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Wannabebig: Switching gears here a little. I’d like to know why there’s such a fuss over Leptin and ‘refeeds?’
Lyle M: How much time do you have?
Wannabebig: Hah! Hey, I can’t pass up an opportunity like this. Take all the time you need.
Lyle M: I’d say leptin may be one of, if not THE most important hormone when it comes to dieting and fat loss.
To give you the quick course, leptin is a hormone released from fat cells which tell the brain, essentially, two things: how much bodyfat you have, and how much you’re eating. Leptin basically ‘tells’ your brain what’s going on with your fat and energy stores. When you overfeed, leptin goes up; when you diet, leptin plummets. It changes more slowly in response to real changes in bodyfat percentage. In response to this, your brain modulates various neurochemicals (such as Neuropeptide Y and corticotrophin releasing hormone, NPY and CRH) which further regulate other aspects of metabolism such as appetite, metabolic rate, testosterone, cortisol, GH, and a bunch of others.
That’s on top of doing about a billion other things in the body. Leptin inhibits fat storage in fat cells, promotes glycogen storage in muscle (and increases fat oxidation in muscle), plays a role in immune system function, is involved in fetal development during pregnancy, can kill fat cells permanently, is probably involved in bone growth, and a whole bunch of other things.
I originally ‘discovered’ leptin while looking at something else, the issue of nutrient partitioning (where calories go when you eat them). For years, I’ve wanted to know why fat people lose less muscle when they diet than lean people. My idea was that ‘If we can trick the body into thinking we’re fatter than we really are, we can lose less muscle when we diet.’ Maybe we can gain muscle more easily without putting on fat too.
So I went looking for major differences between fat and lean folks. You’ve got the obvious, bodyfat percentage. YOu see differences in insulin levels, differences in blood free fatty acid levels (which is part of the story, it gets harder to mobilize fat for fuel when you’re lean, so your body uses muscle; it’s also why ephedrine/caffeine and GH both increase fat loss and spare muscle) and a lot of other differences. But none really stood out.
In looking at the topic, I kept coming across references to differences in leptin levels. Now, I’m inherently fairly lazy, and I had ignored leptin (which was discovered in 1995) up until that point. It was just another hormone system that I didn’t want to learn about, and I couldn’t bring myself to care. That and the research was too fragmented to really draw any conclusions. By the time I started looking at the topic (in 2000), the picture had become much clearer about what leptin was, what controlled it and what it did. And the answer was that it controlled nearly everything and did almost as much. Especially in animals, but also in humans.
In response to falling leptin, appetite goes up, metabolic rate crashes, hormones go to hell, fat storage increases. In response to increasing leptin (to a degree), appetite goes down, metabolic rate goes up, hormone levels increase, the body tries to put a brake on fat storage and pushes calories to muscle for burning. Leptin was the partitioning hormone we’d been looking for.
Wannabebig: So I take it you stumbled upon the Holy Grail of fat loss in a way.
Lyle M: I guess you could say that, suddenly a puzzle I’d been working on for nearly 10 years started to fall together. Why leaner folks lose more muscle than fatter folks, why you can gain muscle and lose fat as a beginner (actually, that only works for fat beginners), a whole bunch of other stuff too.
Now you may remember that researchers had tried injecting leptin into fat folks to cause weight loss. But it only worked a little bit at high doses. That’s ultimately why everybody forgot about it as a drug, it didn’t do what obesity researchers wanted it to do (make them a billion bucks by solving obesity). So they moved on. That would seem to sort of derail my enthusiasm and interest.
There were two problems though with this approach. The first is that fat folks already have tons of leptin. But their brains and other tissues aren’t responding to it. They are leptin resistant (this is analogous to insulin resistance/type II diabetes where there’s plenty of insulin but it doesn’t work very well). Just jacking in more leptin wasn’t going to solve the problem. Leptin didn’t really cause weight loss in that respect anyhow. Research looking for ways to sidestep leptin resistance (or increase it) is still ongoing.
