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Let me introduce myself. My name is Mark Sisson. I’m 63 years young. I live and work in Malibu, California. In a past life I was a professional marathoner and triathlete. Now my life goal is to help 100 million people get healthy. I started this blog in 2006 to empower people to take full responsibility for their own health and enjoyment of life by investigating, discussing, and critically rethinking everything we’ve assumed to be true about health and wellness...

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June 17, 2010

A Primal Primer: Leptin

By Mark Sisson
167 Comments

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)

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167 Comments on "A Primal Primer: Leptin"

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Ely
Ely
6 years 3 months ago

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.

Primal Toad
6 years 3 months ago

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)

Duncan
Duncan
6 years 3 months ago
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,… Read more »
Buuuuh!
Buuuuh!
3 years 6 months ago

Bah! what a weirdo!!

V Cook
V Cook
4 years 2 months ago

Quinoa is a seed not a grain. Maybe it has the same effect as grains, but it also has protein.

KitKat
KitKat
2 years 7 months ago

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?

SerialSinner
SerialSinner
6 years 3 months ago

Thanks for the great post Mark

Melodious
Melodious
6 years 3 months ago

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?

Jean-Patrick
6 years 3 months ago

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).

Jay
Jay
6 years 3 months ago

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.

Jean-Patrick
6 years 3 months ago

Yes, that’s what I was hinting at.

Buuuuh!
Buuuuh!
3 years 6 months ago

LOL, they are fat because they don’t have to do nothing to get food, you weirdo number 2, hahahaha!

Ely
Ely
6 years 3 months ago

I’ve seen hugely fat squirrels too – they had been eating birdseed, not human food, but perhaps it has a similar impact on them?

Rob
Rob
6 years 3 months ago

I got a squirrel eattin my bird seed…Maybe I have some squirrel stew soon. They love bird seed.

hobos
hobos
6 years 3 months ago

And french fried ‘Taters, mmm hmmmm…

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

kelly
kelly
4 years 7 months ago

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

m
m
6 years 3 months ago

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.

Ashley
Ashley
6 years 3 months ago

Ha! Same here. Do you happen to go to a large public university in Los Angeles?

Kat
Kat
3 years 7 months ago

I had a fat squirrel at UCLA mug me for a cookie once. While I normally love squirrels, that was not a happy time.

Derek
Derek
2 years 1 month ago

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?!”

Jean-Patrick
6 years 3 months ago

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.

Zach
6 years 3 months ago

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.

Jeff
6 years 3 months ago

Finally, some good info on Leptin. And here I thought it was just a brand of tea all along. Oh wait, that was Lipton!

Rodney
Rodney
6 years 3 months ago

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?”

chris
chris
6 years 3 months ago

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.

Mountain Dew
Mountain Dew
6 years 3 months ago

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.

Kinda.

Steve1907
Steve1907
6 years 3 months ago

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?

Farley
Farley
6 years 3 months ago

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?

Thanks,
Farley

BarbeyGirl
6 years 3 months ago

I second the motion.

lovestoclimb
6 years 3 months ago

third

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[…] Original post by Mark Sisson […]

lovestoclimb
lovestoclimb
6 years 3 months ago

Thanks for posting my suggestion Mark! Although I’m sure many people wanted to know about this. Much appreciated.

Mike Alzen
Mike Alzen
6 years 3 months ago

Nice post. I’ve been meaning to read up on leptin. Thanks Mark!

physicistjedi
physicistjedi
6 years 3 months ago

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:
http://scholar.google.com/scholar?hl=en&q=high+fat+diet-induced+obesity+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.

Tony the Pink Panda
6 years 3 months ago

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.

slacker
slacker
6 years 3 months ago

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!

Elizabeth
6 years 3 months ago

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.

Emily M.
Emily M.
6 years 3 months ago

I want the rest of the story! You are leaving us hanging, Mark!

nathan
6 years 3 months ago

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!

David
David
6 years 3 months ago

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?

Minxxa
Minxxa
6 years 3 months ago

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!

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[…] post by Mark Sisson […]

Julie
6 years 3 months ago
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… Read more »
m
m
6 years 3 months ago

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?

Suvetar
Suvetar
6 years 3 months ago

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.

MamaSofi
MamaSofi
6 years 3 months ago

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?

Stabby
Stabby
6 years 3 months ago

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!

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[…] A Primal Primer: Leptin […]

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[…] everything the low-carb/primal/paleo community come up with, I do find MDA talks a lot of sense. What is Leptin? | Mark's Daily Apple Interested to see where Part 2 goes – especially given the way many diets utilise leptin via […]

Taylor
Taylor
6 years 3 months ago

“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?

ryantgrady
ryantgrady
6 years 3 months ago

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.)”

-ryan

sam
6 years 3 months ago

it’s all about the hormones!

Darrin
6 years 3 months ago

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.

Jared
6 years 3 months ago

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
6 years 3 months ago

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

Michael
6 years 3 months ago

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.

trackback

[…] isn’t enough for everyone, though. To go back to yesterday’s “hormones as software” analogy, some people are hackers who relish digging deep into the fine print of software manuals discussing […]

GymX
GymX
6 years 3 months ago

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!
Jim

Robert
Robert
6 years 3 months ago

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?

http://www.kerentech.com/?p=4219

Jessica
Jessica
6 years 3 months ago
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,… Read more »
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[…] A Primal Primer – Leptin – Marks’ Daily Apple […]

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[…] isn’t enough for everyone, though. To go back to yesterday’s “hormones as software” analogy, some people are hackers who relish digging deep into the fine print of software manuals discussing […]

Mr. T
Mr. T
6 years 3 months ago

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?

joey
joey
5 years 7 months ago

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.

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[…] the Primal Blueprint 101 page. Thanks for visiting!I mentioned a few of the working hypotheses for avoiding leptin resistance in my posts last week, including fructose and lectin avoidance, getting adequate nightly sleep, and […]

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[…] mentioned a few of the working hypotheses for avoiding leptin resistance in my posts last week, including fructose and lectin avoidance, getting adequate nightly sleep, and […]

Peachy
Peachy
6 years 3 months ago

Another fantastic, interesting and informative post. Thank you, thank you, thank you. Now – to part 2!!!

trackback

[…] you have available, you can do it the same way you manipulate other hormones, like insulin, leptin, growth hormone, and cortisol. You tinker with your diet, your exercise, and your basic daily […]

Tyler
Tyler
6 years 3 months ago

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…..

Jared
6 years 3 months ago

Wisconsite here, as well (Go Badgers!) and I would say we have the same problem with many of our people…hmmmmm

Dan
6 years 3 months ago

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.

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[…] about the Primal Lifestyle by visiting the Primal Blueprint 101 page. Thanks for visiting!In my leptin series a few weeks ago, I hashed out how dietary choices direct leptin levels – as well as leptin […]

floppyk2011
5 years 8 months ago

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