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| PRACTICE CHANGING CONTINUING EDUCATION - CLINICS IN NEUROPHYSIOLOGY |
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| Year : 2016 | Volume
: 3
| Issue : 3 | Page : 148-152 |
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Orexin neuropetides: Physiology and significance in food metabolism
Shikha Jain, Ajay K Jain
Department of Physiology, Maulana Azad Medical College, New Delhi, India
| Date of Web Publication | 27-Feb-2017 |
Correspondence Address:
Dr. Shikha Jain
CG-3,606, Supertech Capetown, NOIDA, Sector 74, Uttar Pradesh - 201 301
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2349-0977.201002
Orexin is a neuropeptide secreted by a group of hypothalamic neurons. Orexin neurons in hypothalamus have widespread projections throughout the brain and peripheral structures. Orexin actions are mediated by calcium and raise cytoplasmic Ca+2 via a mechanism based on G-protein. Orexin activity is modulated by the biological clock. Orexin-A influences the hypothalamic and pituitary hormone release along with a role in arousal, energy homeostasis, goal-orientated behavior, and autonomic nervous system control. Orexin neurons receive indirect circadian signals that integrate with metabolic signals to regulate energy homeostasis. The metabolism of carbohydrates and fats is also linked to orexin. Orexin-A increases metabolic rate; insulin-induced hypoglycemia activates orexin-containing neurons, thus orexins regulate energy metabolism. The orexin-induced increase in energy metabolism is not simply due to increased wakefulness and physical activity but orexin increases metabolism independent of sleep/wake, locomotion, and food intake. Thus, orexin appears to be an essential factor for maintaining energy balance and body weight. Excess energy intake and decreased energy consumption due to sedentary lifestyle are the main contributors to the metabolic syndrome epidemic, and whether there is any correlation of metabolic risk markers with orexin levels is yet to be established. Orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding. Hyperglycemia caused by insulin insensitivity during ageing or by consumption of a high-fat diet leads to reduction in orexin expression in hypothalamus, which further exacerbates peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for future treatment of hyperglycemia in patients with type 2 diabetes. Keywords: Food metabolism, functions, orexin
How to cite this article:
Jain S, Jain AK. Orexin neuropetides: Physiology and significance in food metabolism. Astrocyte 2016;3:148-52 |
| Introduction | |  |
Orexin is a neuropeptide produced by a specific subset of neurons located in the lateral hypothalamic area. It regulates appetite and food intake. Orexin/hypocretin was first described in 1998 by De Lecea et al.[1]
Orexin-A and B (also known as hypocretin 1 and hypocretin 2) were discovered independently by two groups using different techniques. De Lecea et al.[1] identified the prohormone pre-prohypocretin and its peptide products hypocretin-1 (Hcrt-1) and hypocretin-2 (Hcrt-2) by nucleotide sequencing, whereas Sakurai et al.[2] used orphan receptor cloning technique for the discovery of orexins, i.e. orexin-A (Orx-A) and orexin-B (Orx-B).
Based on the anatomic location of neurotransmitters, their name was coined from the words hypothalamus. Orexin A and Orexin B correspond to hypocretin 1 and 2, respectively. Hypocretin and orexin are used synonymously. They were named “orexin-A” and “orexin-B,” orexin being derived from orexis, which means appetite.
Takeshi Sakurai initially identified Orexin A and Orexin B as endogenous peptide ligands for two orphan G-protein coupled receptors [Hcrtr1 (Orxr1) and Hcrtr2 (Orxr2)]. The Hcrtr1 receptor has a significantly higher (100 to 1000-fold) affinity for Hcrt-1 than for Hcrt-2. The Hcrtr2 receptor seems to have equal affinities for both neuropeptides.
Orexin A is 33 amino acid peptide of 3562 Da size with an N-terminal pyroglutamyl residue and C-terminal amidation residue. Molecular mass of the purified as well as its sequencing analysis indicate that the four Cys residue of Orexin A formed two sets of interchain disulfide bonds.
Orexin B is a 28 amino acid, C-terminal amidated linear peptide of 2937 Da size, which was 46% (13/28) identical in sequence to Orexin A. The C-terminal half of Orexin is very similar to that of Orexin A whereas the N-terminal half is more variable.
| Orexin Neurons and Its Receptors | | |
Orexin neurons in hypothalamus have widespread projections throughout the brain including the cortex, hippocampus, amygdala, nucleus accumbens, hypothalamus, thalamus, ventral tegmental area (VTA), locus coeruleus (LC), and the raphe where abundant orexin receptors are present.[3] The OxR1 is located in the ventromedial and lateral hypothalamus, hippocampus, locus coeruleus, and pineal and pituitary gland, whereas OxR2 is present in the thalamus, hypothalamus, septum, cortex, and brain stem.