The bigger problem is that the researchers weren’t using it correctly at all, but apparently nobody but me could see the problem. It’s not that leptin per se is the problem or cause of obesity (or the reason diets fail). It’s falling leptin during the diet (very low leptin, as seen in lean folks is a problem too but nobody really cared to inject lean folks with leptin, why bother). The researchers didn’t need to be increasing leptin under normal conditions; they needed to be maintaining leptin during a diet. Of course, obesity researchers want drugs that work without diet or exercise because most people are lazy as shit so this idea didn’t really scan.
See, during a diet, leptin drops much faster than bodyfat percentage. After 7 days on a diet, leptin may be down by 50% from normal. Of course, you haven’t lost 50% of your bodyfat. After that, leptin will continue to go down along with bodyfat percentage. It’s the drop in leptin that ‘tells’ your brain “Hey, we’re starving, shut the system down.” One researcher (in a 1998 paper) had made oblique reference to my idea that maintaining leptin levels on a diet might be more important. But nobody followed it up until a few months ago.
In the first study, on rats, they wanted to find out if dropping leptin was the reason that sibutramine (Meridia, a new diet drug) stopped working. So they gave rats either leptin alone, nothing, sibutramine, or sibutramine+leptin (just enough leptin to maintain levels at pre-weight loss levels). the nothing group lost nothing, neither did the leptin group. The sibutramine group lost weight and then plateaued (as metabolic rate and the rest adapted) and the sibutramine + leptin group just kept on losing weight with no plateau. But that’s rats.
Finally, last month, someone tested the idea in humans. In that study, they injected low dose leptin into dieting individuals to restore normal leptin levels (i.e. at pre diet levels). And, no surprise to me, this corrected the drop in metabolic rate and thyroid (and caused more fat loss). This is how injectable leptin should be used: to maintain pre-diet levels and prevent the normal adaptations to dieting.
I had realized this back in 2000, that falling leptin levels during a diet were the cause of the problem (and the very low levels of leptin seen in very lean folks were causing other problems). One researcher put it best ‘Leptin exists as an anti-starvation hormone’; it works to keep you alive when you’re starving to death (and dieting and starvation are fundamentally the same to your body).
So we (we at this point was myself and Elzi Volk) started looking for ways to raise leptin. Short of drug solutions, the easiest way is to overfeed for short periods of time (there are also nutrients like zinc, vitamin E and fish oils that play a role too).
In one of the early leptin studies, this had actually sort of been demonstrated but the researchers were too dense to see what was going on. In that study, they dieted the hell out of a bunch of fat women for 4 weeks. Leptin and bodyfat both dropped. Then they refed them gradually for a week. Leptin came back up. But fat continued to be lost. To me, this was a profound observation, I don’t recall the researchers even really noticing it (I may be wrong: this may have been the study where the one guy said ‘maybe keeping leptin up on a diet is important’, well, duh!).
Now, fundamentally, there was really nothing that new about refeeds. Bodybuilders have been using cyclical diets (of one sort or another) for decades.
And the idea of raising calories to ‘shock the system’ or what have you, wasn’t new either. I’d known since the early Bodyopus days that having someone eat at maintenance (or even a little bit higher, say 10% over) for a week to 10 days was frequently the best way to break a fat loss plateau. That it ‘reset metabolism’ or however you want to look at it. Even Dan’s old dieting scheme was 4 weeks diet, 2 weeks off, 4 weeks diet, 2 weeks off. We always figured that it was through increasing thyroid levels and, make no mistake, thyroid is involved (no shock, leptin controls TSH levels and the study using low-dose leptin above found thyroid to be normalized) but there are other systems too. Leptin is controlling sympathetic nervous system activity which is a key player in metabolic rate, on top of controlling fat and glucose use in the body peripherally.
We were able to explain why they were working and were able to try and optimize them (by looking at what combinations of calories, macronutrients, etc raised leptin the best). If nothing else, we could give a good physiological rationale behind refeeds (you’d be amazed how much the average dieter hates the idea of breaking their diet, and the reasoning of ‘it just works’ doesn’t get you very far).
Now, at the risk of droning on about leptin, I had originally hoped that leptin could be used to increase mass gains (by limiting fat gains) because of it’s effects. That is, leptin blocks fat storage and ‘pushes’ nutrients away from fat cells and towards muscle for burning (sparing glycogen at the same time). To me, this seemed like the perfect solution to avoiding fat gains on a mass diet. Raise leptin and the body doesn’t store calories in fat cells, preferring to burn them for energy in the muscle cell. Unfortunately, my original excitement was shot down by the simple fact that it doesn’t work.
