Marks Daily Apple
Serving up health and fitness insights (daily, of course) with a side of irreverence.
17 Jun

A Primal Primer: Leptin

Just about every physiological process occurring under the hood can be attributed to one hormone or another. Hormones are like software programs, directing our bodily processes, modulating our reactions to foods, and guiding energy metabolism and balance. We don’t consciously control our hormonal responses – that is, we don’t think to ourselves, “Hmm, let’s get some testosterone flowing,” or “Insulin: release!” But we can heavily influence our hormonal responses through the things we do, the stress we undergo, the foods we eat, the weights we lift, and the sleep we get.

One crucial hormone that we’re still learning about is leptin. We do know a few things, however. Leptin is the lookout hormone – the gatekeeper of fat metabolism, monitoring how much energy an organism takes in. It surveys and maintains the energy balance in the body, and it regulates hunger via three pathways:

  • By counteracting the effects of neuropeptide Y, a potent feeding stimulant secreted by the hypothalamus and certain gut cells.
  • By counteracting the effects of anandamide, another feeding stimulant.
  • By promoting the production of a-MSH, an appetite suppressant.

Leptin is secreted by fat cells and is received by receptors in the hypothalamus. If leptin is absent, feeding is uncontrolled and relentless. In normally healthy people, if leptin is present and receptors are sensitive, feeding is inhibited. More body fat means less food is required, and so leptin is secreted to inhibit feeding and the accumulation of excess adipose tissue. Overweight people generally have higher circulating leptin, while leaner people have lower leptin levels. Leptin also responds to short-term energy balance. A severe caloric deficit will result in reduced leptin secretion – this is your body’s way of getting you to eat when you need energy. It’s the hunger hormone. Overfeeding temporarily boosts leptin, reducing hunger.

Put simply: long-term, leptin signals that the body has adequate adipose tissue (energy) stores; short-term, leptin signals that the body has had enough to eat. Both are supposed to result in the reduction in appetite.

But why are so many people so overweight? Why don’t overweight people respond to all that circulating leptin and curb their food intake? And if they’re overfeeding, why isn’t the resultant leptin increase having an effect. They shouldn’t be hungry, but they are. There’s a disconnect, a disruption of the leptin pathway.

Something is causing the leptin receptors in the hypothalamus to down regulate (leptin resistance), or something is blocking the leptin from reaching the receptors. Either way, leptin isn’t working as it should.

Why is that? What’s causing the breakdown of the leptin pathway? I mean, take a look at wild animals. It seems to work pretty darn well for them.

They eat varying amounts of food, sometimes gorging, sometimes fasting, but never counting calories. Except for a few special apes given a lifetime of expert instruction and lured with endless bananas, they can’t even count. And yet these animals seem to be experts at maintaining excellent body composition. Unless it makes sense for their environment (like with walruses and hippos, for example), animals don’t accumulate a lot of adipose tissue. For an older dude, I’m happy with my body, but even I get a little envious of that squirrel with the rippling deltoids and bulging, heavily striated glutes who visits my property and never seems to exercise (I even see him eating grains on occasion – what the heck?). My wife doesn’t even let me get near the ape exhibit anymore; I swear the bonobos, with their effortless sub-10% body fat, are mocking me (are frequent orgies really that energy intensive?). How do they do it?

All signs, it seems, point to leptin, leptin resistance, and leptin sensitivity as being dependent on the dietary environment we provide. As long as they do not stray far from their evolutionary diets, wild animals do not have damaged metabolisms, and the leptin pathway is preserved. Most modern humans, having strayed far from their evolutionary diets, are metabolically deranged, with misguided or disrupted leptin pathways.

Much of our knowledge of leptin comes from the study of two brands of lab mouse: the ob/ob mouse, deficient in genes responsible for leptin production; and the db/db mouse, deficient in the leptin receptor gene. The former responds to leptin but produces none, while the latter produces plenty but responds to none. An ob/ob mouse suffers from an uncontrolled appetite. It is literally always hungry and massively obese, because the normal satiety signaling hormone – leptin – is absent from circulation. Researchers typically use the ob/ob mouse as a model for type II diabetes. When you inject an (obese) ob/ob mouse with leptin, it loses weight and its health markers normalize. Its appetite dwindles to normalcy and the energy balance is restored. When you inject an obese db/db mouse with leptin, it doesn’t improve. It already has high circulating leptin, since its considerable fat stores are secreting it, but there is no receptor to accept it.