Moreover, orexin receptors are present in peripheral structures–in vagal nerve, in testes, thyroid, adrenals, kidneys, placenta,[4],[5],[6],[7] as well as in the gut enteric nervous system, pancreatic plexus, islets, acini, and endocrine cells in stomach and small intestine.[8]
The wide distribution of orexigenic neurons and orexin receptors in the tissues suggest the pleiotropic functions of this peptide and their important role in neuroendocrine regulation and autonomic nervous system control. Therefore, orexins have both central and peripheral effect.
| Mechanism of Action | | |
Orexins raise cytoplasmic Ca +2 via a mechanism based on G-protein enhancement of calcium influx through plasma membrane channels.[9],[10] In Chinese hamster ovary cells, activation of Orexin-A receptor leads to Ca +2 influx and stimulation of phospholipase-C (PL-C).[11] Simultaneously, low concentration of orexin-A causes production of inositol triphosphate-3 production. Thus, orexin causes release of noradrenaline from rat cerebrocortical slices that is partially Ca +2 dependent.[12] The adrenal gland stimulation of Orexin-A causes CAMP and IP3 production in a dose dependent manner.[13] Thus actions of orexin are calcium mediated, as presented in [Figure 1].
| The Circadian Clock of Orexin | | |
The suprachiasmatic nucleus (SCN) projects onto Orexin cells.[14] It suggests that orexin activity may be modulated by the biological clock. Orexins increase during the second half of the active period in rats under entrained conditions.[15] This fact provides a concept of SCN-dependent alertness, a system that has also been suggested to be abnormal in orexin deficient narcolepsy.[16]
A wake promoting signal generated from the SCN in the second part of the active phase is seen in the opponent model of sleep regulation. In humans, this helps to maintain a constant period of wakefulness and alertness.[17]
Orexin Functions
Orexin-A could be considered not only as a neurotransmitter and/or neuromodulator but also as a hormone due to the secretion of this peptide into circulating blood.[11] It has been found that Orexin-A influences the hypothalamic and pituitary hormone release in rats.
Orexin, as the name implies, is not only an orexigenic peptide instead it has a variety of pharmacological actions [Figure 2]. Recent studies suggest a role of orexins/ hypocretins in sleep disorder narcolepsy and maintaining wakefulness. The feeding behavior, especially the behavioral satiety sequence, energy expenditure, and metabolism is also under orexins control. This is because the Orexin neurons are the target of multiple neuronal cell types including those regulating the sleep–wake cycle, energy homeostasis, and motivation. The resulting neuronal circuit supports Hcrt function, integrating arousal, energy homeostasis, and goal-orientated behaviors.[2],[18] | Figure 2: Effect of Orexin in peripheral tissue and central nervous system.
Click here to view |
Studies reveal that the role of orexin include autonomic nervous system control.[19],[20] Intracerebroventricular injection of orexins increases blood pressure and heart rate.[21]
The neuroendocrine effects of the hypocretins include a lowering of plasma prolactin and growth hormone and an increase in the levels of corticotropin, cortisol, insulin, and luteinizing hormone.[22],[23],[24],[25],[26] Russell et al.[27] demonstrated in rat the Orexin-A interaction with hypothalamo-pituitary-gonadal axis. Orexin A may play a role in the thermoregulation, and the hypothermic effects of Orexin-A are mediated byneuropeptide-Y (NPY).[28] The role of OXR1 in mediating apoptosis has been demonstrated.[29]
| Role of Orexin in Metabolism and Energy Expenditure | | |
Orexin neurons act as a “primary” sensor of metabolic changes in our body. They receive indirect circadian signals that integrate with metabolic signals to regulate energy homeostasis.
These effects of orexin were understood on the fact that the anatomic location of orexin neurons, i.e., the lateral hypothalamic area, is considered to be a feeding centre and locus coeruleus is a centre for wakefulness. Mice lacking the orexin peptide (prepro-orexin knockout mice), as well as those in which orexin-expressing neurons were absent, were narcoleptic and obese.[30],[31],[32] Furthermore, prepro-orexin mRNA was not detected in the brain of humans suffering with narcolepsy.[33] Human narcolepsy, which is accompanied by a specific loss of hypothalamic orexin neurons, is associated with metabolic abnormalities, including an increased incidence of type 2 diabetes and obesity.[34] Taken together, these data suggest that the orexin system plays a critical role in regulating the sleep–wake cycle, causing alertness and feeding in a state of negative energy balance.
