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The drug rimonabant (Acomplia) that failed to pass muster with the FDA panel last week works by blocking some of the hunger receptors in the brain. In other words, those who take the drug – assuming it works as touted – will be less hungry. Less hunger means less food consumption. Less food consumption typically results in weight loss. So, if you take rimonabant, assuming you don’t become suicidal and do yourself in (the big worry of the FDA panel since the major side effects are varying degrees of psychoses), you should lose some weight. But there is a better, cheaper way.
The low-carbohydrate diet working through the hormone leptin reduces hunger much more than rimonabant on its best day. And without the risk of serious side effects. And without the for the drug.
Leptin is a hormone made by fat cells. When there are a lot of fat cells they secrete a lot of leptin. What does leptin do? It seems that every day a new function for leptin is postulated, but for our purposes now, let’s stick with what most scientists consider the primary function of leptin: regulation of the fat mass by regulating hunger.
No, far from it. Obese people make a large amount of leptin, way more than non-obese people in fact, but they are resistant to the effects of their own leptin in much the same way they’re resistant to the effects of their own insulin.
Before we go into the whys and wherefores of all this, I want to digress for a moment to show you just how potent leptin is. Let me start by telling you about how leptin was discovered. The discovery of leptin came about as the result of a search for the cause of obesity in a mutant strain of mice that had been around for years. By comparing these mice with normal mice, researchers at Rockefeller University isolated a substance they called leptin (from the Greek word meaning thin: leptos) as being a hormone that the obese mice were not producing. A mouse from this line, called an Ob mouse – or technically Ob/Ob, meaning that it lacks the leptin genes on both chromosomes – produces no leptin in its fat cells. As a consequence it never gets the ‘don’t eat’ signal, so it eats all the time and becomes obese. Hugely so. Way more than just a typical mouse that is over fed. In fact, here are some pictures to show you the magnitude of the obesity.
If you give these Ob mice leptin, they lose weight, or if you give it early enough, they don’t gain and are like their non-Ob mice brethren.
As you might imagine, this discovery caused quite a stir. For a brief moment everyone thought the magic bullet for obesity had been found. All we have to do is give fat folks leptin, and, Voila!, they get thin. Problem was that when researchers started checking, they discovered that obese people had plenty of leptin and that giving them more didn’t particularly help things. So another great weight-loss idea bit the dirt. But no one lost interest in leptin and there is still a huge amount of leptin research underway all over the world.
Leptin is an enormously powerful substance in the regulation of the size of the fat mass. Especially when it doesn’t exist. Just as there are Ob mice with no leptin, there are Ob people who make no leptin. These people get more and more obese to the point of grotesqueness, and, fortunately for them, the administration of leptin does indeed work to reduce their size.
To demonstrate the power of the lack of this hormone, I want to show you a video of a little girl whom I’m pretty sure is leptin deficient. Nothing much else could account for this situation. Maybe a pituitary tumor, but I doubt it. I don’t know if she is leptin deficient, but I would bet a fair amount of money that she is. In any case, this is what kids with a leptin deficiency look like.
As you can see, leptin is quite powerful, at least in its absence. It’s also powerful when present, but not in such dramatic fashion. When leptin is doing its job, the result is normalcy.
How does it all work to keep things normal?
Here is a graphic from a recent paper on leptin showing the leptin-feedback cycle in technical terms. Take a look, then we’ll go through it in non-technical terms.
The Arcuate Nucleus is a part of the hypothalamus, which is the part of the brain involved with appetite regulation.
The Leptin Receptor is the protein structure in the Arcuate Nucleus that leptin binds to allowing leptin to exert its effect.
The pinkish/red tube represents a capillary in the brain tightly packed with the epithelial cells making up the BBB.
Here’s how it all works:
The fat mass – the stored fat on the body – produces leptin, which is secreted into the blood in the circulatory system. When leptin reaches the capillaries (the tiniest blood vessels) in the brain, leptin makes its way across the BBB and into the fluid around the brain cells where it binds to the leptin receptors on the arcuate nucleus of the hypothalamus. The arcuate nucleus then sends signals to decrease food consumption and increase metabolic rate.
As the fat mass decreases in size -as it does when you don’t eat for a while and the stored fat is burned for energy – the amount of leptin in the circulation decreases as well. Less leptin crosses the BBB, less binds to the leptin receptors, and the arcuate nucleus sends out the ‘It’s time to eat’ signal. You eat and replenish the fat mass, leptin goes up, and the cycle starts again.
So as leptin levels wax and wane, so does your sense of hunger and even, to an extent, your metabolic rate.
Where does the low-carb diet fit into the picture?
There is a critical point in the cycle described above. That critical point is when the leptin crosses the BBB. If the leptin can’t get across the BBB, it can’t get to the brain. If it doesn’t get to the brain, it doesn’t shut off the hunger response irrespective of how much is circulating in the blood.
Most obese people find themselves in this very situation: high blood levels of leptin but still hungry. And eating makes more fat, which makes more leptin, which should shut off the hunger response, but it doesn’t because the ever increasing levels of leptin telling the brain to tell the obese person to quit eating don’t get to the brain to do their job.
Why not?
Research done a couple of years ago in St. Louis and in Japan pinpointed the problem. Triglycerides – fat circulating in the blood – interrupts the passage of leptin across the BBB. If trigylcerides are high, which they are in most obese people, then, basically, they block the movement of leptin into the brain. So, leptin levels are elevated in the blood, and triglycerides keep the leptin from getting to where it needs to get to shut off hunger. (click for the abstract and full text of this research paper.)
We all know that the commonest lab finding in people following a low-carb diet is a dramatic reduction in triglyceride levels. This reduction in triglycerides allows the leptin that is already circulating in relatively large amounts to get through to the brain where it can reduce hunger. I believe that this reduction in triglycerides (which happens fairly quickly) is the primary reason that people substantially decrease their hunger on low-carb diets. And remember from the graphic above that leptin – once it gets to the brain – actually increases thermogenesis as well, which means that the metabolic rate increases.
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