omnipresent
Orexin is found in many tissues, including the hypothalamus, spinal cord, sensory ganglia, pancreas, pituitary gland, adrenal glands, salivary glands, and lacrimal glands. Orexin levels can be easily measured in blood, urine, and cerebrospinal fluid. Orexins are involved in a variety of biological functions, including wakefulness, sleep, food and fluid intake, pain, and memory. Orexin is also involved in the regulation of glucose metabolism. Orexin appears to be ubiquitous and has multiple biological functions. Further research may uncover additional functions for this relatively new neuropeptide. It could play a therapeutic role in the near future.
Orexin-A and Orexin-B
Orexin (also known as hypocretin) was discovered through reverse pharmacology in 1998 as an endogenous ligand of two orphan G protein-coupled receptors. Orexin exists in two molecular forms, orexin-A and orexin-B, derived from the same 130 amino acid residue precursor (preproorexin). Orexin-A is a 33 amino acid residue peptide with two intrachain disulfide bonds that are completely conserved in tetrapods. Orexin-B is a linear 28 amino acid residue peptide. Orexin specifically binds to the orexin receptors OX1R and OX2R. Orexin-A binds OX1R and OX2R with high affinity, while orexin-B selectively binds OX2R with similarly high affinity. The orexin system plays a role in regulating eating and drinking behavior, metabolism, sleep-wake cycles, and the endocrine system.
can lead to pathological diseases
Orexins have multiple effects and influence many functions, including autonomic regulation, endocrine function, food intake, appetite, arousal, and sleep. Orexin and its receptors are found in various organs outside the central nervous system. These molecules are involved in a variety of physiological mechanisms. Based on the current findings, there is strong evidence supporting their functional role in the periphery. Furthermore, many studies have shown that disturbances in the expression or levels of orexin peptides can lead to pathological diseases such as late-onset obesity, impaired insulin sensitivity, hyperinsulinemia, and intestinal dysfunction. However, the exact mechanism by which orexin exerts its effects is not fully understood.
Neurotransmitters produced by small groups of neurons in the lateral hypothalamus and perifornical region
Orexin (also known as hypocretin) is a neurotransmitter produced by a population of small neurons in the lateral hypothalamus (LH) and perifornical (PFA) regions. The name orexin comes from the Greek root "orexis". Orexin peptides are known to regulate arousal, arousal, food intake, and reward-related behaviors through their actions in a perturbed group of brain nuclei (for review, see the hypothalamus in the Brain Peptides section of this book Secretin/orexin chapter). Orexin peptides exist in two forms, both produced by cleavage of preproorexin: orexin-A (33 amino acids) and orexin-B (28 amino acids). Orexin-A can bind to the orexin-1 receptor (O×1R) and with lower affinity to the orexin-2 receptor (O×2R), whereas orexin-B has preferential binding affinity to O×2R. Both orexin receptors are G protein-coupled receptor subtypes and are widely distributed throughout the central nervous system. 20 Due to the lack of effective and commercially available O×2R antagonists, orexin-A signaling at the O×1R has been more extensively studied and better characterized.
Orexin neurons are interconnected with basal structures in the hypothalamus that are involved in the control of food intake. In particular, orexin-producing neurons in the LH receive input from neuropeptide Y-/agouti-related peptide-expressing neurons in the arcuate nucleus, leading to the idea that LH orexin neurons are “secondary” in the integration process involved in facilitation Neurons. Food intake. However, other evidence suggests that orexin neurons may function as "first-order" neurons. In this capacity, they are sensors of metabolic status, directly regulated by circulating factors such as leptin, glucose, and ghrelin. Orexin neurons may exhibit primary and secondary properties in a complex integration of neuropeptide and fat inhibitory signals that exert counterregulatory effects on feeding behavior (i.e., increased and decreased food intake). In terms of feeding behavior, many reports describe the orexigenic properties of orexin-A on food intake. For example, intracerebroventricular (icv) administration of orexin-A increases food intake in rodents. When given a choice, administration of orexin to rats will selectively increase intake of the preferred diet, and more specifically, increase intake of a diet high in saturated fat. Furthermore, pharmacological antagonism of orexin-1 receptors effectively blocks orexin A-induced hyperphagia and behavioral satiety.