First and foremost, leptin protects against underfeeding (dieting) far better than overfeeding. There are clear evolutionary reasons our bodies work this way (all discussed, plug plug, in my bromocriptine book): why they work harder to keep us from starving than from getting fat. As well, to get the real anti-fat storage effects, leptin has to be extremely high, much higher than any self-conscious bodybuilder would let it. That is, my original idea was to take your average natural bodybuilder, at say 10% bodyfat, and try to make his body ‘think’ it was 15% bodyfat, storing more calories in muscle cells and less in fat cells. Even if you only repartition a little bit, gaining a little less fat and more muscle at the same time; since you can now diet with less muscle loss you still come out ahead in the long-run.
But it doesn’t work. To get leptin where it needs to be to really stop fat storage in fat cells would require a male get to 20% bodyfat or higher, which defeats the purpose of the exercise. Leptin is simply way too low at low bodyfat percentages to make it work for massing. It’s hard enough to make it work when dieting to very low bodyfat levels, but that at least works a little bit. It’s still not perfect but, short of drug solutions, it’s certainly better than nothing.
Wannabebig: If thats a short answer I guess a book would be in order for the long version. I think that pretty much summed up Leptin and ‘refeeds.’ So, now, where does Bromocriptine fit in all of this?
Lyle M: Well, I don’t want to give out too many of the details, since that’s most of what’s in my new booklet. But I can say a little. Normally I’m not that terribly interested in drug solutions. They aren’t my area of expertise (that’s for sure) or interest. I’d rather find ways to ‘trick the system’ naturally. But sometimes you come across something that’s cool enough to care about.
Now, fundamentally, the solution to all of the above problems (with dieting and such) from a drug standpoint seems pretty easy, right? Injectable leptin. Except that there’s another problem: cost. Since it never got out of the research stage, leptin is ungodly expensive. I shit you not but a daily dose would be something like $1000 per day and that’s not a typo. So using leptin just isn’t workeable.
That’s on top of potential problems with resistance. As I alluded to above, another potential solution would be to sidestep leptin resistance (which appears to actually describe a combination of factors from blood brain barrier transport to receptor function) completely. There’s a compound called ciliary neutrophic factor (CNTF) that does this, tricks the brain into thinking the system is fine (apparently they’ve brought it to market under the name of Axokine or something like that). Another compound called oleyl estrone does the same thing.
Now, in looking at another topic (fat cell death, or apoptosis), I came across references that bromocriptine might be mimicking some of the effects of leptin in the brain without involving leptin. There was already animal research showing that it had profound repartitioning effects (especially in mice who lack leptin completely, the OB mutant mouse), and some limited human research suggesting fat loss and other benefits such as correcting some of the problems in Type II diabetics (another mouse, the DB mouse which is 100% leptin resistance, and diabetic as hell, shows a correction of symptoms when you give it bromocriptine with a another drug). So I looked into it some more and some more and that’s what I talk about in my booklet.
Actually, to let readers know, the booklet isn’t so much about bromocriptine as it is about bodyweight regulation, how the body knows what you’re doing to it (over vs. underfeeding) and how it adapts (I talk about leptin, and NPY and CRH from above as well as the evolutionary reasons certain things happen).
I don’t even talk about bromocriptine until chapter 4 and readers get the ‘joy’ of following my mental processes from defining the problem (dieting sucks and screws you) to how your body knows what’s going on (leptin) to the solution (bromocriptine).
Bromocriptine just turns out to be a quick, cheap, and relatively safe way of fixing some of the problems with dieting. The side-effects are generally minor (nausea, dizziness, low blood sugar) and transiest (going away after a few doses). It has some other nice benefits too, it may have pro-sexual effects (shortening refractory period), as well as improving hormone levels post-steroid cycle. Of course, since it’s very old (30 years), nobody can patent it for weight loss and get exclusivity, but I bet dollars to donuts that dopamine receptor agonists (what bromocriptine is) will come out for weight loss in the next few years.
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