Orexins: neuropeptides for all seasons and functions

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Abstract
The neuropeptides orexin (ORX) A and B were first identified by a screen for novel hypothalamic homeostatic regulatory peptides ([15][1]). Because of the substantial homology in amino acid sequences with secretin, they were named hypocretins by one group ([9][2]). Because they stimulated food intake, they were called ORXs by another ([42][3]). While the relatively small number of ORX-expressing neurons are localized specifically within the lateral hypothalamus (LH), their G protein-coupled receptors [ORX1R (Hcrtr1) and ORX2R (Hcrtr2)] ([42][3]) and presumptive target neuronal populations are widely distributed throughout the nervous system in a variety of cortical, limbic, hippocampal, thalamic, brain stem monoamine neuron-containing, and spinal cord areas ([8][4], [32][5], [39][6], [52][7], [53][8]). This broad distribution of potential anatomical targets made it obvious from the beginning that these neurons were involved in much more than just the simple act of eating. In fact, ORX neurons exemplify the way in which a few thousand neurons can modulate many complex behaviors and physiological functions. A review of their targets suggests that ORX neurons can regulate ingestion by activation of pathways that stimulate the drive to eat (hunger); produce behavioral arousal; increase motor and supporting cardiovascular systems required to seek, procure, and ingest food; and autonomic and neuroendocrine systems required to digest, assimilate, and store ingested nutrients and generate satiety signals required for termination of individual meals ([8][4], [19][9], [20][10], [24][11], [35][12], [53][8]). Although they undoubtedly receive inputs from higher cortical centers relating to the cognitive and motivational aspects of ingestion, ORX neurons have a critical reciprocal feedback loop with hypothalamic arcuate nucleus anabolic neuropeptide Y/agouti-related peptide (NPY/AgRP) and catabolic proopiomelanocortin neurons. The interaction with NPY/AgRP neurons appears to be important for modulation of feeding ([10][13], [33][14], [41][15], [54][16], [58][17]), but these feedback loops also provide the anatomical substrate for the control of the ingestive, neuroendocrine, autonomic, and thermogenic components of energy homeostasis ([2][18], [4][19], [12][20], [14][21], [21][22]). As opposed to most orexigenic peptides, the feeding stimulatory effects of ORX are most pronounced during the light phase when rodents are satiated and largely inactive ([20][10], [24][11], [59][23]). Thus the ORX system may be maximally activated during the dark phase when normal feeding occurs and therefore is not amenable to further exogenous stimulation. This fits with the idea that ORX, like NPY, may have a major role in arousal and the motoric and autonomic activation required to seek and procure food rather than providing the primary motivational forces needed to initiate feeding ([43][24]). However, ORX is also likely to be involved in the motivational aspects of hunger because ORX injections into the nucleus accumbens shell, a brain area involved in reward behavior, stimulate both feeding and motor activity ([49][25]). Melanin-concentrating hormone (MCH) neurons are the other important group of orexigenic LH neurons. They have projections that largely overlap those of ORX neurons ([11][26], [51][27]). Because MCH neurons express ORX receptors ([2][18]), local release of ORX onto MCH neurons or the focal injection of ORX into the LH probably stimulates feeding by a combined effect on both sets of neurons with engagement of the full range of behavioral and physiological systems required for the expression of ingestive behavior. There is some dispute as to how responsive ORX neurons are to changes in the nutritional status of the organism. This is due to conflicting studies regarding their responses to fasting and exogenously administered leptin. Thus ORX neurons do increase their expression of ORX mRNA and immunoreactive protein after short-term fasts and insulin-induced reductions in glucose but not after prolonged fasting, streptozotocin-induced diabetes, voluntary overconsumption of palatable foods, or hypoglycemia when food is available ([6][28], [31][29], [50][30]). On the other hand, there is good evidence that ORX neurons are true glucosensing neurons, i.e., neurons that alter their firing rate when ambient glucose levels change. They are prototypic glucose-inhibited neurons that are activated by low- and inhibited by high-glucose levels ([5][31], [34][32], [45][33]). Interestingly, although ORX and MCH are both orexigens and have largely overlapping targets, MCH neurons have the opposite response to changes in ambient glucose levels. They are typical glucose-excited neurons that are activated by high- and inhibited by low-ambient glucose levels ([5][31]). In addition to responding to glucose, ORX neurons also express Lepr-b, the signaling form of the leptin receptor ([18][34], [22][35]). Leptin inhibits the increase in ORX expression that occurs during short-term fasting ([31][29]). Paradoxically, although ORX expression is not altered by long-term fasting, leptin administration increases its expression in chronically fasted mice ([50][30]). Collectively, such studies suggest that ORX neurons may be involved in the short-term regulation of food intake, especially during states of low glucose availability ([3][36], [6][28], [16][37], [44][38], [50][30]). The discovery of ORX and MCH neurons in the LH supported the dual-center hypothesis for the control of ingestion in which the LH is the feeding center and the ventromedial hypothalamus is the satiety center ([47][39]). This hypothesis was based on the effects of large hypothalamic lesions that had marked effects on feeding and body weight. These profound effects mistakenly led to the conclusion that the hypothalamus was the almost sole controller of energy homeostasis. However, several sets of findings amassed over many years have finally led us away...

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