hypocretin/orexin hormone and obesity


we have billions of cells inside our brain. 10,000 to 20,000 cells between them produce a chemical called orexin/hypocretin. to be more precise, These cells produce two types of orexins/hypocretin, called orexin-A/hypocretin-1 and orexin-B/hypocretin-2.

the reason there are two names for this substance is that it was explored by the same time by two group of scientists and they both gave them a different name. from now on both of these names mean the same thing.

neurons(Nerve cells) communicate with each other via chemical messengers called neurotransmitters. Neurotransmitters control practically everything we do, even our thoughts and feelings. they also coordinate our actions. neuropeptide is a type of neurotransmitter.

effects of orexins in the body is huge. Research in this area increases our understanding of the human body. hypocretin also offers promising new ways to treat a multitude of conditions, including insomnia, narcolepsy, depression, and even obesity. Having too much or too little orexin activity has been linked to depression and other mental health conditions, such as anxiety, panic disorder, addictions, and post-traumatic stress disorder(PTSD).

The orexin-A/hypocretin-1 (a neuropeptide composed of 33 amino acids) and orexin-B/hypocretin-2 (a neuropeptide composed of 28 amino acids) are neuropeptide hormones synthesized by a cluster of neurons in the hypothalamus(The cell bodies responsible for hypocretin production are localized to the tuberal part of the hypothalamus, the so-called feeding centre, Researchers think that the source of orexin might be directly released from the pituitary into the bloodstream, leaked from the cerebrospinal fluid, or produced by the gut or pancreas. More research is needed).

It’s believed that the main role of orexins is to control sleep and arousal, and the neurons that release orexins are most active during the day. To keep us awake, these neuropeptides stimulate other neurons to release neurotransmitters that promote alertness, such as dopamine, serotoninnorepinephrine, histamine and acetylcholine.

Their actions on serotonin, histamine, acetylcholine and dopamine neurotransmission is also thought to be excitatory.
Without enough orexins, the body has a hard time staying awake and alert. People diagnosed with type 1 narcolepsy have an 85% to 95% reduction in the number of neurons that produce orexins, supporting the crucial role of orexins in maintaining wakefulness. Orexin is not just any molecule in our body. Some scientists say that whenever we’re tired or fatigued, orexin is suppressed. researchers also claim higher levels of orexin-A makes people happier since the incidence of depression is higher in narcolepsy. Moreover, Orexin-A seems to be crucial for social memory.

Apart from their huge role in sleep and arousal, the hypocretins have been implicated in multiple functions including feeding and energy regulation, neuroendocrine regulation, gastrointestinal and cardiovascular system control, regulation of water balance, and converting pain signals.

The neuroendocrine effects of the hypocretins include a lowering of plasma prolactin and growth hormone and an increase in the levels of corticotropin and cortisol, insulin and luteinizing hormone.

hypothesis suggests that orexins regulate behaviour during times of physiological need, exposure to threats, and opportunities for reward.

research found that orexin and its receptors may decline with age.

Research suggests a link between orexin and chronic inflammation. Persistent, low-grade inflammation also seems to be tightly tied to fatigue and low cellular energy, according to recent scientific findings.

Orexins are important in the body’s response to stress. orexin-producing neurons respond to pressure by exciting other neurons that increase heart rate and blood pressure, helping the body transition from a resting state to one where it’s ready to respond and move(fight or flight mode/also called catabolic phase).

Orexin system seems to play a unified role in coordinating motivational activation under numerous behavioural conditions for example, by its involving in alcohol use and drug-addiction. It is believed orexin neurons modulate reward system and play a predominant role in mechanisms of addiction to drugs.

hypocretin/orexin, exercise and obesity

Obesity is a complicated disease which degrades health and many aspects of it like metabolic syndrome, type 2 diabetes mellitus, coronary heart disease(CHD), sleep apnea syndrome, and reduced in life expectancy.
although Environmental and genetic factors affect large properties amongst us and cause obesity, Physical activity and non-exercise induced thermogenesis(NEAT) are also big factors determining our body fat levels.
We know from experience that physical activity in any form makes us feel better, we also know that exercise is able to increase orexin levels in the human bloodstream and some scientists think orexin might be one of the reasons that we feel good after exerciseExercise acidifies our blood since it increases lactate temporarily. this is thought to cause the firing of orexin neurons. Interestingly, orexin-A may cross the blood-brain barrier. Theoretically, if it’s elevated in the blood after exercise, it may also be elevated in the brain.

