Leptin, low-carb and hunger

The drug rimonabant (Acomplia) that failed to pass muster with the FDA panel last week works by blocking some of the hunger receptors in the brain. In other words, those who take the drug – assuming it works as touted – will be less hungry. Less hunger means less food consumption. Less food consumption typically results in weight loss. So, if you take rimonabant, assuming you don’t become suicidal and do yourself in (the big worry of the FDA panel since the major side effects are varying degrees of psychoses), you should lose some weight. But there is a better, cheaper way.

The low-carbohydrate diet working through the hormone leptin reduces hunger much more than rimonabant on its best day. And without the risk of serious side effects. And without the $250 per month for the drug.

Before we get into the explanation as to how the low-carb diet works to reduce hunger, we need to define a couple of terms that may not be familiar to all: the blood brain barrier and leptin.

First, the blood brain barrier (BBB). The BBB is a ‘barrier’ between the exquisitely sensitive cells of the brain and any chemicals or harmful substances in the blood. This barrier is composed of tightly joined cells lining the capillaries that carry blood throughout the brain. The tight ‘packing’ of these cells prevents the passage of chemicals, drugs, and other substances that might have an adverse effect on the brain. Drugs made to work in the brain have to be structured in such a way as to permit their passage from the blood through the BBB into the brain.

Leptin is a hormone made by fat cells. When there are a lot of fat cells they secrete a lot of leptin. What does leptin do? It seems that every day a new function for leptin is postulated, but for our purposes now, let’s stick with what most scientists consider the primary function of leptin: regulation of the fat mass by regulating hunger.

Leptin acts almost like the gas gauge on a car. As you drive your car, sensors in the gas tank monitor the level of the gasoline (fuel) in the tank and send signals to a gauge on your dashboard. When the fuel gauge on your dashboard starts to signal that your tank is close to empty, you start looking for a gas station.

When your fat cells are full, they send a signal (leptin) to your brain that says, ‘Hey, we’re full, shut off the food.’ After a period of no eating because you’re not hungry, your fat cells start to get a little smaller. As they do, they produce less leptin. Less leptin hitting your brain tells it you need to fill up the fat cells, the brain responds by increasing your hunger. You eat, the fat cells fill up, they send more leptin, the brain shuts off your hunger.

That’s the way it works in a perfect world. That’s the way it worked in our Paleolithic past. But, unfortunately, that’s not always how it works now. If it did, no one would be obese. But, we’re in the throes of an obesity epidemic, so something is clearly wrong with this picture. Have all these obese people quit making leptin?

No, far from it. Obese people make a large amount of leptin, way more than non-obese people in fact, but they are resistant to the effects of their own leptin in much the same way they’re resistant to the effects of their own insulin.

Before we go into the whys and wherefores of all this, I want to digress for a moment to show you just how potent leptin is. Let me start by telling you about how leptin was discovered. The discovery of leptin came about as the result of a search for the cause of obesity in a mutant strain of mice that had been around for years. By comparing these mice with normal mice, researchers at Rockefeller University isolated a substance they called leptin (from the Greek word meaning thin: leptos) as being a hormone that the obese mice were not producing. A mouse from this line, called an Ob mouse – or technically Ob/Ob, meaning that it lacks the leptin genes on both chromosomes – produces no leptin in its fat cells. As a consequence it never gets the ‘don’t eat’ signal, so it eats all the time and becomes obese. Hugely so. Way more than just a typical mouse that is over fed. In fact, here are some pictures to show you the magnitude of the obesity.

fatmouse.jpg

obese_mice.jpgIf you give these Ob mice leptin, they lose weight, or if you give it early enough, they don’t gain and are like their non-Ob mice brethren.

As you might imagine, this discovery caused quite a stir. For a brief moment everyone thought the magic bullet for obesity had been found. All we have to do is give fat folks leptin, and, Voila!, they get thin. Problem was that when researchers started checking, they discovered that obese people had plenty of leptin and that giving them more didn’t particularly help things. So another great weight-loss idea bit the dirt. But no one lost interest in leptin and there is still a huge amount of leptin research underway all over the world.

