Orexin

Physiology

• Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.
• The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or 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. They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours. There are two types of orexin peptide and two types of orexin receptor.

Function

• Orexin system increases food intake.
• Orexin stimulates wakefulness, regulates energy expenditure and modulates visceral function.

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

• Orexin promotes wakefulness. It integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep, or awake and active. Orexin neurons strongly 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 strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure.
• Orexin-deficient people with narcolepsy have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide.

Absence of orexin-producing neurons in people with narcolepsy may be the result of an autoimmune disorder.

• Orexin increases food craving but some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.

• Orexin-A (OXA) has been demonstrated to have a direct effect on an aspect of lipid metabolism.

• High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.

Orexin neurons

Orexinergic neurons can be differentiated into two groups based on connectivity and functionality.

• Orexinergic neurons in the lateral hypothalamic group 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.
• 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 system dysfunction

• Takotsubo syndrome: Orexin system dysfunction has been proposed as a novel pathophysiological model of Takotsubo syndrome (acute failure syndrome).

• ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) is an umbrella term covering a wide range of neurodevelopmental disorders and difficulties (i.e. ADHD, developmental coordination disorder, ASD), as well as, ESSENCE-associated conditions (behavioural phenotype syndromes; some neurological conditions and disorders; and severe early-onset mental disorders). Orexin/hypocretin system dysfunction might be associated with many symptoms in a variety of ESSENCE.