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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:

Imagine you’re George Clooney. Take a moment to admire your grooming and wit. Okay, now imagine someone walks up to you and asks, “What’s your name?” You say, “I’m George Clooney.” Or maybe you say, “I’m the Clooninator!” You don’t say “I’m George of George Clooney Sells Movies Blog” and you certainly don’t say, “I’m Clooney Weight Loss Plan”. So while spam is technically meat, it ain’t anywhere near Primal. Please nickname yourself something your friends would call you.

  1. I have noticed, in just a few weeks of attempting a Primal diet, when I eat grains I get hungry. I ate bread & quinoa early this week and the next day I was ravenous all day no matter what. If I lay off the grains, I’m full at less than 1200 cal/day.

    Ely wrote on June 17th, 2010
    • Thats why the primal lifestyle will always win. Everyday I am incredibly grateful that I stumbled upon (aha!) this blog when I was having digestive problems because of a lot of gluten intake.

      I have been primal for 2.5 months and will NEVER look back. Grains are a bitch! (sorry, but its true)

      Primal Toad wrote on June 17th, 2010
      • I am also amazed at how eliminating grains solves so many problems, and so quickly. I really thought my weekly heartburn bouts, other digestive problems and, um, inflamation, blotchy skin, and low energy level after about 3:00 p.m. was just middle age creeping up on me.

        After only one month of about 90/10 primal (gotta have my morning mocha!), I have absolutely no digestion problems, clear skin, lots of energy without the afternoon crash, and no cravings. I have not felt this good in 20 years.

        Quitting the grains was not even as hard as I thought it would be, and I was a confirmed pasta freak with a serious bagel habit. (Whole grain, of course, thanks to CW).

        I also stumbled across this site accidently, from a link from another site. It has profoundly changed my life.

        Duncan wrote on June 17th, 2010
      • Bah! what a weirdo!!

        Buuuuh! wrote on March 28th, 2013
    • Quinoa is a seed not a grain. Maybe it has the same effect as grains, but it also has protein.

      V Cook wrote on July 16th, 2012
    • I was under the impression that Quinoa is a seed not a wholegrain – if this is the case – i think it will still be o.k. for you?

      KitKat wrote on February 7th, 2014
  2. Thanks for the great post Mark

    SerialSinner wrote on June 17th, 2010
  3. Quick note on squirrels.
    At my university, we had a problem with fat squirrels. I’m serious. They were hugely fat – I’ve never seen a “wild” animal shaped like these squirrels were.
    Very humbling to realize that they were just eating our scraps and that’s why they were so huge.
    (They also had absolutely no fear and actually would take your food away from you if you weren’t careful.)
    Maybe their leptin response was messed up?

    Melodious wrote on June 17th, 2010
    • Hey, i think you might be right. I noticed the same about our raccoons. Those I see in the wild are normal. Those who seems to feast on humans garbage (those that are somewhat ”domesticated”) are huge (high % of fat).

      Jean-Patrick wrote on June 17th, 2010
      • Probably because they are eating human foods like bread, corn, etc instead of natural foods. Both the squirrels and raccoons are getting fat on our foods instead of eating what they would normally be eating.

        Jay wrote on June 17th, 2010
        • Yes, that’s what I was hinting at.

          Jean-Patrick wrote on June 17th, 2010
      • LOL, they are fat because they don’t have to do nothing to get food, you weirdo number 2, hahahaha!

        Buuuuh! wrote on March 28th, 2013
    • I’ve seen hugely fat squirrels too – they had been eating birdseed, not human food, but perhaps it has a similar impact on them?

      Ely wrote on June 17th, 2010
      • I got a squirrel eattin my bird seed…Maybe I have some squirrel stew soon. They love bird seed.

        Rob wrote on June 18th, 2010
        • And french fried ‘Taters, mmm hmmmm…

          A little sorry, but there was just something a little too back-country about your post..

          hobos wrote on June 18th, 2010
      • they probably aren’t “foraging” for their food as bird seed comes on a silver platter to them. and I’m sure that trans-fats and squirrels doesn’t mix lol

        kelly wrote on February 20th, 2012
    • did you go to ucla? i was once eating a muffin, and a fat squirrel came right up to me and barked at me as if demanding his share.

      m wrote on June 17th, 2010
    • Ha! Same here. Do you happen to go to a large public university in Los Angeles?

      Ashley wrote on June 19th, 2010
    • I had a fat squirrel at UCLA mug me for a cookie once. While I normally love squirrels, that was not a happy time.

      Kat wrote on February 10th, 2013
    • Did you happen to go the U of Minnesota? I had one of those furry buggers run right up my pant leg (the outside) and stop at my pocket looking at me, silently shouting, “Where’s my food, b*tch?!”

      Derek wrote on August 9th, 2014
  4. Excellent primer mark.

    While I do know a bit about other important hormones, leptin is one that I know the least about. Thanks for the instructive post.

    Jean-Patrick wrote on June 17th, 2010
  5. Awesome overview, I learned a lot. As you noted, much of what you wrote about is just becoming known. Would be interesting to compare the body of knowledge presented in this essay in a few years to see what further insights will appear.

