Leptin: Catching Chemicals

Leptn is often considered the anti-ghrelin.    It is produced by fat cells to say “I exist and am full, you do not need to feed me.”  Animals with their leptin gene knocked out grow enormously fat.  This is a perfectly lovely story that can be conclusively proven by a picture of a fat rat.

Bring me Solo and the wookie

If you do not find this story compelling, please consider that I also have a photo of a fat mouse.

Well, if it isn't Lone Star. And his sidekick, Puke
Well, if it isn’t Lone Star. And his sidekick, Puke

Are you convinced yet?  Look, I know last week I said all hormones are almost fractally complicated and anyone who says they completely understand one is lying, but that entry forever to write (thanks for publishing that a week early, wordpress), and this entry has pictures of obese rodents.  Surely you believe the rodents?

Original source: http://commons.wikimedia.org/wiki/File:Big_Fat_Red_Cat.jpg
If no, would a cat be sufficient?

*sigh* I’ve created a monster.

Like ghrelin, leptin is important to fetal lung development because, and I quote, “I don’t know stop asking me.”  Leptin is also produced by the ovaries, skeletal muscle, stomach (some cells produce both ghrelin and leptin), mammary epithelial cells, bone marrow, pituitary, liver, and of course adipose tissue.

Leptin stimulates ovulation and sperm production, which makes some evolutionary sense: getting pregnant when you don’t have the resources to carry it to term in a healthy way is extremely costly (men have to be nearly dying before they stop producing sperm entirely, but levels can drop incompletely before then).  This doesn’t explain why the ovaries (but not testicles) produce leptin, since they don’t have any independent information about fat stores.  This may be an example of an override (in which the ovaries decide they want a baby even though the rest of the body doesn’t believe it has enough fat), but the fact that I can come up with a clever anthropomorphization does not make an explanation legitimate.  You can sort of see why leptin facilitates the onset of puberty, since puberty takes a lot of energy.

What you can’t see is why, despite everything we know about pregnancy and eating, the placenta produces leptin. Excess amounts appear to cause hyperemesis gravidarum (extreme morning sickness aka Kate Middleton’s one weakness).


High amounts of leptin appear to be good for your brain.  Just so story: brains are extraordinarily expensive, so if you don’t have sufficient savings your body turns on the dimmer switch.  They also have a long term protective effect against Alzheimers.  On the other hand, high levels of leptin alter the immune system in a way that encourages artery hardening.  I am way more afraid of living with Alzheimers than I am of dying of a heart attack, so I will count this as one point for fat.

Leptin’s overall effect on the immune system is complicated.  Leptin is an inflammatory agent, possibly to prevent damage from overreating as your body suddenly tries to shove extra calories that won’t fit in the white adipose tissue under the bed and in the coat closet (the organs).  Which may explain why ghrelin is an anti-inflammatory.  Leptin and ghrelin chose opposite powers and color schemes, like an early 90s superhero cartoon.

Or an early 90s cartoon
The safe represents the hypothalamus

Fatness in humans does not appear to be a problem of inadequate leptin production, and more leptin does not make people thinner.  Instead, it appears that the brains of obese individuals are less sensitive to leptin.  No one knows exactly why, but “crash dieting” is high on the list of suspects.  Two people with identical body compositions but different genes or life history may produce very different amounts of leptin, which means they may require very different behavior to stay the same weight, in ways we do not understand at all.  Which I could have told you before we went on this magical photographic tour of my childhood.  But now we know for sure, plus I learned that fetal lung development is creepily intertwined with food in a way no other organ is.  Let us go forth and use this new knowledge

The Rescue Rangers also want me to play video games.
The Rescue Rangers also want me to play video games.

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.

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.