Bodyweight Regulation: Leptin Part 6

In Bodyweight Regulation: Leptin Part 5, I explained that, while injectable leptin would be a true boon for dieters, it appears unlikely that it will ever reach commercial or clinical use.

This leaves us with other approaches (e.g. nutritional, supplements, training) to attempt to manipulate either leptin levels or signaling.

There are basically three places where dieters might impact leptin levels and/or activity in terms of fighting off the adaptations to dieting.

1. Production at the fat cell

2. Signaling in the brain

3. Transport into the brain

Leptin production in the fat cell
I talked a little bit about #1 in a previous post, when I talked about refeeds. At this point, and this topic is discussed to some degree in nearly every book I’ve written at this point, interjecting high carbohydrate, high calorie refeeds of varying lengths (anywhere from 5 hours to 3 days) is (currently) the best way to raise leptin while dieting.

One of the interesting (and often missed points) is that, as dieters get leaner (and leptin drops more and more), refeeds need to become larger and/or more frequent. That is, rather than necessarily dieting harder as they get leaner, some people are actually doing better by ‘breaking their diet’ (with specific high-carb refeeds) more frequently.

I’d note again that leptin production is related primarily to carbohydrate intake in the short-term, high-fat refeeds aren’t the best way to raise leptin levels. I’d also note that single ‘cheat’ meals won’t impact on leptin levels significantly as leptin doesn’t really change on a meal to meal basis.

Tangent: I’d note that, in this regards, some of the work being done with intermittent fasting and every other day refeeds has relevance here as some data suggests that leptin may be maintained better with that approach to dieting. But until I get Martin Berkhan in here from LeanGains for an interview and dig into it more, I’m not going to talk much about IF’ing as a dietary strategy other than to say: there’s some compelling shit going on here.

An additional strategy, talked about in some detail in my Guide to Flexible Dieting is the idea of full diet breaks, periods of 10-14 days in-between periods of active dieting where calories are brought back to maintenance (and carb intakes brought back to at least moderate levels).

Not only does this provide a psychological break from the grind of continuous dieting, it helps to ‘reset’ some of the metabolic adaptations that occur with dieting. Leptin levels will come up, thyroid conversion in the liver is improved, etc. Assuming dieters have no strict time constraints, I strongly feel that inserting full diet breaks every so often (how often depends on body fat levels) is important for long-term success. Again, for both physiological and psychological reasons.

There are at least two other regulators of leptin levels here, both zinc and Vitamin E intake appears to regulate leptin production and I have suggested supplementation of both in the past to try to help raise leptin. How much (if any) impact this actually has I can’t say.

Leptin action in the brain
Although it seems a bit out of order, I want to jump next to leptin activity in the brain. This is part of the area that gets generally referred to as ‘leptin sensitivity’ in the literature and is, unfortunately, poorly studied and even more poorly characterized.

What causes it, what (if anything) can be done about it is a huge question mark although finding ways to improve leptin sensitivity would probably also have huge benefits. Similar to improving insulin sensitivity, increasing leptin sensitivity would mean that the same level of hormone sends a larger signal. A supplement or drug that increased leptin sensitivity would be expected to do some very nice things.

I would mention that there is indirect evidence that regular exercise improves leptin sensitivity. I say indirect because measuring leptin sensitivity in humans is very difficult. Improved leptin sensitivity is being inferred from the fact that endurance athletes often have leptin levels below what you’d expect given their body fat level; this suggests increased sensitivity. Again, it’s hard to measure in humans.

It does appear that increasing levels of leptin induce resistance to itself (I’ll spare you the mechanism) so it’s conceivable that reducing leptin levels (e.g. with a diet) could transiently reduce leptin resistance/improve leptin sensitivity. How much of an effect or how long this would take is currently unknown.

If this were the case, would provide more support for cyclical dieting approaches such as my Ultimate Diet 2.0. During dieting periods, leptin levels would go down (but sensitivity would go up); during periods of deliberate overfeeding, improved leptin sensitivity (until such time as it went down again) could possibly be taken advantage of.

A similar logic could be applied to weight gain, eventually chronic overfeeding/weight gain might potentially induce leptin resistance; inserting periods of dieting to deliberately lower leptin might offset this.

While I’m on the topic, I should mention that leptin resistance can occur at other tissues such as skeletal muscle (I haven’t talked much about leptin’s actions there).In animals at least, both exercise and fish oils increase skeletal muscle leptin sensitivity.

Leptin transport into the brain
The final topic I want to talk about is that of leptin transport into the brain, something else I haven’t really talked about in this series. But it’s thought that leptin transport issues at the blood brain barrier may be part of the overall ‘leptin resistance syndrome’ and impaired leptin transport into the brain may be part of the problem. It’s thought that leptin transport into the brain can become saturated, that is, once leptin gets above a certain level in the bloodstream, no more can be transported into the brain.

But leptin transport into the brain is also actively regulated by the blood brain barrier, by a variety of things, let’s look at a few:

High blood triglycerides tend to reduce leptin transport and it’s interesting to note that, despite being high in fat, low-carbohydrate diets often reduce blood TG levels; is enhanced leptin transport part of the often observed appetite blunting effect that is often seen (along with other potential mechanisms of course)?