Leptin is an enormously powerful substance in the regulation of the size of the fat mass. Especially when it doesn’t exist. Just as there are Ob mice with no leptin, there are Ob people who make no leptin. These people get more and more obese to the point of grotesqueness, and, fortunately for them, the administration of leptin does indeed work to reduce their size.

To demonstrate the power of the lack of this hormone, I want to show you a video of a little girl whom I’m pretty sure is leptin deficient. Nothing much else could account for this situation. Maybe a pituitary tumor, but I doubt it. I don’t know if she is leptin deficient, but I would bet a fair amount of money that she is. In any case, this is what kids with a leptin deficiency look like.

As you can see, leptin is quite powerful, at least in its absence. It’s also powerful when present, but not in such dramatic fashion. When leptin is doing its job, the result is normalcy.

How does it all work to keep things normal?

Here is a graphic from a recent paper on leptin showing the leptin-feedback cycle in technical terms. Take a look, then we’ll go through it in non-technical terms.

leptin-cycle.jpeg
The Arcuate Nucleus is a part of the hypothalamus, which is the part of the brain involved with appetite regulation.

The Leptin Receptor is the protein structure in the Arcuate Nucleus that leptin binds to allowing leptin to exert its effect.

The pinkish/red tube represents a capillary in the brain tightly packed with the epithelial cells making up the BBB.

Here’s how it all works:

The fat mass – the stored fat on the body – produces leptin, which is secreted into the blood in the circulatory system. When leptin reaches the capillaries (the tiniest blood vessels) in the brain, leptin makes its way across the BBB and into the fluid around the brain cells where it binds to the leptin receptors on the arcuate nucleus of the hypothalamus. The arcuate nucleus then sends signals to decrease food consumption and increase metabolic rate.

As the fat mass decreases in size -as it does when you don’t eat for a while and the stored fat is burned for energy – the amount of leptin in the circulation decreases as well. Less leptin crosses the BBB, less binds to the leptin receptors, and the arcuate nucleus sends out the ‘It’s time to eat’ signal. You eat and replenish the fat mass, leptin goes up, and the cycle starts again.

So as leptin levels wax and wane, so does your sense of hunger and even, to an extent, your metabolic rate.

Where does the low-carb diet fit into the picture?

There is a critical point in the cycle described above. That critical point is when the leptin crosses the BBB. If the leptin can’t get across the BBB, it can’t get to the brain. If it doesn’t get to the brain, it doesn’t shut off the hunger response irrespective of how much is circulating in the blood.

Most obese people find themselves in this very situation: high blood levels of leptin but still hungry. And eating makes more fat, which makes more leptin, which should shut off the hunger response, but it doesn’t because the ever increasing levels of leptin telling the brain to tell the obese person to quit eating don’t get to the brain to do their job.

Why not?

Research done a couple of years ago in St. Louis and in Japan pinpointed the problem. Triglycerides – fat circulating in the blood – interrupts the passage of leptin across the BBB. If trigylcerides are high, which they are in most obese people, then, basically, they block the movement of leptin into the brain. So, leptin levels are elevated in the blood, and triglycerides keep the leptin from getting to where it needs to get to shut off hunger. (click here for the abstract and full text of this research paper.)

We all know that the commonest lab finding in people following a low-carb diet is a dramatic reduction in triglyceride levels. This reduction in triglycerides allows the leptin that is already circulating in relatively large amounts to get through to the brain where it can reduce hunger. I believe that this reduction in triglycerides (which happens fairly quickly) is the primary reason that people substantially decrease their hunger on low-carb diets. And remember from the graphic above that leptin – once it gets to the brain – actually increases thermogenesis as well, which means that the metabolic rate increases.

So, the triglyceride reduction from following a low-carb diet does does double duty when more leptin gets to the brain: hunger goes down and metabolic rate goes up. That duo increases weight loss. Is it any wonder that low-carb diets virtually always manhandle low-fat diets in terms of weight loss in all of the studies in which they are compared? And it it any wonder that when people are allowed to eat an ad lib low-carb diet, they always consume fewer calories than those consuming an ad lib low-fat/high-carbohydrate diet?