Limited research suggests that orexin increases metabolism and body temperature. According to this theory, people that feel cold and tired may, among other factors, have low orexin. orexin may cause people to increase oxygen use because it might increase metabolism

also it is believed Hypothetically by professionals that people who eat less or have calorie restriction may have higher orexin because their body senses they’re not getting enough caloriesSome researchers even speculate that losing extra weight may help increase orexin and energy levels. Theoretically, elevated glucose concentration might block or restrict the activity of orexin neurons(The hypothesis is that under low-energy conditions such as starvation, it could be advantageous for ingested glucose to suppress the orexin-driven net energy expenditure, thereby ensuring that more fundamental processes such as keeping the brain alive, receive enough glucose. In addition, scientists think that orexin neurons are stimulated by falling glucose levels).

The observation that hypocretin-1 increases metabolic rate and the demonstration that insulin-induced hypoglycaemia activates up to one-third of hypocretin containing neurons has led to the suggestion that the hypocretins are mediators of energy metabolism.

Ghrelin is a hormone secreted by the stomach before a meal which is also called the hunger hormone which rises before a meal when your stomach is empty, Then decreases shortly after when your stomach is full. Orexin-producing cells have recently been shown to be inhibited by leptin, but are activated by ghrelin and hypoglycemia. keep in mind that glucose inhibits orexin production. orexin will increase craving for food, and giving a hormone like leptin (a signal of fullness), inhibits orexin.

This is based on the theory that Leptin inhibits orexin. High leptin levels are characteristic of being overweight, while leptin levels tend to drop as a result of weight loss
It’s a good idea to get adequate amounts of healthy protein foods on a daily basis. Various amino acids are hypothesized to affect orexin signalling, but there are no clinical studies to determine their impact.


keto and orexin/hypocretin

during ketosis, glucose levels will be low, which is more likely to activate orexin. it is also claimed that since ketones are theoretically energy molecules, they would signal to the brain that there’s not a famine, which should activate orexin. This is thought to be the underlying logic for why lactate allegedly prevents orexin suppression. ketones are also acidic, so people say that this will also increase orexin. Remember that there has not been a human data to back up keto relationship with orexin yet.

also one hypothesis says orexin is the main factor why sugar makes people gain fat. this is because people feel tired after eating sugar(which causes blood sugar levels to spike and orexin to fall). So, instead of burning calories, people go to sleep. Although plausible, this hypothesis has yet to be tested.

what affects orexin?
Bright light (like from sun) increases orexin. animal research suggests that this is the likely mechanism by which it’s effective for depression and seasonal affective disorder (SAD). Proper human data are still lacking to back up this mechanism, though.
Lactate is an energy source which acts as a regulator of the orexin system. Scientists believe that lactate release from central nervous system plays an integral part in balancing brain activity and energy supply. Lactate might disinhibit and sensitize these orexin neurons for future excitation.
GLP-1 is a gut hormone that activates or excites orexin neurons in the hypothalamus (which increases orexin). it is believed that it might be useful in making us feel satiated as well, which may make us eat less and further activate orexin.
Resistant starch may increase GLP-1 and also produces butyratebutyrate is also acidic. this might block glucose-induced suppression of orexin. high-butyrate foods or drinks like kombucha also have shown to increase energy levels after a big meal.
Caffeine(especially from coffee and tea) also activates orexin but green tea is the highest in antioxidants which control free radicals as well.
in a study done with healthy participants, there was a correlation between omega 3s and orexin A.
Animal studies suggest that long-term fructose consumption increases orexin. Also, 25% of fructose turns into lactate during digestion. Fructose, fructans, and FOS might also excite orexin neurons by increasing GLP-1, thereby potentially increasing wakefulness
Although the effects of cold showers on orexin activity and wakefulness haven’t been studied, many people advocate for this traditional cooling method.

orexin and animal studies

In animals, ketosis increases ghrelin and Ghrelin stimulates orexin. However, human studies show that ketosis doesn’t increase ghrelin.
Researchers believe that amino acids excite orexin neurons, though this has yet to be confirmed in humans. 
Animal studies suggest that orexinergic system may enhance hippocampal neurogenesis influencing learning and memory processes.
Moreover, transgenic mice with gradual and then loss of hypothalamic orexin-containing neurons show feeding abnormalities and dysregulation in energy homeostasis determining obesity despite the reduction of food intake/calories. Interestingly, it has been reported an increased prevalence of obesity in narcoleptic subjects in all ages. These data confirm that orexin neurons mediate energy balance and arousal, maintaining a consolidated state of wakefulness in hungry animals in order to promote alertness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart.
Orexin signalling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity.