Ghrelin: The Hunger and Lung Development Games

Writing about hormones is hard because anything I say will be incomplete by necessity.  I can only do so much research,  and will undoubtedly miss something.  More worryingly, there’s a lot nobody knows about our endocrine system, and all available overviews tend to overstate our level of certainty.  I will be ecstatic if in 10 years this entry turns out to be 60% true.  But we go to war with the facts we have, so:

Ghrelin is best known as… well if you’re me it’s “proof calories in/calories out is bullshit“, but it’s more commonly known as “the hunger hormone”.  The simple story is that cells in your stomach produce ghrelin in response to perceived space in the stomach (which may be one way gastic bypass surgery leads to decrease in food consumption: your stomach reports fullness almost immediately).  Your hypothalamus detects this and informs the brain, which interprets it as hunger, which should lead you to get food.

But nothing in the human body does just one thing.  For one, ghrelin is produced in other areas of the body.  Pancreas, intestines (sure, they have information about current digestion status), placenta (okay, the fetus needs a way to direct you to eat more), gonads, adrenal cortex, pituitary gland (well those are pretty general hormone production factories), kidneys (for…water…consumption?), and lungs (the hell)?

Ghrelin encourages storage of calories as fat, which could mean that eating more (to suppress ghrelin production)  would help you avoid fat gain or even allow fat loss.  But (one form of) ghrelin also triggers production of human growth hormone (in fact, that’s where the name comes from: Growth Hormone RELease INducing factor), which encourages burning fat and building muscle.  The important lesson here is that if someone every tells you “Do X lose weight because hormone Y does Z”, you should laugh at them, even if Y and Z are correct, because Y does 4 million other things, some of which are the opposite of Z.  Ghrelin’s presence in the lungs might be a mechanism to trigger HGH to trigger fetal lung development.  Or maybe not.  We don’t know.

Still in the realm of possibility, high ghrelin levels delay puberty and discourages ovulation.   This is a reasonable second job for the hunger hormone to have because transforming a zygote into a baby is an epic amount of work and you want to be well fed.   I seriously wonder about the effects on ghrelin on libido: given that humans have sex for both reproduction and social bonding,** I could see the effect going either way.

Ghrelin appears to have some mood effects.  When I first read this I assumed high ghrelin -> stress and depression, which would be a convenient way of explaining why I was so jumpy before my hypochlorhydria was treated.  Turns out, nope, ghrelin is an anti-depressant* , which may be one mechanism reinforcing anorexia.  But ghrelin also makes pleasant activities (eating, but also drugs, and it’s at least in the same brain neighborhood as sex) more rewarding.  It also has a bunch of effects on learning and memory and stress-based learning, mostly apparently positive.  This is the opposite of what I would have predicted, given how I and people I know act when hungry.

I'm sorry for what I said when I was hungry

Lastly, ghrelin inhibits inflammation. To the point it may be useful as a treatment for autoimmune diseases like rheumatoid arthritis and multiple sclerosis.   This concerns and confuses me, possibly even more than growth hormone effects. Hunger and long term calorie deficits are associated with increased susceptibility to disease (as your body prioritizes short term goals over long term health), so maybe this is a happy accident?  But no, ghrelin promotes development of at least one kind of white blood cell.  The anti-inflammatory effect may explain why people often don’t want to eat while injured- your body lowers ghrelin levels to allow healing to occur, and the loss of appetite is a side effect.  But that’s highly speculative, the truth is we just don’t know.

For all that, ghrelin is one of the simplest hormones I’ve studied.  It has one obvious primary job, and several of its lessen effects seem at least related to that job.  We know where it is produced and a good chunk of how it achieves its (known) effects.  More fundamental hormones like progesterone, testosterone, or oxytocin are infinitely more complicated.  So this post is a little bit about the science of hunger, and a lot about how the human body is complicated and people with simple answers are liars.

*Should you be laughing at me right now?  Maybe.  The study in question shows actual behavior change, not a potential mechanism of behavior change (that’s this paper), but it is just one study.  Perhaps compromise on chuckling.

**What about pleasure, you ask?  Irrelevant from an evolutionary standpoint.  We feel pleasure because there is some actual useful purpose served.

Open access journals

Scientific research is distributed in journals, a system which has a number of flaws, one of which is it is expensive.  Journals charge authors to publish their articles, readers to read the articles, and advertisers for space in the journals. This smells like bullshit before you know that both publication and access fees are often paid for out of government grants, with the second most popular source being “companies that want you to buy their product based on the publication.”  It’s why I’m often forced to work from abstracts, rather than full journal articles.  I can get the authors’ conclusions from abstracts, but they rarely contain enough information to evaluate the experimental methodology.  The US government has made various efforts at enforcing “open access” policies, which would force research funded by public money to be accessible to the public, but they’ve always been defanged.

The system persists because publishing is a prestige based system.  Scientists are most rewarded for publishing in the most respected journals (in biology that’s Cell, Nature, and Science), none of which are open access, and have no incentive to be as long as they are the first choice for scientists.  An individual scientist can make a principled stand and insist on publishing in open access journals, and I’ve known some who’ve done it.  After they get tenure. Before then, they can’t afford the risk that some committee member who still thinks the internet is a dump truck will take publishing in a less glamorous open access journal as a sign of failure.

But not all research is funded by the government or for-profit enterprises.  The Gates Foundation has just declared that any research they fund must be published under a creative commons license.   They also require the underlying data to be publicly available, which might be even more significant.  It’s not clear to me how this will play out: maybe a bunch of awesome Gates-funded research will be publicly available.  Maybe promising young academics will refuse to take Gates money (although given the relative availability of talented academics and money, they’re probably replaceable).  Maybe this will start a marginal revolution of ever higher prestige journals going open access, giving the public access to additional non-Gates research as well.

Either way, I think the Gates Foundation did a really good thing here, and I really want to see what happens.

HAES pre-check

I’ve been meaning to do a “science of fat and health and food” series for a while now, but have never quite gotten it together. There’s too much stuff I remember reading in some blog years ago but can no longer find.  The library has finally delivered Health at Every Size to me (just in time for Thanksgiving), and I’m hoping to use that as both a serious source and a jumping off point for other research I want to do.  In the spirit of inquiry, here are my basic beliefs, as cobbled together from an undergrad biology degree, personal experience, things people said on the internet, and scientific studies I read the abstracts of.  When possible I’ve included a citation but mostly this is just stuff from my brain.

  1. Some diets are lead to a better functioning body than others.
    1. The healthiest diets supply all necessary trace nutrients, including ones we haven’t identified as necessary yet.
    2. Protein, fat (of multiple kinds) and carbohydrates are all necessary for proper functioning.  Right now a lot of people are pretty sure that you should minimize carbs and especially sugars, but 20 years ago they were equally sure fat was evil, so I’m unconvinced even though their numbers look very shiny.
  2. Exercise is super good for you right up until the point it is super damaging.
  3. Despite our astonishing lack of genetic diversity, humans have a pretty wide range of how they react to identical food and exercise inputs.  Additionally, the same person can react differently to things over time.
    1. For example, people’s beliefs about the deliciousness of the milkshake they are about to receive affects ghrelin production, which definitely affects satiety and probably affects nutrient and calorie absorption.
    2. Medication can do the same.  Cortisol makes you gain weight. Several psychiatric medications lead to severe weight gain.  Hormonal birth control definitely used to make you gain weight. Many scientists claim the newer drugs haven’t been shown to do so, but my feeling is that “baby chemicals lead to weight gain” is the default assumption and the burden on them is to prove it doesn’t.
    3. Past deprivation, including in utero, can decrease basal metabolic level, or make it more likely to decrease in the face of further calorie deficits.
  4. At the same time, people are remarkably resilient to environmental changes.  A given person can eat a wide range of calories and stay at the same weight.  No one understands why.
  5. So while calories in/calories out is literally true, in the sense that everyone is taking in and using calories, it’s not useful, because so many things affect intake and output.
  6. It is possible to have an excellent diet and exercise routine and still be fat.
  7. But any given person will probably be fatter the worse their diet and exercise.
  8. When you tease these out, fat is mostly a symptom of things that lead to bad health, not a cause of bad health.  Extreme amounts of fat are hard on the joints and heart.  But all evidence says (good diet, good exercise, 40% body fat) > (bad diet, no exercise, 20% body fat)
  9. Nonetheless, the general and medical public alike seem extremely fixated on fat, and this is hurting fat people.
  10. Shame around fat seems to contribute to both fat and the negative health outcomes associated with being fat.  Shaming fat people for the health is right up there with rescuing prostitutes by arresting them.
  11. To the extent fat itself affects health, the ideal body fat % from a health perspective is much higher than the ideal body fat % from an American aesthetic perspective.
  12. Lab animals are fatter than they were a generation ago despite provably identical conditions.  This has got to mean something about our food, and it’s probably not good.
  13. It is possible to be both fat and undernourished.  Most poor Americans are.
  14. Your body needs calories to run.  Faced with a calorie deficit, your body may choose to cut programs (like the immune system, or thinking) rather than dip into savings (stored fat).  This means that maintaining even an “unhealthy” weight may be the healthiest choice a person can make.

…and the Wisdom to Tell the Difference

I haven’t gotten too much into my own dental stuff because I spend enough time thinking about it as is, but the current count is:

  • 3 completed surgeries
  • 2-5 more planned, depending on what you count as a surgery
  • painful nerve damage on the lower right
  • a hole in my lower left gum.  You can see a good chunk of bone if you look in my mouth.

After the last surgery (wow, two months ago now), my pain level actually dropped significantly.  We took out a major part of the problem, which not only helped on its own merits, but meant I stopped clenching/grinding, which made the nerve damage on the other side stop hurting continuously.  It was still touch sensitive, but I can handle that.  My ability to focus skyrocketed, limited only by my exhaustion.  I dropped CBD in favor of naproxen, and then didn’t need anything at all. I read a book a day for a month.  You can roughly see this increase in focus in my blogging, although the signal on your end is a little messy because publish can come long after writing, unless wordpress screws up, which it usually does.  I went on forays to the library to practice thinking around other people.  I even started to program a little bit.*

Then the surgery site started to hurt.  And my upper right (which needs surgery but hasn’t had it yet) began to ache from the sudden chewing burden.  I saw myself faced with two possible paths: a life where the pain just kept increasing and no amount of treatment could keep up with it, and I was never able to accomplish anything because it rendered me stupid, or a life where I was never in pain and I went on to be Brene Brown’s more medical second coming.   Obviously future #2 is better than future #1, and in future #2 I don’t take pain medicine, so I needed to just keep not taking pain medication and everything would be fine.

Causality does not work that way

If you’d tracked self reported pain it probably wouldn’t have gone up that much, because I have a lot of practice pushing dental pain out of conscious awareness.  But my reading rate plummeted, and I stopped going to the library.  Blogging which had felt like a thing I needed to do to clear my head a week before now felt like a chore.

I had just started to give in and take more CBD when I had a follow up appointment with my dentist, who explained that there was a hole in my gum where the jaw was growing in order to push out an infection.  I started crying the minute he said it.  I went home and took real pain meds.  A few days later, when I didn’t have to drive anywhere, I took twrugs o days and took way more pain medication than I consciously thought I needed.  Since then I’ve continued taking more-than-forebrain-thinks-is-necessary at night, but NSAIDs only during the day.  My reading and writing productivity has picked up significantly, talking barely hurts anymore, and I feel safe being in touch with my pain level again.

This is what I call the “nuke if from orbit” pain medication option, and it really seems to work.  Catching the pain before it “settles in”, or sending a surge against it, moves the baseline pain level back significantly, and lets you use less drugs over all.  The reluctance or inability to do this is another casualty of our awful attitude towards pain, where medication is essentially viewed as a failure of the individual to tough it out.

But nuke it from orbit doesn’t always work either.  Right now I’m in a tiny bit of pain.  It would take a lot of drugs to get that to zero, possibly an infinite number.  I faced a stronger version of this problem right before the last surgery, where the nerve damage side just kept upping the pain level to keep up with whatever amount of drugs I took.  In that case, I was better off simply accepting that pain was the state of being I was in right now.  The most helpful thing to do was meditate, except that while meditation often helps by relaxing the jaw, meditation for the goal of pain relief doesn’t.  Since most of the emotional impact of the pain was frustration and fear over my ability to think (read/write/plan) while in pain, practicing thinking while hurting would definitely lead me to look back more fondly on the experience, although it probably would have led to more distress at the time.

The first lesson here is to treat for the pain level you have, not the pain level you wish you had.  The second is to aggressively counteract pain at the first peep of its head.  The third is to learn to live with pain instead of fighting it.  I guess this is one of those “wisdom to tell the difference” situations.

*Fine, I started to set up a dev environment and that took two weeks because I was still very sleepy and android development studio is stupid.

Costly Signalling and the Scheherazade Effect

One of my great frustrations in life is how evolutionary psychology, a fascinating scholarly subgenre that provides unique and valuable insights into many problems across the disciplines of biology and psychology, became evopsych.  Click bait before there was click bait, evopsych is justifies whatever the author believes by using the (white, middle class, suburban families of the) 1950s as the evolutionary relevant time period.  So now I can’t talk about cool things like costly signalling without a disclaimer that it’s not one of those evopsych articles.

Costly signalling is the act of doing something stupid to prove your genes are so good you can afford to do so.  The most popular example is the peacock’s tail: it is energetically expensive and makes you attractive to predators.  Surely if you have it you must posses many great genes that I, a female peacock, would like to secure for my offspring.  The tail is also a canvas for parasites, so if it looks good, you must not have many.  That is good for me and implies good genes for our future offspring.  Let the peacock sex commence.  Costly signalling doesn’t have to be about mating.  Certain ugulates will signal a predator that they see them and are not worth chasing by stotting (jumping in a uniquely pointless way).

The key here is that the signals are very expensive.  A weak peacock who attempts to grow a beautiful tail will be eaten.  A weak ugulate will have an unimpressive stot.  Males of a bird species whose name I can no longer remember get more female attention when their breast is redder, but are also challenged more by other males.  Males artificially reddened by experimenters temporarily attract more females, but they also attract more fights from other males, and are ultimately worse off.  That cost is what makes the signal work.

My second favorite theory hypothesis speculation about humans and costly signalling is that it, and not utility, led to male upper body strength.  If the hypothesis that humans broke out from the other hominids via endurance hunting is correct, upper body strength is mostly dead weight.  Useful in some circumstances, but a cost during hunting.  I want to be really really clear that this is basically me making something up after reading a book that wasn’t even that scientific, but you have to admit it would be super interesting if it were true.

My favorite speculation about humans and costly signalling is the Scheherazade effect, which I learned at school rather than making up but is only slightly proven.  The Scheherazade effect can refer to two related but distinct things.  The first is that individual humans can signal how much energy they have to spare (implying they are good hunters or have efficient energy usage elsewhere) with pointless feats from our most energy intensive organ: the brain.  Humor?  Art?  Chess?  All attempts to impress the opposite sex.  This + the fact that male reproduction is tournament-style and female reproduction is roughly linear with respect to fitness may explain why men are more likely to pursue truly stupid wasteful hobbies.*

The second Scheherazade effect is the cumulative effect of the first.  After tens of thousands of generations, individual attempts to impress one another via kick ass drumming actually humans better at drumming.  Or juggling.  Or story telling.  Or joke telling.  Or that it may even be the origin of language itself.

The Scheherazade effect is unfortunately untestable, so it’s only real use is to parallel “he’s so hot” when telling your friends about someone who became impressive to you via feats of intellect.   But if you travel in the right circles, that is pretty useful.

*Although it is impossible to separate this effect from that of socialization.