Orexin (hypocretin)

Orexin also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.

Narcolepsy type 1, is most common form of narcolepsy in which the individual experiences brief losses of muscle tone  or drop attacks/cataplexy, is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

It exists in the forms of orexin-A and orexin-B.

There are 50,000–80,000 orexin-producing neurons in the human brain, located predominantly in the perifornical area and lateral hypothalamus.

Orexin producing neurons project throughout the CNS and regulate wakefulness, feeding, and other behaviors.

There are two types of orexin peptides and two types of orexin receptors.

There are two types of orexin: orexin-A and orexin-B (hypocretin-1 and hypocretin-2).

Orexins are excitatory neuropeptides with approximately 50% sequence identity, produced by cleavage of a single precursor protein.

This precursor protein is known as prepro-orexin (or preprohypocretin) and is a 130 amino acid pre-pro-peptide encoded by the gene HRCT and located on chromosome 17 (17q21).

Orexin-A is 33 amino acid residues long and orexin-B is a linear 28 amino acid residue peptide.

These peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. 

The orexin peptides bind to the two G-protein coupled orexin receptors, OX1 and OX2.

The orexin system was suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. 

The orexin system also stimulates wakefulness, regulates energy expenditure, and modulates visceral function. 

The orexin system may function by exciting other neurons that produce neurotransmitters, as well as by inhibiting neurons in the ventrolateral preoptic nucleus, which is a region of the brain who’s neuronal activity is imperative to proper sleep function.

Orexin neurons regulate brown adipose tissue (BAT) activity via the sympathetic nervous system to enhance energy expenditure.

Orexin seems to promote wakefulness. 

The orexin system integrates metabolic, circadian and sleep debt influences to determine whether one  should be asleep, or awake and active. 

Orexin neurons excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilizing wakefulness and sleep

 Central administration of orexin-A promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. 

Sleep deprivation increases orexin-A transmission. 

The orexin system may thus be more important in the regulation of energy expenditure than in the regulation of food intake. 

Orexin-deficient people with narcolepsy have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide. 

Narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.

Genome-wide analysis shows that, in addition to the HLA variant, individuals  with narcolepsy also exhibit a specific genetic mutation in the T-cell receptor alpha locus.

Genetic anomalies cause the immune system to attack and kill the critical orexin neurons, suggesting the absence of orexin-producing neurons in people with narcolepsy may be the result of an autoimmune disorder.

Orexin increases the craving for food.

Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback.

Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. 

Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake. 

Orexin-producing cells have been shown to be inhibited by leptin. but are activated by ghrelin and hypoglycemia.

Glucose inhibits orexin production.

Long-term sleep deprivation is thought to increases food intake and energy metabolism/catabolism, with lethal consequences on a long-term basis. 

Sleep deprivation leads to a lack of energy. 

To make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. 

Amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.

Orexin blockers are being evaluated in the treatment of cocaine, opioid, and alcohol addiction. 

Orexin-A (OXA) has a direct effect on an aspect of lipid metabolism, stimulates glucose uptake in adipocytes and that increased energy uptake is stored as lipids.

Orexin-A increases lipogenesis, and also inhibits lipolysis and stimulates the secretion of adiponectin: via the PI3K pathway.

High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness: suggesting that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression. 

Orexins are hypothesized to aid in the development of resilience to the stress response.

Orexin is implicated in addiction and depression, is also involved in the display of anhedonia in ADHD. 

Orexin has been shown to have a large degree of control over behaviors that are motivated by a need to survive, such as searching for food when an organism is starving. 

Impaired orexin function as intended, impairs the ability to feel pleasure from strongly motivated actions.

Orexinergic neurons have been shown to be sensitive to inputs from glutamate receptors, cannabinoid receptor 1 and CB1–OX1 receptor heterodimers, adenosine A1 receptors, muscarinic M3 receptors, serotonin 5-HT1A receptors, neuropeptide Y receptors,cholecystokinin A receptors, and catecholamines,as well as to ghrelin, leptin, and glucose.

Orexinergic neurons themselves regulate release of acetylcholine,serotonin, and noradrenaline.

Orexinergic neurons are closely associated with reward related functions, such as conditioned place preference. 

These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex, and neurons found in the ventral tegmental area, the ventromedial prefrontal cortex, and the nucleus accumbens shell are strongly implicated in addiction and the sensitization of neurons to stimulating drugs, such as amphetamines.

Orexin producing neurons in these areas aremprimarily indicated in seeking behavior when externally stimulated by environmental signals such as stress.

The perifornical-dorsal group of orexinergic neurons are involved in functions related to arousal and autonomic response. 

These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes.

Orexin/hypocretin system dysfunction has been proposed as a novel pathophysiological model of Takotsubo syndrome.

ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) refers to neurodevelopmental disorders and difficulties (ADHD, developmental coordination disorder, autism spectrum disorder), behavioural phenotype syndromes, some neurological conditions and disorders, and severe early-onset mental disorders, that may be associated with

Orexin/hypocretin system dysfunction.

The orexin/hypocretin system is the target of the insomnia medication suvorexant (Belsomra), which works by blocking both orexin receptors.

Other FDA-approved orexin antagonists are lemborexant Dayvigo and daridorexant (Quviviq).

Orexins are also thought to have potential implications in learning and aiding in fending off diseases such as dementia and other disorders that impair cognition.


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