Regulate sleep/wakefulness
Substantial evidence supports the role of endogenous orexins in regulating sleep/wakefulness and metabolic status. Central to all of orexin's effects is the consistent finding that multiple stress indicators are displayed after orexin administration, and that some stress indicators disappear when orexin production or action is compromised. Remarkable progress has been made in understanding the importance of the endogenous orexin system, largely due to the development of transgenic models that compromise the orexin peptide or receptor. In particular, the development of orexin-ataxin-3 transgenic mice and rats was a milestone in our ability to understand the broad effects of these peptides on multiple behavioral, endocrine, and cardiovascular systems. Now, with the advent of selective OX1R antagonists and at least one relatively selective OX2R agonist, the site and mechanism of orexin action in the brain can be further elucidated. Since peptide replacement can restore normal sleep/wake patterns in genetically modified animals, there is great promise in using orexin or orexin analogs to treat narcolepsy/cataplexy in humans. Key to the development of these potential therapeutic strategies is understanding the receptor subtypes responsible for orexin's effects on cardiovascular and neuroendocrine function. Clearly, potential side effects related to cardiovascular control and hormone release are possible and should be monitored if the therapeutic effects of orexin are to be tested in humans.
Stress and wake/sleep
Orexin/hypotocretin neurons are located in the perifornical region of the lateral hypothalamus and are necessary for maintaining wakefulness and behavioral arousal. Loss or reduction of orexin/hypotocretin peptides or receptors can lead to narcolepsy and cataplexy. Orexinergic neurons project extensively to the forebrain, including the cerebral cortex, brainstem, and spinal cord, and like the acetylcholine basal forebrain system, orexinergic neurons project to subcortical relays in the basal forebrain. Orexin/hypotocretin regulates multiple wake-promoting neurotransmitter systems, including noradrenergic, histaminergic, and serotonergic neurons. Orexinergic neurons fire selectively during wakefulness and cease firing activity during REM and non-REM sleep. In the hypothalamus, extracellular concentrations of orexin/hypotocretin and orexin/hypotocretin mRNA expression also vary in a diurnal manner.
Increased drinking, food seeking, and spontaneous activities
Orexin, also known as hypocretin, is an appetite-inducing neuropeptide involved in the regulation of sleep-wake cycles and eating. Two hypocretins, orexin A (a 28-amino acid peptide) and orexin B (a 33-amino acid peptide), are synthesized in the LH. Orexin binds to two orexin receptor subtypes, OX1-R in the VMH and Arc and OX2-R in the PVN and hindbrain. Injection of orexins A and B into the ventricles or hypothalamus increases food intake but is not as effective as NPY. Orexin also increases drinking, food seeking, and locomotor activity.
The orexin system and the NPY system are bidirectionally connected. Intracerebroventricular injection of orexin can increase NPY expression, and NPY Y1 and Y5 receptor antagonists can reduce the orexigenic effect of orexin injection. GABA is also involved in the regulation of orexin activation. GABA neurons co-express orexin, and orexin neurons are activated by GABA agonists.
Orexin neurons are glucose sensitive and respond rapidly to changes in blood glucose levels, making them an early hypothalamic factor that triggers food intake. Glucose sensitivity makes orexin highly sensitive to changes in food intake. Reduced food intake results in increased orexin concentrations in the LH, increased orexin gene expression, and orexin receptor expression. Like NPY, orexin is also sensitive to changes in leptin levels. Leptin inhibits orexin gene expression, so increases in leptin due to satiety or increased obesity inhibit orexin activity in the hypothalamus, resulting in reduced food intake.
