Eat your eggs to promote hypocretin/orexin since absence of these neurotransmitters for happiness/joy can lead to obesity, depression and narcolepy (irresistible sleepiness). Stress lowers levels of orexin while family/social support system and love increases levels of orexin.
A little over a decade ago, scientists discovered that narcolepsy, the neurological disorder that leads to episodes of irresistible sleepiness, is caused by the loss of brain cells that produce hypocretin, a neurotransmitter that promotes wakefulness.
But the discovery did not shed light on two other mysterious problems associated with the disorder. Narcoleptics have profoundly high rates of depression — up to six times the rate in the general population — and they have a tendency to collapse when swept by some emotions, a phenomenon known as cataplexy.
Now research shows that in addition to regulating sleep, hypocretin also appears to govern emotion, particularly experiences of joy and happiness.
The study has implications that extend beyond narcolepsy. It suggests that the brain has several different arousal systems, and that one of them, driven by hypocretin, has the specific function of keeping people awake for pleasure.
A 2008 study indicated that orexin plays an essential role in mediating reduced depression-like symptoms induced by calorie restriction.
Food source: Eggs (hormone-free)
The Cambridge team found that protein components of the type found in egg whites stimulated the neurons much more than other nutrients, the amino acids in the egg whites appearing to stop glucose from blocking the cells.
Senior study author, Dr Denis Burdakov, says further: “We found that activity in the orexin/hypocretin system is regulated by macronutrient balance rather than simply by the caloric content of the diet, suggesting that the brain contains not only energy-sensing cells, but also cells that can measure dietary balance.”
British Egg Information Service nutritionist Dr Carrie Ruxton says: “This study provides yet more proof that eggs are a superfood. As well as being rich in vitamins, minerals and protein, eggs make us feel fuller for longer after meals, thus helping with weight control. This latest study confirms the benefits of the special proteins found in eggs. Another good reason to go to work on an egg!”
It also raises concerns that drugs that block hypocretin could potentially cause depression and other unexpected side effects. One such medication, a sleeping pill from Merck called suvorexant that works by blocking hypocretin, essentially causing narcolepsy for a night, is awaiting government approval.
The new research, published this month in the journal Nature Communications, involved a small group of patients with epilepsy who had special electrodes implanted in their brains that could directly monitor seizure activity and hypocretin levels around the clock.
“Apart from their seizure disorder, these patients were normal,” said Dr. Jerome Siegel of the V.A. greater Los Angeles Healthcare System, the study leader and a psychiatry professor at U.C.L.A. “They’re watching TV, they’re talking to their relatives, walking around the hospital, going to the bathroom. They’re not mentally handicapped in any way, and we are observing them with video and periodically asking them to complete forms indicating how they feel – whether they’re happy or sad, hungry or thirsty, in pain or not.”
Dr. Siegel, along with graduate student Ashley Blouin and their colleagues, expected to find that the ebb and flow of hypocretin mirrored the sleep cycle, rising in the morning and falling at night.
“But what we found was more complex,” Dr. Siegel said. “The maximal release of hypocretin was not really related to arousal in the usual way. It happened during waking for sure, but the maximal release was simply when people reported they were happy.”
The findings showed that hypocretin levels surged when the patients experienced joy and pleasure – while watching a favorite team win a baseball game, for example, or spending time with family. But when they experienced pain from their surgical implant, or anxiety about their medical situation, their levels of hypocretin fell.
Dr. Siegel has shown in animal studies that hypocretin is associated with reward-seeking behavior. Release a dog into a yard to run, dig and play, and its hypocretin levels soar. But force the same dog to run on a treadmill, and its hypocretin levels remain flat. Similarly, hypocretin levels fall when mice are forced to press a bar to escape an unpleasant shock, but spike when the same animals press a bar to obtain food.
“This shows that hypocretin is related to a particular kind of arousal,” said Dr. Siegel. “There is an arousal system in the brain whose function is keeping you awake for pleasure, to get rewards. It is related to positive affect, and in its absence you have a deficit in pleasure seeking.”
In narcoleptics, cataplexy is most frequently caused by sudden joy. It is not uncommon to see someone with narcolepsy abruptly lose all muscle tone and collapse when laughing.
But in some ways, we can all relate.
“In almost every culture there’s an expression equivalent to falling down with laughter,” Dr. Siegel said. “Normal individuals don’t actually fall down. They may brace themselves or sit down. But narcoleptics will feel weak and unable to speak. In some instances they’ll fall down and won’t be able to get up for a few minutes.”
In most people, laughter causes a surge of hypocretin, which maintains muscle tone. But in narcoleptics, the hormone is largely absent, and the system goes haywire.
In narcoleptics, the loss of this pleasure-seeking hormone has severe effects on mood. Narcoleptics are prone to depression, and they have a strange resistance to addiction. Some of the medications used to treat narcolepsy are notoriously addictive, like amphetamines and GHB, the so-called date-rape drug. Yet narcoleptics generally do not abuse them.
