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A Primal Primer: Leptin
Posted By Mark Sisson On June 17, 2010 @ 9:58 am In Carbs,Diet,Weight Loss | 82 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:
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.
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.
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.
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.
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! 
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URL to article: http://www.marksdailyapple.com/leptin/
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 stress we undergo: http://www.marksdailyapple.com/cortisol/
 foods we eat: http://www.marksdailyapple.com/category/smart-fuel/?submit=view
 weights we lift: http://www.marksdailyapple.com/gain-weight-build-muscle/
 sleep we get: http://www.marksdailyapple.com/how-light-affects-our-sleep/
 hypothalamus: http://en.wikipedia.org/wiki/Hypothalamus
 counting calories: http://www.marksdailyapple.com/the-context-of-calories/
 body composition: http://www.marksdailyapple.com/hunter-gatherer-body-composition/
 I’m happy with my body: http://www.marksdailyapple.com/body-composition-how-diet-and-exercise-affect-muscle-mass-and-body-fat/
 grains: http://www.marksdailyapple.com/definitive-guide-grains/
 frequent orgies: http://en.wikipedia.org/wiki/Bonobo#Sexual_social_behavior
 immunity: http://www.ncbi.nlm.nih.gov/pubmed/11037963
 heavier kids reach puberty earlier than leaner kids: http://www.newscientist.com/article/dn11307-childhood-obesity-brings-early-puberty-for-girls.html
 given a diet of 60% fructose for several weeks and then injected with leptin: http://www.ncbi.nlm.nih.gov/pubmed/18703413
 leptin injections reduce energy intake and hunger: http://www.marksdailyapple.com/leptin-fructose-appetite/
 affect the leptin pathway: http://www.ncbi.nlm.nih.gov/pubmed/15111494
 fructose intake: http://www.marksdailyapple.com/fruit-fructose-availability-seasons/
 increases satiety: http://www.marksdailyapple.com/curb-your-appetite-high-fat-diet/
 berries: http://www.marksdailyapple.com/best-fruit-choices/
 wrote about this: http://wholehealthsource.blogspot.com/2008/12/leptin-resistance-and-sugar.html
 thinks: http://www.biomedcentral.com/1472-6823/5/10
 lectins: http://www.marksdailyapple.com/lectins/
 observes: http://www.ncbi.nlm.nih.gov/pubmed/17983356
 established issues most people have with grains: http://www.marksdailyapple.com/why-grains-are-unhealthy/
 Primal law: http://www.marksdailyapple.com/definitive-guide-primal-blueprint/
 inadequate sleep can lead to excessive levels of cortisol: http://www.marksdailyapple.com/the-definitive-guide-to-sleep/
 insulin resistance: http://www.marksdailyapple.com/diabetes/
 weight gain: http://www.marksdailyapple.com/how-stress-can-make-you-fat/
 sleep deprivation has been linked to lowered serum leptin: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC535701/
 Grok on!: http://www.marksdailyapple.com/what-does-it-mean-to-grok-on/
 jjones123497: http://www.flickr.com/photos/51214860@N02/4708972963/
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