    Now, with that said, if you come out with a new book called “The Bonobos Blueprint” I suggest you sell it wrapped it in plastic.

    Zach wrote on June 17th, 2010
  6. Finally, some good info on Leptin. And here I thought it was just a brand of tea all along. Oh wait, that was Lipton!

    Jeff wrote on June 17th, 2010
  7. I have heard mention of people who say that eating a slightly higher calorie meal or two once every 1-2 weeks helps stimulate leptin that might have dropped on their regular diet. This is assuming something close to the Primal diet.

    Would the elevated leptin stay elevated for several days to justify this approach, or is it much more transient that this? Is there an optimal frequency to do these “re-feeds?”

    Rodney wrote on June 17th, 2010
    • I usually just go for once or twice a week. In grok terms, think about it as you just killed some wild animal. You’re definitely gonna gorge because you probably don’t get to eat this everyday. You might go weeks without getting a nice fresh hunk of protein.

      chris wrote on June 17th, 2010
  8. Awesome post! I just recently stumbled on leptin so this is a good primer.

    Speaking of squirrels, does anyone know any good recipes for acorns?? I’m kidding.


    Mountain Dew wrote on June 17th, 2010
  9. Intellectually it all makes sense. One question I would have, if someone is Leptin resistant, how long does it take eating an evolutionally (I think I made that word up) correct diet before their hypothalmus reacts normally?

    Steve1907 wrote on June 17th, 2010
  10. Mark,

    Maybe you will be covering this in part 2 of leptin, but curious about your take on ‘cheat days’ when dieting to reset leptin levels. I’ve read a lot about this and have actually cycled fasting (few weeks on one day a week, few weeks constant feeding all week)with some good weight loss results. So, it seems to be working for me. Your thoughts?


    Farley wrote on June 17th, 2010
  11. Thanks for posting my suggestion Mark! Although I’m sure many people wanted to know about this. Much appreciated.

    lovestoclimb wrote on June 17th, 2010
  12. Nice post. I’ve been meaning to read up on leptin. Thanks Mark!

    Mike Alzen wrote on June 17th, 2010
  13. Hi Mark,
    I generally agree with many of your points on leptin. But you should also address that there are several high-fat diet studies that show increase in leptin resistance:
    Can you cite a study on the contrary? Also I know from some private communication that high fat diet also increases satiety in ob/ob mice, so there should be something other than leptin.

    physicistjedi wrote on June 17th, 2010
  14. Obviously it’s common sense that the less you eat the more hungry you will get, but this post really helped me understand WHY I got so hungry when I was in a severe calorie deficit, and why refeeds/rest periods are so important. Thanks for the great post, Mark.

    Tony the Pink Panda wrote on June 17th, 2010
  15. Very helpful post, Mark! Lots of new and useful information. Thanks.

    I’ve spent lots of time wondering why achieving a healthy weight with the SAD and CW diets was so impossible for so many people, myself included. Putting those foods that defeat leptin sensitivity at the base of the USDA food pyramid sets us up for failure!

    slacker wrote on June 17th, 2010
  16. It’s really too bad that the link between dieting and leptin problems isn’t covered more often. Most people can feel when a diet’s starting to become hell. You know, that feeling that World War III is occuring inside of you: you against your body. I say if you start feeling that way it’s a good time for a diet break! Not a junk food break, mind you, but a time to stop worrying about calories and just work on good eating habits.

    Elizabeth wrote on June 17th, 2010
  17. I want the rest of the story! You are leaving us hanging, Mark!

    Emily M. wrote on June 17th, 2010
  18. Nice post, I remember all the body building mags talking about Leptin years ago but nothing panned out (no new supplements that stuck around).

    I just want to comment that I bought the Primal Blueprint a while back and I find it fascinating!

    I thought I knew my stuff but now I realize that I still have a ton to learn. Great work Mark!

    nathan wrote on June 17th, 2010
  19. Nice – I knew high fructose was a culprit in leptin resistance. I assume the symptoms of leptin resistance are excessive eating and constant feelings of hunger? My sibling has eaten around 10 apples a day for the majority of his life so far and he is piling on the pounds and just never stops eating. Is there any way to reverse the effects of leptin resistance? To sensitise an individual who’s hormones have been sent out of whack from excessive fructose and perhaps lectin intake?

    David wrote on June 17th, 2010
  20. Great primer and good timing as fixing hormonal imbalances is my newest personal passion!

    Also, just another reminder/reason to skip the fructose. I’m not missing it most times, and the longer without and the more I learn about it, the easier it is to stay away from.

    Can’t wait for part 2!

    Minxxa wrote on June 17th, 2010
  21. Speaking as someone who has lost a little over 40 pounds in a little over 4 months on a Primal diet (although not anywhere near a perfect Primal diet) I can say that I’ve thought a lot about why this is working for me when nothing else in the last 20 years has.

    When I started I weighed 292 lbs so I think it is safe to say that I was very leptin resistant. And apparently for me at least, it wasn’t that difficult to reverse that resistance even after 20 years.