The metabolism of carbohydrates and fats is linked to orexin. Glucose and insulin are under the control of orexins. Orexins affect the plasma lipoprotein profile and insulin glucose homeostasis. Orexins stimulate insulin release from pancreatic cells in vivo and in vitro.[35],[36] The lateral hypothalamus contains neurons that are stimulated by a decline in glucose levels,[37] consequently a subset of orexin neurons concentrated in this area is also affected by this change in glucose,[38] and through neuropeptide-Y neurons cause counter regulatory responses that maintain glucose levels. This regulation is because Orexin neurons interact with glucose sensitive neurons in hypothalamus, which are of 2 types, namely, the glucose-responsive cells (glucose-excited neurons: stimulated by rising glucose levels) found predominantly in the ventromedial nucleus (VMH), and the glucose-sensitive neurons (glucose-inhibited neurons: stimulated when glucose levels reduce) that constitute 30% of the lateral hypothalamic area (LHA) neurons.[39] The synaptic connections between both neurons regulate sugar levels.
In addition, orexin expression increases in response to insulin-induced hypoglycemia and also to food deprivation, which ultimately reduces glucose as well as insulin.[40] Further studies are needed to characterize a possible relationship between the orexins and body metabolism under physiological conditions. Obesity due to excess feeding raises the possibility that orexins are responding to either a rise in total caloric intake or body weight.
Muroya et al.[41] demonstrated that orexins directly regulate NPY, POMC, and glucose responsive neurons in the ARC and VMH, and these results coincide with the orexigenic action of orexins.
Adam et al.[42] showed that orexin levels were reduced in obese individuals, which correlated negatively with plasma leptin level. Serum Orexin has negative association with fasting glucose levels in women with metabolic syndrome.[43] Orexin A concentration has been demonstrated to significantly correlate with body mass index in normal individuals.[44],[45] Similar results were found in my study which showed that fasting plasma glucose is positively correlated with circulating orexin level (unpublished data).[46]
Orexins stimulate energy expenditure by increasing alertness, increasing sympathetic activity, and increasing spontaneous physical activity. Orexin-A increases metabolic rate, and the insulin-induced hypoglycemia activates orexin-containing neuron suggesting that the orexins are mediators of energy metabolism. Hypothalamic orexin actions critically involve metabolic, autonomic, and endocrine functions.[47] The orexin-induced increase in energy metabolism is not simply due to increased wakefulness and physical activity. In fact, Orexin-A increases oxygen consumption and body temperature even in anesthetized rats,[48] and intracerebroventricular injection of orexin-A during the light period increases the metabolic rate without affecting food intake and locomotor activity in mice.[49] In addition, orexin neuron-deficient mice display reduced energy expenditure that is independent of sleep/wake, locomotion, and food intake.[50]
Orexin neuron deficient mice exhibit late-onset obesity despite the reduced food intake and gain more weight than wild-type mice on a high-fat diet.[51] Thus, orexin appears to be an essential factor for maintaining body weight.
Excess energy intake and decreased energy consumption due to sedentary lifestyle are the main contributors to the metabolic syndrome epidemic, and whether there is any correlation of metabolic risk markers with orexin levels is to be established.
The orexin-elicited feeding behavior is mediated by the NPY pathway and food intake induced by ghrelin, a peptide produced in the stomach and hypothalamus, is partly mediated via the orexin pathway.[52],[53] However, acute central administration of Orexin-A stimulates food intake only when it is administered during the resting (daytime) phase of rodents, and chronic Orexin-A administration does not change food intake and body weight.[54] In addition, administration of an Orexin-2R selective agonist suppresses food intake in mice fed on high-fat diet but not low-fat diet. Orexin neurons in the perifornical hypothalamus are fat-responsive, and orexin gene expression was stimulated by a high-fat diet in close association with elevated triglyceride levels.[55],[56] There is evidence that circulating fatty acids derived from triglycerides can cross the blood–brain barrier and gain access to the brain. This suggests that the orexin peptides may have multiple functions depending on the nutritional status of the individual.[57],[58]
Therefore, orexins increase or decrease food intake depending on plasma fuel levels to maintain energy homeostasis.
Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signaling confers resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycemia due to insulin insensitivity during ageing or by consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, which further exacerbates peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for future treatment of hyperglycemia in patients with type 2 diabetes.[59]
Orexin receptor agonists and antagonists are being developed to provide a new way to treat hypothalamic dysfunctions including sleep disorders (narcolepsy or insomnia). Moreover, this role of orexin in the development of novel therapeutic strategies to prevent or treat metabolic disorders, such as obesity, metabolic syndrome and type 2 diabetes, can be considered in future. Further studies to know more about how the neural circuit of orexin can integrate peripheral metabolic signals, and higher brain functions to maintain whole-body energy homeostasis, appears to be a promising way to reach an exciting new frontier in neurometabolic biology.
| Conclusion | | |
Orexin neuropeptides have varied functions and exert integrated control on body metabolism and body weight. Although much is known about orexin functions, its role in the pathogenesis of obesity and metabolic syndrome is yet to be established on human data. Glucose homeostasis by Orexin can emerge as a key target for therapeutic intervention in hypothalamic dysfunctions, including narcolepsy, hypersomnia, and metabolic syndrome.
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Conflicts of interest
There are no conflicts of interest.
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