Anthropocentrism, insulin, and obese, long-lived cavefish

I have something to confess about myself. I have a pernicious prejudice hidden deep within me that colors my perception of the world. I was probably born with it, I was definitely raised with it, and now, it’s so deeply embedded within me that I don’t think I’ll ever get it out. You see, I’m anthropocentric.

I know what you’re going to say: “How can you be so anthropocentric? Don’t you know that humans are only one species out of millions on this planet? And besides, don’t you run a company making drugs for cats?”

And you’re right. I do run a company making drugs for cats. I should be able to think about other animals at the same level as humans. And yet, I still think of our lead drug, a cyclosporine formulation, as a human drug, even though it’s really just a natural product derived from fungus that’s just as “human” as it is cat, mouse, horse, or whatever animal is dosed with it. I am ashamed of this bias. I think if my company’s investors can find a qualified cat to bring on board, I’d be happy to accept them as a cofounder or at least an advisor.

I don’t bring this up just to flagellate myself, though. I bring this up to introduce an interesting paper that I found recently that reveals some of my anthropocentric bias. As you likely recall, I’ve recently been writing quite a bit about insulin, glucose, and metabolism. I started with my confusion that insulin resistance and weight loss have a surprisingly rapid response to one another, then discussed the fascinating adaptations hummingbirds have to a high glucose diet that helps them avoid diabetes.

Looking back at both pieces, one thing I notice is that I can’t help but think of insulin as a “human” hormone. So, I see how insulin resistance and weight loss work in humans, and I think, “Why did insulin evolve to work that way in humans?” Or, I see how glucose metabolism works in hummingbirds, and I think, “That’s a weird variation on insulin and glucose.”

But that’s the wrong way to think about it. Insulin is an ancient molecule that is everywhere across the animal kingdom, from insects to apes, and it’s even present in some fungi and protists. Insulin didn’t evolve for humans and it didn’t evolve for hummingbirds. We’re both just borrowing an old tool for our own ends.

This comes into stark focus when we take a look at how other organisms use and abuse insulin to control fat metabolism in much harsher circumstances than humans ever face. You see, humans have it pretty easy when it comes to metabolism. We eat regularly. I mean, we have to. If we go much more than a month without food, we die. 

But that’s because we have evolved in habitats where potential food surrounds us. On the other hand, imagine what it’s like to be a cavefish. Not only do you live in complete darkness all of the time, both because you live in a cave and because you don’t have any eyes, you also literally never get any plants to eat and neither does any organism around you¹. Your only food sources are bat droppings, the rare smaller creature that happens to bump into you, and the occasional seasonal flood bonanza.

And yet we must imagine the cavefish happy.

This means you have to be able to last months on a single large feeding. More specifically, you need to be able to eat a ton and then rapidly build up fat reserves, so that you can store a massive amount of food. There’s no point in eating a lot of food all at once if you’re just going to turn it into short-term reserves like glycogen, or just poop it out. So, how do you do this?

Well, first, obviously, you need to be hungry all the time. If it’s seasonal flood season, you need to be able to eat every single day until the food is gone. That means your appetite should not be affected by the last time you ate, which is a pretty weird way to be. The way you do that is via a mutation in the melanocortin 4 receptor to make it less effective at transducing signals, which, in humans, is a receptor that’s heavily associated with obesity (no pun intended). The receptor is supposed to signal to you when you’re full, so mutations in the receptor make it harder for you to notice that².

Second, you need to be able to pack on the fat everywhere. You need to be able to pack it in the skin, in between the organs, in the muscles, and in the liver.

Third, you need to be insulin-resistant, so that your body doesn’t let glucose leave the bloodstream and get absorbed into the muscles or liver. You need it for fat. You do this via a mutation in the insulin receptors³, so that your insulin receptors are not sensitive to the demands of insulin. 