    As I analyze why this is working for me even though I usually have some form of bread every day (like I said I have plenty of room for improvement in my diet) I’m beginning to zero in on Intermittent Fasting as the best explanation for my success. About 6 weeks in I started doing an 8 hour eating window every day and then one day a week not eating at all. But I was also deliberately varying my calorie intake day to day. Some days I would eat a lot, probably 2500 calories. Other days only 1600 or 800 and, like I said, one day where I ate nothing. I just felt like it would be a good idea to keep my body constantly guessing.

    So even though I am still eating carbs, I keep my fat intake high and focus on getting enough protein so I guess for my genetics I’m still low enough with the carbs that my body stays in fat burning mode a lot of the time.

    So I am curious if the next installment will say something about Intermittent Fasting having something to do with lowering leptin resistance.

    I think this is a great post. Thanks Mark!

    Julie wrote on June 17th, 2010
  22. Mark, does leptin regulate fat stores independent of appetite? In other words, if one is eating a calorie-restricted diet, but not feeling ravenous or deprived, and continuously gaining fat or unable to lose fat, is this likely to be a leptin problem?

    m wrote on June 17th, 2010
  23. Now I know why IF did not work for me.
    I was already only taking in around 1000-1500 calories a day, but felt I was overeating, eating primal seems like I munch all day but in the end it only comes to around 1k-1.5k calories because everything I eat is real food.
    As soon as i stopped skipping breakfast ( i truly wasn’t hungry and had to force myself to take in some food in the morning hours) I lost weight.

    Suvetar wrote on June 17th, 2010
  24. Looking forward to hearing the next post so I can learn how to eat the right food to balance my hormones (though I am sure it goes something like “eat primal!”). Thanks for the great info. Is there any way to test your leptin sensitivity?

    MamaSofi wrote on June 17th, 2010
  25. If you don’t discuss eicosanoid activity, polyunsaturate balance and its effects on SOCS and cortisol, etc I’m going raw vegan. Don’t let me down, Mark!

    Stabby wrote on June 17th, 2010
  26. “That might explain why heavier kids reach puberty earlier than leaner kids”

    Couldn’t one also conclude the opposite? I.e., heavier kids tend to be leptin resistant, leading their bodies to (falsely) believe they are energy deficient, thereby encouraging frugal expenditure of resources?

    Maybe there are two kinds of “heavy” kids- those with a naturally higher bodyweight “setpoint” and those with SAD induced leptin resistance?

    Taylor wrote on June 17th, 2010
  27. Mark,
    Excellent article, and I’m really looking forward to reading more about, “(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.)”


    ryantgrady wrote on June 17th, 2010
  28. it’s all about the hormones!

    sam wrote on June 17th, 2010
  29. Big ups for the bonobo reference. We as a species can learn a lot from those hippies, haha.

    Leptin resistance plays such a key role in fat accumulation it’s a shame more people don’t understand it. Thanks for getting the good work out, Mark.

    Darrin wrote on June 17th, 2010
    • When I was in undergrad, I took an anthropology course. Our prof’s husband was an expert on bonobos and she would get into all these crazy tangents about her husband’s work. For example, they are the only members of the animal kingdom who exchange goods for sex (present company excluded). They also exhibit oral sex and homosexual relationships. I apologize in advance for the visuals.

      Jared wrote on June 18th, 2010
  30. Great post, Mark. The Paleo solution guys talk about Leptin a lot in their podcast (and they give a lot of love to Mark).

    I have found that this system is wholly misunderstood by most people. Now I have somewhere to direct them for a concise, practical explanation. Thanks, Mark!

    I wonder what the high fructose corn syrup folks would think about this!!! Haha

    Jared wrote on June 18th, 2010
  31. Great post as usual Mark!
    I don’t know how you do it, but you continually put out relevent and informative articles. Thanks for all you do.

    Michael wrote on June 18th, 2010
  32. Mark,
    Great post. You provide real-world information with enough technical detail to inform without drowning me in biochemistry. Thanks for all the work you do to provide the latest information available to get and stay healthy!

    GymX wrote on June 18th, 2010
  33. I do think Leptin is an important player in metabolism. However, as this article suggests, hormones are truly a symphony and they all work together and affect each other. What do you think about multiple hormone therapies?

    Robert wrote on June 18th, 2010
  34. Oh man, the follow-up post can’t come soon enough! After spending years (yes, years!) on a very reduced calorie diet trying to lose weight, I had had enough of the “semi-starvation” and a few years back went back to just eating normally (aka eating according to my hunger). It took me 1.5 years to finally have a normal-sized appetite (not having to eat ridiculous amounts of calories to get full). I’m thrilled that I can now eat normal-sized meals and b/c of Primal, can remain satiated for hours. The only thing I’m still dealing with is that when I eat, I get this massive brain fog and HAVE to eat almost right then. It usually happens most significantly in the late afternoon and I can’t usually wait until dinner. I’m hoping something you address in the next post will help!

    Jessica wrote on June 18th, 2010

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