain more weight than wild- situationsforrodentselicitincreasesincore may act to conserve metabolic resources type controls despite reduced food intake; temperature to which BAT thermogenesis during a behavioral state in which energy however, a decrease in spontaneous motor may contribute.48,49 Ablation of orexin stores are not being replenished. Indeed, activity likely also contributes to their neurons, but not the absence of orexin per by modulating the gain of BAT excitatory weight gain.10 Conversely, augmented se, reduces the increase in core body 118 Adipocyte Volume1Issue2 temperature evoked by repeated handling pups.47 Thus, the genotype of the dam Summary stress, indicating that orexin-containing could determine the development of BAT neurons release neurotransmitters other in the offspring, requiring cautious inter- An orexinergicinput to therRPa has been than orexin (e.g., dynorphin or glutamate, pretationofphenotypicdatarelatedtoBAT demonstrated to potentiate the excitatory which are normally co-expressed in orexin thermogenesisfromgenetically-drivenabla- drives to medullary sympathetic premotor neurons50,51)toelicitstress-evokedincreases tion and knockout models of orexin- neuronscontrollingBATsympatheticout- in body temperature.52 However, orexin, producing cells. Considering the potential flowandBATthermogenesis.Theseresults likelyderivedfromtheplacenta,isrequired for differences in the development of BAT provide a potential mechanism contri- for the development and differentiation of to contribute to altered body temperature buting to the disrupted regulation of BAT and systemic orexin administration responses, BAT thermogenic competence body temperature, energy metabolism and duringgestationinorexin-nulldamsrescues andUCP-1expressionlevels(seerefs.47vs. body weight in the absence (narcolepsy) this developmental defect in the newborn 50)mustberigorouslyassessed. ordysregulationoforexinsecretion. References 12. 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