Fourth, you need to avoid all the problems that come with the adaptations mentioned above, like the constant low level inflammation that comes with fat, the malfunctions of fatty liver, and the glycation of tissues that comes with excess glucose in the blood. And this is when things get a little tricker, because there aren’t good answers as to how cavefish manage to not only avoid these problems, but actually live longer than their surface cousins.

There are, however, some intriguing clues. You might think from their strange physiology that cavefish are some genetically isolated species that have been evolving in isolation for millions of years. However, as I’ve already alluded to, they aren’t. Not only have they been only evolving in isolation for thousands of years (not millions), they haven’t even been that isolated. Multiple different cavefish populations have been established from multiple different surface fish populations, and there's been enough intermixing between the two from seasonal flooding that they can actually interbreed.

So, genomically, the eyeless, obese, always hungry, insulin-resistant, long-lived cavefish are not that far from their seeing, slim, normal-appetite, normal insulin, normal-lived surfacefish cousins. And we even get a clue of exactly how close they are evolutionarily. Surfacefish who are placed in complete darkness for just two years develop a surprising number of cavefish-like traits, including starvation resistance, decreased metabolic rate, and obesity. The change from normal surfacefish to troglodyte cavefish can seemingly happen in just a few generations.

This makes me think that there’s perhaps some sort of switch that gets triggered here, from a “normal” system to a “food scarce” system. This could cause a cascade of effects within a relatively short time frame, from insulin resistance to obesity to hyperphagia. Diabetes would then just be a syndrome of what happens when the body is challenged in the wrong system, like how altitude sickness is a syndrome of being in an oxygen-poor environment without getting accustomed to it or heart attacks caused by being a “weekend warrior”.

I like this switch explanation because it does explain why in normal people insulin resistance is difficult to build up and goes away so rapidly at the start of weight loss. Insulin resistance is part of a system that’s meant to be controlled by some master regulator, like perhaps the circadian rhythm. It has some switch that can be forced by fat buildup, but its natural state is to remain closed. This is maybe analogous to a series of dependent gears in an engine: you could force one gear in the middle of the series to move by great force, and that would have ripple effects on the rest of the gears in the series, possibly causing mechanical damage to one or more of the gears. But moving the first gear would much more easily cause all the other gears to move, and eventually cause the electricity to flow that would keep all the gears moving with no effort on your own.

This is hypothetical, of course, but it’s testable. If I’m right, trying to figure out insulin resistance by looking at human obesity is like trying to figure out how a car works by looking at a Flintstones cartoon. Yes, technically, they make the car go, but there’s a reason why they move so slowly and their cars get such weird mechanical problems. They’re operating at the wrong part of the chain. You can only make sense of how the car is supposed to work by looking at someone operating a car correctly and seeing how the pieces fit together and cause each other to move and then the car itself to move.

Insulin is a crucial part of how organisms handle metabolism. It’s a signal of how much glucose the organism should keep in the bloodstream. Being resistant to insulin is only a bad thing insofar as it causes harm to the organism, which seems to be generally true in humans. However, that’s not always the case everywhere. We’d do wise to remember that we’re just borrowing insulin, and others might use it very differently.

1. I am going to be using this paper a lot for this blog post. If I don’t reference something else, I’m probably referencing this paper.

2. The MC4 receptor is interesting overall. As you might expect from the description, MC4 receptor agonists make obese people lose weight, and MC4 antagonists make skinny people gain weight. But, it has the opposite effect on sexual appetites. An MC4 agonist was approved for promotion of female sexual appetite, with nausea (and presumably weight loss) as a very common (40%) side effect. I also don’t entirely understand how the subjects can feel sexy while they’re nauseous, but who am I to judge?

3. Fascinatingly, the same mutation, P211, which can lead to Rabson-Mendenhall syndrome in humans, an inherited form of insulin resistance. But, in humans, unlike in cavefish, this leads to early death and wasting. Cavefish actually live longer than their non-mutated surfacefish cousins, even though cavefish and surfacefish are otherwise very similar and can even interbreed and produce viable offspring.