“They’re missing this working-for-pleasure system,” Dr. Siegel said. “When hypocretin is missing, you have a deficit in getting addicted and a deficiency in getting interested in things — that’s what depression is.”
So, could a sleep aid like suvorexant, which reduces hypocretin, lead to depression in a healthy person? In clinical trials involving thousands of patients, the drug helped people with insomnia fall asleep faster and stay asleep longer than placebo. And there were no signs that it induced depression or caused falls resembling cataplexy, said Dr. Darryle Schoepp, senior vice president at Merck.
“We had to measure psychiatric mood, including depression,” he said, “and we didn’t see anything worrisome there.”
But Dr. Siegel said it is too soon to say that tinkering with hypocretin will not create unwanted consequences.
“The initial reports are rosy,” he said. “But they come from a drug company with an enormous investment. And there is a long list of drugs acting on the brain whose severe problems were only identified after millions of people were taking them.”
Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer briefly loses muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.
The brain contains very few cells that produce orexin; in a human brain, about 10,000 to 20,000 neurons in the hypothalamus. However, the axons from these neurons extend throughout the entire brain and spinal cord, where there are also receptors for orexin.
Orexin was discovered almost simultaneously by two independent groups of rat-brain researchers. One group named it orexin, from orexis, meaning “appetite” in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, a hormone found in the gut. The scientific community has not yet settled on a consensus for which word to use.
There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptide hormones with approximately 50% sequence identity, are produced by cleavage of a single precursor protein. Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide. Studies suggest that orexin-A may be of greater biological importance than orexin-B. Although 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, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent at OX1.
The orexins are strongly conserved peptides, found in all major classes of vertebrates.
The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A increases food intake. In addition, it stimulates wakefulness and energy expenditure.
Brown fat activation
Obesity in orexin knockout mice is a result of inability of brown preadipocytes to differentiate into brown adipose tissue (BAT), which in turn reduces BAT thermogenesis. BAT differentiation can be restored in these knockout mice through injections of orexin. Deficiency in orexin has also been linked to narcolepsy, a sleep disorder. Furthermore narcoleptic people are more likely to be obese. Hence obesity in narcoleptic patients may be due to orexin deficiency leading to brown-fat hypo activity and reduced energy expenditure.
Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin system is to 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.
The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy. Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease. Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.
Central administration of orexin-A strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30–36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.
In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex. Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus. In conjunction, these genetic anomalies cause the autoimmune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.
Orexin increases the craving for food, and correlates with the function of the substances that promote its production.
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 recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation. Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis.
The research on orexin mimics is still in an early phase, although many scientists believe that orexin-based drugs could help narcoleptics and increase alertness in the brain without the side effects of amphetamines.
Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, suvorexant, fell asleep faster and slept an hour longer. Suvorexant was tested for three months on over a thousand patients in a phase III trial.
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism. Lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.
A study has reported that transplantation of orexin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.
Because orexin-A receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats. By blocking the orexin-A receptor with low doses of the selective antagonist SB-334,867, nicotine self-administration decreased and also the motivation to seek and obtain the drug. The study showed that blocking of receptors in the insula decreased self-administration, but not blocking of receptors in the adjacent somatosensory cortex. The greatest decrease in self-administration was found when blocking all orexin-A receptors in the brain as a whole. A rationale for this study was the fact that the insula has been implicated in regulating feelings of craving. The insula contains orexin-A receptors. It has been reported that smokers who sustained damage to the insula lost the desire to smoke.
Orexin-A (OXA) has been recently demonstrated to have direct effect on a part of the lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes. The link between OXA and the lipid metabolism is new and currently under more research.
Obesity in orexin-knockout mice is associated with impaired brown adipose tissue thermogenesis.
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness. The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression. Likewise, it helps explain the incidence of depression associated with narcolepsy.
Interaction with other neurotransmitter systems
Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors, 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, so despite the relatively small number of orexinergic neurons compared to other neurotransmitter systems in the brain, this system plays a key regulatory role and extensive research will be required to unravel the details. Orexins act on Gq-protein-coupled receptors signaling through phospholipase C (PLC) and calcium-dependent as well as calcium-independent transduction pathways. These include activation of electrogenic sodium-calcium exchangers (NCX) and a non-specific cationic conductance, likely channels of the transient receptor potential canonical-(TRPC) type activation of L-type voltage-dependent calcium channels, closure of G-protein-activated inward rectifier potassium channels (GIRK), and activation of protein kinases, including protein kinase C (PKC), protein kinase A (PKA), and mitogen-associated protein kinase, also called mitogen-activated protein kinase (MAPK). Postsynaptic actions of orexins on their numerous neuronal targets throughout the CNS are almost entirely excitatory.
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