When leptin was discovered, it was hailed as the key to the obesity epidemic. Researchers figured if they could just administer leptin to the obese, appetite would be curbed and food intake would reduce. It actually worked for some people, but it was expensive (about $500 per day) and unsustainable, and for others, it had no effect. These were the leptin resistant. Like the db/db mice, these folks had dull leptin receptors, and adding exogenous leptin was pointless. If anything, the problem worsened, as chronic exposure to leptin can dull the leptin receptors even more.

Leptin doesn’t just regulate bodyweight and energy intake, though. It’s also important for fertility, libido, immunity, and even puberty. In a sense, we can think of leptin as an overall energy barometer. If insufficient energy is available to the body, the body down-regulates all the “extra” stuff, like reproduction, sex drive, puberty, and immunity, while the presence of leptin indicates sufficient energy, enough to spend on other bodily functions and physiological processes. That might explain why heavier kids reach puberty earlier than leaner kids. The loss of menstrual cycles in women and reduced sex drive in both men and women who reach extremely low body fat levels might also be explained by low leptin levels.

How do we maintain adequate levels of leptin – enough to keep from going mad with hunger – without growing resistant to its effects? There are a few things to keep in mind.

Watch Your Fructose Intake

In rats, fructose feeding inhibits leptin receptors. Rats were given a diet of 60% fructose for several weeks and then injected with leptin. In normal rats, leptin injections reduce energy intake and hunger. The leptin binds with leptin receptors in the hypothalamus and satiety is induced. In the fructose-fed rats, leptin had no effect. Energy intake continued unabated, while normal rats reduced their intake in response to the leptin. Rats on the fructose diet gained even more weight when switched to a high-fat diet.

Fructose appears to affect the leptin pathway in two ways. First, fructose directly renders the hypothalamus resistant to leptin. Normally responsive receptors in the brain have a muted, or even silent, response to leptin when fructose intake is high. Second, high blood triglycerides – brought on by a high fructose intake – block the passage of leptin to the brain. High tris actually physically prevent leptin from passing through the blood-brain barrier, and the leptin that does get through elicits a poor response from leptin receptors.

As we all know, a high-fat, low-carb, low-fructose diet generally decreases serum triglycerides and increases satiety; perhaps the lower triglycerides are allowing more leptin to pass through and inhibit hunger. The fructose found in reasonable amounts of fruit, like berries, shouldn’t affect leptin sensitivity.

Stephan wrote about this some time ago.

Avoid Lectins

Dr. Staffan Lindeberg thinks that lectins, specifically those from cereal grains, are direct causes of leptin resistance. He observes that wheat germ agglutinin, or WGA, (a lectin present in wheat, barley, and rye) actually binds directly with the leptin receptor and prevents leptin binding. The inability of leptin receptors to bind with leptin adequately describes leptin resistance, making lectins a potential aggravator of leptin resistance. Abnormally high levels of WGA were used to bind receptors, though, so it remains to be determined whether normal dietary levels of WGA are enough to induce leptin resistance.

Given the established issues most people have with grains, I wouldn’t be surprised if they share some responsibility for leptin issues, too.

Get Good Sleep

We know that getting adequate sleep is an important Primal law, and that inadequate sleep can lead to excessive levels of cortisol, the stress hormone, which can induce insulin resistance and (especially in the belly) weight gain, but we also know that sleep deprivation has been linked to lowered serum leptin.

Get your eight-ish hours a night and try avoiding late night electronic usage, which can disrupt sleep patterns.

Avoid Severe Calorie Restriction

Too much dieting inhibits leptin secretion. In fact, drastic reductions in caloric intake reduce leptin levels, faster than could be explained by body fat losses (the same goes for overfeeding, which increase leptin levels faster than can be explained by body fat gain). This can make getting really lean really difficult – the leaner you get and the less you eat, the lower your leptin gets and the more your appetite increases. Anyone who’s dieted knows that sheer intellectual willpower cannot win out against the hormonal urge to eat. Hormones always win.