In a similar vein, high-carbohydrate diets, especially combined with low levels of activity often raise blood triglyceride levels, probably hindering leptin transport into the brain.

Both insulin and epinephrine increase leptin transport into the brain. Tying in with my comments above, this might be another reason that high-carbohydrate refeeds ‘work’ after a period of dieting; between (potentially) increased leptin sensitivity in the brain and insulin increasing leptin transport, there is a brief period where leptin signalling should be increased.

The supplements ephedrine and synephrine would be expected to increase leptin transport, ephedrine by raising epinephrine levels and synephrine by directly binding to beta-receptors.

And, of course exercise raises levels of epinephrine and, at least transiently should increase leptin transport into the brain. In that vein, quite a bit of research suggests that the body better regulates food intake when exercise is performed, increased leptin transport (and signalling) might be part of the mechanism.

And while I can’t find the paper now, I seem to recall a rat study suggesting that long-term (4 months if my memory isn’t failing me) fish oil supplementation could increase leptin transport into the brain. But it would likely take a very very long time to occur in humans.

And, at least for the time being that’s pretty much all I have to say about leptin. Next time, I’ll take a quick look at some of the other hormones involved in this system before (finally) moving onto some psychological issues that play a role in dieting.

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14 thoughts on “Bodyweight Regulation: Leptin Part 6

  1. Insulin controls fat storage.
    Fat storage increases triglyceride levels.
    Insulin correlates with triglyceride.

    Exericse improves leptin sensitivity / transport because exercise reduces insulin (thus fat storage and triglycerides). Low carbohydrate diets work the same way, by reducing insulin and triglycerides.

    Insulin makes leptin, so exericse (like calorie restriction and carb restriction) will logically lower leptin. People who exercise a lot (or who stringently restrict calories and/or carbohydrate) will have lower leptin, and lower body fat because they have low insulin.

    Even though I was morbidly obese, I appear to have fantastic leptin sensitivity, which I relate to having extremely low triglycerices (35 last measure) and following a low carbohydrate diet so as to maintain this loss of weight. Just a teeny tiny dose was enough to bring my body back to life.

    Eating carbs/calories to raise leptin is tricky because it works through increased insulin. Insulin is what ultimately signals for the fat cell to make leptin (which is why carb feeding is so good at raising leptin). You don’t want to raise your triglycerides though, because that will reduce the leptin that is working in your brain.

    I suspect refeeds help primarily for psychological reasons, because physiologically it doesn’t seem likely that a day of overfeeding and transient increase in insulin/leptin should foil our genetic anti-starvation mechanisms. The body knows what it is doing, and if it is very weight reduced, it will behave starving until fat cells are refilled.

    Association of Leptin, 25-Hydroxyvitamin D, and Parathyroid Hormone in Women
    This paper shows leptin levels adversely affect 25(OH)D metabolism.

    Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding.
    Chronic fructose consumption caused leptin resistance,

    I find very little evidence that the impact of vitamin d status on glucose metabolism and insulin sensitivity has been considered here.

  3. The extremely elevated leptin that occurs secondary to obesity has little to do with what I’m talking about (dealing with the drops in leptin on a diet). So we’re talking about totally different things.

    But excessive leptin (again, secondary to obesity) cause a number of problems. Again, no real relevance to the topic of this series.

    As well, if you read the abstract of the fructose paper, they provided 60% fructose to rats for 6 months. That is so non-physiological as to be 100% irrelevant. In a typical human diet assuming 2700 calories, 60% fructose would be 400 grams of fructose per day, every day, for 6 months. No human could eat that much fructose, the malabsorption from straight fructose would prevent it.

    And if they got it, from say, 800 grams of sucrose, I daresay that the 3200 calories from table sugar would cause bigger issues than what that paper purports to be about.

    So the paper means nothing even if the internet keeps trotting it out.

    And of course there is ‘little talk of Vitamin D’, it was a series about freaking leptin.

  4. Hi Lyle, I am working towards getting down to mid single digit body fat. Right now I am about 10% and I am feeling the effects of the hormonal responses you have been mentioning in your articles. I have come to the conclusion, that I am just going to have to bite the bullet and deal with the hunger, deal with the lowered immune system, and suck it up. Because I honestly don’t see any easy answer or solution in everything I have read. Getting very lean is hard. Done deal. I must accept it and move forward. I know the rewards will be great! Hey maybe I can get my brain to release some more dopamine thinking about the rewards of becoming very lean:)

    Thanks again for your very informative articles.

    James Scott

  5. Lyle,
    Is there any research on whether leptin levels are affected by absolute carb intake? What I’m talking about is individuals who get some of their caloric deficit through large amounts of calorie expenditure (e.g. running or other endurance activities, in addition to weightlifting), and thus have higher than normal carb intake despite maintaining a caloric deficit. Would leptin production in such people still be stimulated by the large amount of carb intake (for example, on exercise days), even though a caloric deficit is consistently maintained?


  6. The deficit will overcome the carbohydrate intake per se. The body appears to be primarily responsive to caloric availability which is intake – output.

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