Why Doesn't Leptin Fix Obesity?

It should just work.....

I'm pretty convinced that polyunsaturated fats cause all sorts of problems, partly on the basis of my own experiences having given them up, partly on the collective experiences of r/saturatedfat, and partly on the basis of mechanistic arguments and animal studies.

Amongst these problems is atherosclerosis, probably in concert with smoking, where I think smoking is doing damage and polyunsaturated fats are ruining the repair mechanism that would otherwise deal elegantly with the damage. Whether you blame the PUFAs or smoking here is a matter of taste. They're both causal.

A lot of the other problems are due to a sort of general metabolic slowdown or mitochondrial dysfunction, which manifests as a huge number of horrible symptoms, and probably explains most of the other diseases of modernity. The 'epidemic of hypothyroidism', that isn't an epidemic of hypothyroidism at all.

But I'm much less convinced that they cause obesity, which seems like a different sort of thing.

A slow metabolism in itself shouldn't cause obesity.

CICO is a law of physics, but if calories out falls due to slow metabolism, then the homeostat that controls your fat levels should just adjust your appetite to compensate and your weight should stay stable anyway. The most noticeable effects should be that you’re slow and cold and not eating much. You might be ill in lots of ways, but not obese.

Even if PUFAs directly affect your appetite, like cannabis does or even good food, that still shouldn't make you fat by itself

Maybe you'd eat a bit more, and put on a bit of weight, but the weight-controlling mechanism should notice that you're overweight and make you less hungry. So someone who smokes a lot of cannabis, or is surrounded by really good food should find that they put on a bit of weight due to the munchies, but then stabilise at that higher weight.

If there's a functioning weight-control homeostat (lipostat), then disturbances to metabolism and even directly to appetite just shouldn't make much difference.

And certainly they shouldn't cause a spiralling weight problem that leads to "scooter obesity", where you're literally starving all the time and eating as much as you can digest, which seems to be a real and increasing problem in the West.

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I'm convinced on theoretical and historical grounds that such a lipostat has to exist. No other design for an animal makes any sense, and the weight of pre-modern people seems to have been under excellent control.

But modern people certainly don't seem to have their weight under effortless homeostatic control. So in modern people that lipostat mechanism must be broken.

However it's not totally broken in most people. There are a few unfortunate people who are in the "scooter obesity" state, but although most people seem to be overweight these days, their weight is usually pretty stable as long as they eat ad-lib and don't play silly games like trying to starve themselves thin.

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I'm also pretty convinced that the lipostat has to work via the hormone leptin. Low leptin levels, hungry, high leptin levels, not hungry. There's all sorts of evidence in mice and humans that that's how it works in a normal unbroken system.

Let's just assume that all animals have a lipostat, and leptin is the crucial fat-level sensor that tells your brain how big your energy reserves are.

There's a very obvious prediction that this 'broken leptin-based lipostat theory' makes, which doesn't seem to be true.

And that's that exogenous leptin should just fix obesity. It should fix it in humans and it should fix it in mice. Giving people extra leptin should signal to the brain that fat stores are higher than it would like, and it should act to reduce them.

You might need to give continual leptin infusions, or you might be able to get away with regular injections of the hormone, it depends on how quickly leptin is cleared from the blood. But if you can raise someone's leptin levels then they should become less hungry and lose weight.

But it doesn't seem to.

People have tried this. Both in obese people and in mice suffering from diet-induced obesity. And while the effect is there, and leptin causes slight weight loss in both, it doesn't cause the dramatic difference in appetite and weight that you'd expect.

But it does cause those effects very strongly in normal people and in normal mice where the system is working properly.

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This strikes me as strong evidence in favour of "PUFAs cause obesity", because while people might be exposed to a vast variety of chemical poisons and even non-chemical environmental effects, lab mice aren't.

We know how to induce obesity in normal mice. You feed them a high-fat diet. Researchers seem to think that this is evidence that high-fat diets cause obesity and break the lipostat mechanism.

And it is. But the high-fat diet that causes obesity is mainly composed of lard, and modern lard is derived from pigs that contain a lot of polyunsaturated fats.

It would be a bit weird if the mechanism that was supposed to stop you getting fat broke because you got a bit fat, and we know that it worked well in the past pretty much whatever people ate, but there’s no reason to suppose that it can’t be broken by exposure to excessive polyunsaturated fats. It’s just not normal to have them in the blood in large quantities.

