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. 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
  2. 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
  3. Howdy! Someone in my Myspace group shared this website with us so I came to give it a look. I’m definitely enjoying the information. I’m bookmarking and will be tweeting this to my followers! Fantastic blog and amazing design and style.

    sexshop wrote on September 12th, 2011
  4. 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
  5. 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
  6. 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
  7. 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
  8. thanks for the great post!!!!this helped me a lot..great explaination about leptin

    manasa wrote on October 12th, 2012
  9. I used to eat huge amount of PB/J… three sandwiches in the morning (though, I was training pretty hard) and would be ravenously hungry an hour later.

    I eventually cut it down to one sandwich and added three eggs… hunger dissipated immediately.

    Goooo leptin!

    me wrote on March 26th, 2013
  10. I’m a vegan. I eat grain. I prefer to adhere to an Ayurvedic approach to my diet. So far I’m good. I recently read an interesting article about Leptin. I was doing nutritional research and came across it. The gentleman interviewed for the article said when your body is starving it signals for a release of fats for energy. When people are obese, there is a well above normal amount of fats circulation in their body. They still feel hungry because their body thinks they are starving. Historically, there has never been such an abundance of calories and people weren’t fat and/or obese like many are now. The body is still reading the excess leptin (as a result of excessive fat circulating) as a sign of starvation. And to be honest, my opinion is that they are starving. For REAL FOOD. Something with nutrition. MOST of what is stocked at grocery stores is highly processed poison posing as “food”.
    The more I learn, the more I realize the only way to ensure the integrity of your nutritional intake is to eat organic (preferably from your own garden or trusted local source) and make the food from scratch yourself. I know, nobody has the time, right? Think about that thought. You don’t have the time to eat real food. To prepare yourself a real meal. What is taking up your time so you can’t? When you get sick or end up in the hospital, your body makes you slow down to care for yourself. Love yourself and love your body enough to give it a chance to avoid dis-ease.

    Maria wrote on June 11th, 2013
  11. I found that walking to work and home again (15kms a day) Monday to Friday made me so strong and fit that the percentage of fat in my body dropped from 33% to 14% on it’s own, and I just ate what I felt like.

    Another trick is to reduce plate sizes, because we have been conditioned to clean up the plate.

    I found that eating only three times per day meant that I enjoyed my food more than grazing all day.

    4pm is the time of the day that children can become very hungry, tired and anti-social, and need their blood sugar topped up with a good snack.

    Joronda wrote on July 14th, 2013
  12. I’ve been gluten-free for almost two years and while I believe there are compelling reasons to avoid gluten and will continue to be G/F, I personally haven’t experienced any health benefits (no change in gut, no weight change, no effect on hunger, etc.). My overall weight is good but… since going through menopause, I have belly fat that running every other day, a healthy diet (healthy vegan) has not addressed although… windsprints finally budged some belly fat. I eat very little fruit, being vegan.. read all labels and avoid high fructose (and processed foods in general), so the one change based on the website ‘wellsnessmama’ (which linked to this site) is to avoid cardio exercise for a while since it stresses hormones?

    Anyway.. any thoughts are appreciated on how to budge belly fat. Not interested in eating meat or dairy again, but open to other suggestions. Thanks!

    Kate7 wrote on October 1st, 2013
    • Protein. I don’t care what you say, you likely are not getting enough on a vegan diet. And, no, I won’t go all Paleo on you…read other diets such as “The Hormone Diet” by Natasha Turner and high-quality protein is necessary.

      LLY wrote on October 1st, 2013
    • I agree with LLY, you need more protein.
      The way to keep my belly fat is to keep eating grains and beans. Ugh. I really like chili made with beans and corn, however, once I removed those two things it made a HUGE difference in my belly fat from chili. The other parts of my diet were not really grain heavy anyway, except for corn. I loved popcorn, corn on the cob, corn tortillas, corn chips, etc. That had to go as well to get rid of the belly fat. My coworker has only belly fat, she runs marathons and eats a lot of rice. Sometimes if you want to keep eating the same way you can make up your mind to allow for a bit of belly fat I guess. I get most of my nutrition from fat, various forms of protein (no grain/bean) and veggies.

      2Rae wrote on October 1st, 2013
  13. Hello…plz need some help. i think i am leptin resistant, i have normal weight but my body has a fatty structure. I am 80% raw,no sugars, no grain,no salt,mostly hight quality products, i eat quarrel eggs, nuts, seeds some raw fish sometimes, beans like lentils and on. the level of omega3 i control, saw very low recently, but now each at list 1 tea spoon of chia,hemp seeds.
    I am super healthy. i count my proteins and i try to eat min.50 gr mostly vegan quality,today for example i have eaten 101 protein,176carbs,35 fats. it seems a LOT, i count by MyfitnessPal. Am i on the way to higher mu leptin sensitivity?
    I am wandering about fruits, i could not read any much about it, so must ask. By glucose what do you mean? if i eat separately 2 bananas,5 kiwis,300 berries a day, could it affect my leptin resistance?

    Thank you.

    Eleni wrote on October 19th, 2013
  14. I am sure you’re on to something, thanks so much for clarifying this Leptin issue! I am committed to this for a month and I’ll come back and report when the month is over (Feb 2014).

    Leigh wrote on December 30th, 2013
  15. To take just one example, the Telegraph Media Group chief executive Murdoch MacLennan,
    who is leaving No 10 david cameron in May.

    Aidan wrote on March 19th, 2014
  16. Hi Mark,
    This is a relly good article about leptin. Since you wrote it some years ago the issue of leptin resistance became a really hot topic. I wrote an article about it that I hope you will enjoy and find informative.

    Barbara Komorek wrote on June 14th, 2014
  17. With the disease of obesity becoming a long-term problem of both society and economics surely it’s time to give information out that what we eat in the western world is killing us. Times of austerity often mean a re-evaluation of values and the amount we waste on ‘rubbish’ food. Good quality unprocessed food, home grown when possible, will always be a step in the right direction. Marketing quick fix ‘potions and snake oil’ has had it’s day!

    Vanessa wrote on October 31st, 2014
  18. Hi
    Hoe csn you tell if leptin resistant, is everybody that is overweight in that category? 6 weeks ago i started eating LCHF, had been paleoISH previously. Im not really losing weight, chamging shape slowly. Struggling to eat breakfast, happy if i dont eat til lunch, but people are telling me i wont reset my leptin if i dont have a big Breaky, but then there is lots of great info on IF…. Im not really craving anything now and very rarely fall off the wagon only at my birthday and a wedding and thats it. Sometimes i worry im not eating enough, other days i know ive eaten too much fat. Any tips? Do i HAVE to have a big breaky to have success on a letogenic diet? Im very confused,

    Jess wrote on February 18th, 2015

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