PUFAs Cause Obesity
It Is Known
For a while now I've been arguing on evolutionary grounds that weight must be under homeostatic control.
I decided to read up on what we know about it, and it turns out that we understand the mechanism pretty well.
Leptin is the hormone which measures how large your fat reserves are.
It's secreted by fat cells in proportion to how much fat they're carrying. The amount of leptin in the blood looks like a "total fat percentage" sensor.
Leptin makes its way into the brain.
If leptin levels in the brain are high, you're not hungry. You don't eat, but you keep using energy, so your fat melts away and leptin levels fall.
If leptin levels in the brain are low, you're hungry. You eat lots, and you put on weight. Leptin levels rise.
In this way, the amount of fat you're carrying is under very precise control. You will always carry exactly enough fat to make the levels of leptin in the brain right.
If you eat too much and put on fat, you will not be hungry until your fat levels have fallen again.
If you can't find food, then your fat levels will fall below where they're supposed to be, and you'll get hungrier and hungrier until you either find something to eat or die.
This is the simplest, most perfect and most obvious way imaginable for an animal to control its fat reserves.
If you said to an undergraduate engineer, "How might an animal regulate its fat stores?", this is the design that he'd immediately come up with.
So much so that the existence of leptin was predicted long before it was actually found in 1994.
You have a 'set point' for the amount of fat you carry, and it's a bitch to shift it.
Only force-feeding, or deliberately overeating even though you're not hungry can make you fat. Only starvation or the insane use of willpower can make you thin.
You have, in short, a lipostat. Or weight-homeostat, as I've been calling it for the last year.
We actually know that this system works like this, in healthy humans and in healthy mice. In mice we can break bits of the system and it responds exactly as expected.
Mice that can’t make leptin get enormously fat, if you give them leptin they lose weight.
Mice that can’t sense leptin get enormously fat, if you give them leptin it makes no difference.
There are human genetic diseases where mutations affect leptin and exactly what you'd expect to happen happens, starving hyperphagic grossly obese children.
So we've just proved that animals with this leptin system (probably all vertebrates!) can't get fat, or even get thin if there's food around.
And indeed that seems to have been true for almost all animals for almost all of history. There's a very precise perfect mechanism that stops that happening.
That's worked that way since the time of the dinosaurs, probably back almost to the beginning of multicellular life.
I know that this is how it is supposed to work in humans in particular because that is how it worked for me for most of my life.
You can't get thin. You can't get fat. Doesn't matter what you do, within reason.
How is it then, that people are fat these days?
Well, likely something is interfering with this mechanism. Fat people are still producing plenty of leptin, you can measure it.
Suppose that something was stopping leptin getting to the brain.
Your poor brain, seeing that there's not enough leptin, decides that you're critically short of fat reserves and makes you hungry.
You eat lots! And you get fat. Leptin levels rise.
If the leptin signal can't get through at all, then you'll just keep being hungry.
This is where 400kg people who can't ever stop eating come from. They're always hungry, starving hungry in fact. But they can only digest so much food, so however much they stuff themselves they can only take in enough energy to maintain their bodies at around half-a-ton. Poor bastards. And they're so hungry... All the time.
If the leptin signal is only partially blocked, then you'll keep eating until you're producing so much leptin that even though some of it is not getting through, your brain is happy.
This is where 200kg people come from. Only about one seventh of the leptin they make is getting through, so instead of carrying 20kg of fat, they're carrying 140kg of fat. But as long as they eat when they're hungry, and don't eat when they're not hungry, they'll stay at 200kg.
If they deliberately starve themselves so that their weight falls, then they won't generate enough leptin, they'll get hungrier and hungrier, and if they ever relax their inhuman control, they'll go right back to 200kg.
The cause of obesity is this mysterious 'leptin resistance'. Again, I don't think this is even controversial.
What sort of thing might interfere with leptin signalling? Perhaps PUFAs?
Let's do a quick google for PUFAs and leptin and see if anything comes up.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117679/
The expression of leptin is increased in obesity and inhibited by n-3 polyunsaturated fatty acids (n-3 PUFAs), but the underlying molecular mechanisms have not been firmly established.
https://www.cell.com/immunity/fulltext/S1550-4131(05)00112-9
Dietary n-3 PUFA reduced transport of endogenous or exogenously administered leptin into the brain
The ratio of cerebrospinal leptin concentration to blood leptin concentration is clearly lower in obese people than in lean subjects
That'll do. Omega-3s both prevent the production of leptin and prevent it getting into the brain.
Omega-3s cause obesity, by two different mechanisms! We are done.
I'll admit I am surprised. I thought it would be Omega-6s doing these things.
Of course, they might do it too.
More googling:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808858/
High fat diets rich in omega-6 fatty acids have been shown to increase the risk of leptin resistance, diabetes, and obesity in humans and rodents
AA impairs hypothalamic leptin signaling and energy homeostasis in mice
That will also do. Omega-6 PUFAs also cause obesity.
We are done and then some.
PUFAs cause obesity.
Both Omega-3 and Omega-6 PUFAs cause obesity by directly interfering with the lipostat.
In the most obvious ways possible.
This stuff is so easy a child could do it. Work out what has to be true, google for it, and it just turns out that it is in fact true.
I apologise for not spotting this a year ago. I've had this sort of mechanism at the back of my mind all this time, but I just kind of assumed that if it was this obvious someone would have already spotted it.
This leptin theory has been all the rage since at least the 90s and is one of the big parts of mainstream obesity science right now. Stephan Guyenet's The Hungry Brain is all about this.
I think while most of the stuff they talk about is true, it's also not the major cause of the obesity epidemic in most people. It's only one half of the equation, and they don't have any solutions for it.
E.g. you probably also read that while you can restore "slimness" by injecting mice with leptin, this doesn't work in humans? Leptin therapy was thought to be the cure for obesity in the 90s or so, and has turned out to be completely useless.
I'd call this the "signaling defect" theory of obesity. I'm more of a believer in the "fuel partitioning" part.
Signaling theory says there is enough fat, and you can get to it, but the signal is broken. Most fat people make enough leptin, huge amounts in fact, so maybe the brain's leptin receptors are broken.
Fuel partitioning theory says: there is enough fat physically in your body, but you somehow can't ACTUALLY get to it, so you are, in a sense, literally starving - the signal isn't wrong!
I don't deny all the leptin research, I just wonder if it's that relevant. If leptin/signaling theory was the whole deal, then we would see that people who actually just ate less with willpower lost weight and kept it off. But that's not what we see. We'd see me overeat by thousands of calories, but I don't. I actually undereat (both by expected TEE of 3,300 and measured of 4,600), and still I currently am not losing weight.
So I think leptin is a cute mouse experiment, and might explain the circus man/woman from 1830 or whatever, but not the obesity epidemic. At least it's not the major factor I'd say, although leptin resistance probably doesn't help.
Seems true or at the very least plausible since TPTB feed PUFA to cattle to fatten the cattle for market. We share highly conserved pathways and such with our bovine friends.