I don't think you can make normal, wild-type mice fat without feeding them polyunsaturated fats. Exactly as we'd expect if mice normally have a functioning lipostat and PUFAs break it.

So it seems to me that the most likely explanation for obesity is leptin resistance induced by polyunsaturated fat.

And it works the same in mice with diet-induced obesity as it does in humans.

In obese people and in diet-induced-obese mice, leptin makes a little bit of difference in the direction you'd expect, but not much.

Lots of extra leptin produces only a very modest amount of weight loss in the obese, mice or human.

Which strongly suggests that the broken mechanism is broken the same way in lab mice fed the DIO (diet-induced obesity) diet, and in humans 'in the wild' eating processed food.

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To explain what's going on, we have to think about how exactly the system could be broken.

You've got a controller in your brain, which is trying to keep your energy stores "right". 10% fat for a man, 20% fat for a woman, a BMI of about 21 for both. In mice the value is much lower, but it should work the same apart from that. We're all mammals, we share a basic design, and this lipostat system is probably ancient, and probably works in roughly the same sort of way in all animals back to the most recent common ancestor that had fat stores and used leptin to sense their levels and control them.

The controller senses your fat level by sensing the amount of leptin that you're producing, and adjusts your appetite accordingly.

How could this go wrong?

There are various ways where this might be affected.

That control mechanism itself might be damaged¹.

Your fat cells might be producing the wrong amount of leptin.

The leptin receptors in the brain might be damaged, or just interfered with somehow.

Or the leptin that's in your blood might not be getting into your brain properly.

Leptin is produced in the fat cells and released into the blood.

In order to affect the brain, it has to cross the blood-brain barrier and get into the cerebro-spinal fluid (CSF).

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If the problem was just that the fat cells were producing too much leptin, that should be fairly obvious. Fat people should have normal blood leptin levels despite being fat.

I suspect that that is the problem in some people. If someone's got curiously low levels of leptin in their blood despite carrying far too much fat then giving them leptin should just fix the problem.

But most fat people have high levels of leptin, as we'd expect if their fat cells were signalling correctly.

But in most of the other ways in which the mechanism might be broken, there's likely to be a maximum amount of leptin that can have an effect.

You're not really designed to ever have excessive blood leptin, so the sensor mechanism doesn't have to be able to detect levels much higher than normal.

If just the leptin receptors are damaged, the damaged person could be either over or underweight.

It could be that some unexpected molecule is attaching to the leptin receptors and blocking them, or it could be attaching to the receptors and stimulating them.

Either way, depending on how much sensitivity they've got left for real leptin, you should see that blood leptin is at the appropriate level for the amount of fat the person is carrying, and that CSF leptin is at the right level for blood leptin. But adjusting either level might only have a slight effect on their actual problem, because the signal's not getting through properly.

If it's the control system itself that's broken, the symptoms and levels should be similar.

If it's just the transport over the blood-brain barrier that's not working properly, then that should be easy to detect. Blood leptin levels and brain leptin levels shouldn't match.

There might also be a maximum amount of leptin that can get into the brain even in a normal system.

You'd see a person who is quite overweight, with high blood leptin, but normal leptin levels in the brain. Adding leptin to the blood might not make much difference to the levels in the brain, and so might not do much to fix their weight problem.

If the blood-brain barrier can let in too much leptin, then you should see someone suffering from anorexia, with low blood leptin but normal CSF leptin, and in that case if there was some way to lower the levels of leptin in their blood that should restore their appetite.

I’ve actually seen evidence that polyunsaturated fats can do most of these things, and which effect predominates is likely under genetic control, because it will depend on polymorphisms that wouldn’t make much difference under normal conditions, but which might react very differently to strange chemicals.

So most people with a problem probably have a mixture of these things going on. And what their problem is, and how they react to exogenous leptin being used to raise their blood levels will depend a lot on how their system is broken.

But measuring leptin levels in the blood and CSF should give us some important clues about what is wrong in each person, and people who have low blood leptin in spite of being obese should respond well to being given extra leptin, even though most obese people don’t.

1. Which would be very worrying! If one part of your brain is damaged, what about the rest of it?