Carbohydrates cause triglycerides to increase. All of Dr. Dean Ornish’s studies have shown that subjects following his ultra-low-fat/extremely-high-carbohydrate diet find their triglycerides screaming upward. It’s no wonder that most people have difficulty sticking on his diet or any low-fat/high-carb diet for very long without a lot of hand holding, behavioral therapy, meditation and the rest of his total program. People following these Ornish-like nutritional regimens are sabotaged by the elevated triglycerides that these diets cause. Consequently, they are always hungry. And sooner or later, they give in to their hunger.

Why spend $250 per month on a pill that has a high probability of producing untoward reactions to reduce hunger a little bit when you can simply convert to a low-carb diet and get a more substantial hunger reduction along with an increase in metabolism to boot?

Please note: I reserve the right to delete comments that are offensive or off-topic.

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62 thoughts on “Leptin, low-carb and hunger

  1. Hi Mike,

    I’m a medical student and I’ve been reading your posts for a few months. I just want to thank you for the fascinating information you’re bringing forward.

    Paul

    Thanks, Paul.

    I’m glad you’re enjoying them.

    Best–

    MRE 

  2. Hi Mike,

    I have been on a low carb diet for the better part of 3 years now and know that I do better health wise but I have NEVER experienced this reduction in appetite that most others speak of. Even on low carb (and I am anal about what I put in my mouth, I have been studying low carb and nutrition for years) if I eat until I am full (not stuffed) I either maintain or slowly gain wait. I must have hunger present in order to lose weight and must be vigilant about portion size to maintain. I am not petite but I am active. Is this common? Does this mean that I am still having issues with Leptin? I am sure that I am not the only wondering this after reading this post…

    Jennifer

    Hi Jennifer–

    There are other components to the hunger response in addition to leptin.  Blood sugar, for one.  A rapidly falling blood sugar is a powerful, powerful stimulus to eat.  That’s another reason a low-carb diet works so well to prevent hunger in most people.  Low-carb dieters must make a portion of the blood sugar they need from protein, which means they don’t have the roller-coaster ups and downs experienced by those on high-carb diets.

    Over the years, I’ve discovered that most people who have difficulty maintaining their weight on low-carb diets are eating more carbs than they should be.  This happens to me all the time.  I’ll find my own weight creeping up, and when I do, I start cutting carbs to the bone, and down goes my weight.  Eating a piece of bread hear, a half a dinner roll there, etc. etc. and it adds up.  I’m not saying this is what you do, I’m simply saying that in my experience with myself and a whole lot of patients, this is the most common problem.

    Cheers–

    MRE 

  3. Excellent article, sir.

    Not only is that extremely informative in a not talked about area of low-carb dieting, it is also very well written.

    Thank you!

    I’m glad you enjoyed it.

    MRE

  4. Is it generally accepted that triglycerides interfere with leptin crossing the BBB?

    My understanding is that it is accepted that high carb intake causes high triglycerides, but only refined and simple carbs.

    So…they could put 2 and 2 together, but my guess is they’ll continue to push low fat high carb. Even tho the solution is right before their eyes, they will continue to ignore the evidence.

    Hi Cindy–

    Based on the data in the paper I linked to and others, the idea that triglycerides interfere with leptin crossing the BBB is well accepted.

    All carbs raise triglyceride levels, not just refined and simple ones.  In the two studies published by Dean Ornish the subjects who were on his diet, which is not particularly high in refined or simple carbs, but very high in carbs in general, showed dramatic increases in their triglyceride levels.

    And, it’s true, they could put 2 and 2 together, but they don’t very often.

    Cheers–

    MRE 

  5. Hi Mike–another great post. I definitely find that my meals stay with me longer when I’m on a low-carb diet–but not that much longer. If I eat cereal or oatmeal for breakfast I’m hungry 2 hrs. later. Usual breakfast now is 1/2 apple or 1/2 orange and a cheese omelet cooked in butter, which stays with me for about 3-4 hours. I’m wondering whether, if I cut out the fruit and substitute bacon or sausage, I’ll be satisfied for a longer time. I usually eat 5-6 meals per day, even on low carb, and just can’t understand how people who eat 2-3 meals per day aren’t always hungry.

    Hi Paul–

    You could try switching to bacon and sausage.  It works for me.