(In fact, there are ways to tinker with your food intake to produce favorable hormonal responses, especially in regards to leptin. I’ll talk more about that next time.)

I hope you were able to learn a few things with this article. Thanks for reading and hit me up with a comment or questions. Grok on!

jjones123497 Flickr Photo (CC)

You want comments? We got comments:

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  1. Why is it that when I eat canned beans I only get hungrier? I’m not obese or anything, I just can’t get enough of them. I feel that my stomach is full (the pain) but my brain keeps telling me to eat. Leptin?

    Mr. T wrote on June 19th, 2010
    • Mr. T there’s probably mononatriumglutamate in the can,to enhance the flavour. It is also known that a lot of people are intolerant to it,resulting in eating till way beyond full. Another obesity factor,who knows jit might cause leptin problems too. It is known to cause neurological damage in the long run.

      joey wrote on February 22nd, 2011
  2. Another fantastic, interesting and informative post. Thank you, thank you, thank you. Now – to part 2!!!

    Peachy wrote on June 21st, 2010
  3. I’m from Wisconsin and we have a problem with enormous squirrels as well. They feed from the cornfields. Funny, we also have a problem with fat cows as well, which eat the same thing…..

    Tyler wrote on June 23rd, 2010
    • Wisconsite here, as well (Go Badgers!) and I would say we have the same problem with many of our people…hmmmmm

      Jared wrote on June 23rd, 2010
  4. Great Post!!! I have been eating primal/paleo foods but doing calorie restriction. I have nipped that in the but now and am feeling much better. The weight is dropping too.

    Dan wrote on June 26th, 2010
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    floppyk2011 wrote on January 15th, 2011
  6. Look into books by Byron Richards on this subject. Very informative.

    Angela wrote on February 8th, 2011
  7. As good a summary as I’ve seen.
    Ghrelin may be a counterpart hormone to leptin.
    Fructose is interesting, particularly as high-fructose corn syrup sweetener/sugar substitute used in soft drinks and many processed food,s may be linked to obesity – in other words as “stealth glucose”, and converted to fat.

    Tony Dowell wrote on February 9th, 2011
  8. Great post as always, Mark! I am looking forward to the follow-up. If you can, please give us an idea of how much fruit is acceptable per day. I know the carb recommendations, but clearly, not all carbs are created equal. In other words, just how much fructose does it take to cause leptin resistance?

    Thanks for all you do!

    Ron S wrote on August 3rd, 2011
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    sexshop wrote on September 12th, 2011
  10. No wonder that I’ve lost so much weight switching to an ‘eskimo diet’ of meat, blubber and the occassional berry.
    No vegetables here in this house other than a squash or sweet potato once or twice a year.

    Eskimo Ice Cream is the sh*t :)

    Arty wrote on November 16th, 2011
  11. Hi Mark,

    All of those correlations make sense, such as fructose and grains being causes for leptin problems and subsequent weight gain…

    But the problem is….

    There are literally millions of people around the world that eat grains and fructose, and they are slim.

    Yes, these are the “naturally” slim people.

    But nevertheless, has anyone studied THESE people to see how their leptin profiles look like?

    It seems like all those other things (fructose, grains, sleep, etc.) are certainly involved at some level, maybe in correlation….

    But since others are NOT gaining weight with same bad diet, it seems we’re not hitting on the *causal* or root issue.

    Thanks so much for the post.

    Any ideas as to why the naturally thin people are that way (hormonally speaking)?



    Steve wrote on March 19th, 2012
  12. Since long term leptin signals that the body has adequate brown fat, what would happen it some of that fat was liposuctioned? Would it alter leptin secretions or receptors?

    Sharra Moller wrote on May 29th, 2012
  13. Great Post !!! I really enjoyed reading your explanation about leptin. I am wondering how exercise plays a role in improving leptin sensitivity ? Cavemen not only ate a primal diet, but exercised in intervals (high intensity short bursts)to catch food or get out of danger etc. Possibly, the way we exercise may also be linked to improved leptin sensitivity ?

    Daniel Mizzi wrote on July 24th, 2012

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