Starving yourself awake

One day when I was in college, about my second year, I suddenly realized I felt awake. At the time, I had just been diagnosed with narcolepsy, and hadn’t yet discovered gluten free, so to feel actually awake was mind-blowing. After a few days of thinking about it, I realized I was feeling awake because I wasn’t eating. Not only that, but I found several other people talking about not being able to eat without going to sleep, too.  Apparently it was a common experience for some of us.

There is a good blog article documenting this, as well as comments from many other sufferers at N is for Narcolepsy.  While the author describes the opposite of what I previously stated (eating = asleep vs. no eating = awake), the concept is exactly the same.  There’s something about eating that makes many of us tired. Maybe it has to do with glycemic control, carbohydrate content, insulin spikes, and maybe it is a food intolerance, but the it is clear that the orexin/hypocrein system plays a role in controlling postprandial somnolence.

All of this brings me to these four articles:

  1. Sleepiness after glucose in Narcolepsy,
  2. Widespread Distribution of Orexin in Rat Brain and Its Regulation upon Fasting
  3. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting, and
  4. Plasma levels of leptin and orexin A in the restrictive type of anorexia nervosa.

In the first paper, Sleepiness after glucose in narcolepsy, the authors investigated the anecdotal claim (such as those from N is for Narcolepsy shown above), that narcoleptic patients were more tired after ingesting glucose. In this study, they gave 12 narcoleptics (and 12 controls) an additional 50g of glucose in a punch just before allowing them to take a nap.  Overall, they found that narcoleptic patients who ingested glucose had increased sleepiness and decreased wake duration. Additionally, 11 of 12 demonstrated increased REM. This also corroborates the effect of low-carbohydrate diets on sleepiness in narcolepsy demonstrated by Husain et al. covered elsewhere on Autoimmune Patient.com. So, in response to N is for Narcolepsy, I would say that there is good evidence that eating (especially sugar and carbohydrates) makes us narcos sleepy. 

I’m not going to review the second paper, but allow it to serve as a segway to the third paper (Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting). In it, the authors examined expression of the orexin 1 and orexin 2 receptor subtypes (OX1R and OX2R; i.e.  receptors for orexin) in the brain. They looked at where the receptors were, and if they were upregulated in different areas of the brain in response to fasting. It should be noted here that OX1R has a moderate specificity for Orexin A, and OX2R can respond probably equally well to both Orexin A and B. Overall, the found that the different receptors had different distribution patterns, but they had some overlapping areas in their expression as well.  I’ve uploaded a graphic below summarizing where the receptors were found and in which areas of the brain.

The importance of differential expression of orexin receptors in different structures of the brain suggests that they play novel roles in multiple circuits, each of which do different things.

For example, expression of these receptors in the lateral hypothalamic and dosomedial hypothalamic regions implicates orexin involvement in feeding behavior, circadian activity, and body-weight regulation.  

Expression in the hippocampal regions suggest orexins are also involved in regulating the monoaminergic systems (for example, histamines, dopamine, serotonin, melatonin, norepinephrine, epinephine and others).  These systems are of obvious importance, particularly because this is the only region of the brain which produces histamine. Histamine has been shown to be critical for wakefulness, and ablation of histamine in the CNS results in hypersomnolence, sleep fragmentation, and increased REM. Additionally, low levels of histamine are found in the CSF of narcoleptics, and is also reduced in animal models.

Additionally, expression of these receptors in the amygdala implicates partial orexin-regulation of memory, attention and emotion. 

In addition to the receptors, orexin itself has also been shown to be upregulated during fasting (and, interestingly, also by insulin-induced hypoglycemia).  

In another interesting study that investigated circulating orexinA levels in recovering anorexic women, found that as anorexic women who began a recovery program and gained weight (as shown by an increase in BMI and leptin levels), their circulating levels of orexin decreased significantly at every time point during the course study.

So what does this all mean? In the first place, it means that the sleepiness exhibited by narcoleptics after eating is real. For some, this may mean that not eating all day, in order to maintain wakefulness.  While certainly this doesn’t seem optimally healthy, it may be a legitimate alternative method to controlling daytime sleepiness for some, particularly in younger patients who may still have functioning hypocretin neurons that have not yet been destroyed by autoimmune attack.  In the second place, it means that dietary restriction can modulate expression of orexin/hypocretin and their receptors in the brain (and speculatively in the gut and pancreas as well).

While it is certain that more literature on the gut/brain axis and the role of the enteric nervous system in narcolepsy is sure to come, it is an exciting time to theorize major players of the disease that may extend beyond the hypothalamus, which may also pave the way for novel treatments or palliative care.