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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Guide to Flexible Dieting

Want to Learn More About Refeeds and the Full Diet Break?

In A Guide to Flexible Dieting you’ll learn how the proper use of refeeds and full diet breaks can avoid the common problems of runaway hunger and metabolic slowdown on a diet. You’ll also learn some of the behavioral reasons that diets fail and how to avoid them with flexible dieting strategies.