    There are other components to the hunger system besides leptin.  Leptin is just one, albeit an important one.

    Cheers–

    MRE 

    • Yes, removing the fruit and adding the meat WILL keep you satiated longer. That’s why I eat a ZERO carb (meat, eggs, and water ONLY) diet. I started with LCHF/Keto, and I found I was always hungry and still having carb/sweet cravings. ZC solved those issues. Many days I’ll only eat twice a day. I eat large amounts of meat only at each meal, and I’ve maintained my 130 Lb. (5’7″) weight without effort or exercising. To the best of my estimations (I don’t track-don’t need to) my calorie consumption is around 2000-2300 per day! In my low fat/high carb days I would have GAINED weight if I ate over a mere 1700 calories.

  6. And I guess it follows that with weight (body fat) loss, less leptin is produced, the metabolism plateaus, which perhaps would account for weight loss stalling at certain points, or the last few pounds taking the longest to come off.

    Anna

    Hi Anna–

    I think you’re on the money.

    Cheers–

    MRE 

  7. You’ve outdone yourself in explaining a complex phenomenon in simple terms. Very good article!

    I have one question. You say that when fat tissues are burned for energy (ketosis is the longer-term process, I guess), levels of leptin decrease.

    Why then does the level of leptin in the blood stay high in low-carbers? Is dietary fat also releasing leptin?

    Thanks Doc

    No, dietary fat doesn’t release leptin.  Your own fat cells make and secrete leptin.  Even if you’re at a lower body fat percentage, say 15%, and you weigh 160 pounds, you will have 24 pounds of fat making and secreting leptin, which is plenty.

    Cheers–

    MRE

  8. Thank you for the explanation. Is that why I feel more hungry when my body fat levels get lower? It seems to happen if they get down to about 20%.

    If you are a female, and I assume from your name that you are, then 20% body fat is about optimal.  Maybe it’s the decreased levels of leptin at that point or it could be one of a number of other factors.

    Best–

    MRE 

  9. My non-constructive post of the day:

    That obese mouse is really cute and would make a great stress ball.

    I suppose, as long as it didn’t try to eat your hand.

    Cheers–

    MRE 

  10. Nice, nice nice.

    From the capitalistic point of view, if triglycerides are the problem, perhaps some Sci-Fi style nanotech scrubber for the TriG would work nicely in a pharmaceutical intervention, especially if the obese make more leptin anyway. Not saying that the diet doesn’t work (it clearly does), but some folks are just destined to look for a magic bullet and some folks are determined to sell it to them.

    Curious also: Since Hoodia and HCG both seem to lower appetite, is it possible that they lower triG and allow flow of leptin? I seriously doubt if this has been studied, but might be an avenue for research.

    Hi Max–

    Someone beat you to it.  There are already drugs out there that lower triglycerides – Lopid, for one.  But I don’t know if they result in weight loss or not.  But I don’t much think so.  And I don’t know that these drugs lower triglycerides to the levels that low-carb diets do.  In fact, I think not.  So, probably just a little lowering doesn’t help much.

    I don’t know the answer to the HCG/Hoodia question.  My guess is that both increase metabolic rate a little.

    Cheers–

    MRE 

  11. Wow. What a clear and fascinating explanation for why LC works! Actually, after being stalled for four or five weeks, I was contemplating switching from Atkins to WW to give my metabolism a little kick. You’ve just convinced me that this would be very unwise — and explained to me exactly why I don’t experience out-of-control cravings when eating this way. Thanks so much! I’m bookmarking this so I can re-read it to the point where I can explain it to others.

    Hi Emma–

    I’m glad you enjoyed it.

    Cheers–

    MRE 

  12. Dear Mike,

    but does the leptin study correlate with thought-to-be favorable effects of intermittent fasting, as far as judging from leptin feedback cycle, it actually follows that prolonged lack of eating shall bring about continuous hunger (apparently muffled for IF veterans) and, what’s more, overstimulation of the Arcuate Nucleus.

    Will you please clarify (read: allay my fears)?

    Hi Aine–

    I’ll try to allay them.  Fasting, i.e., going without food for short periods of time, decreases triglyceride levels, which bring about an increased transport of leptin to the brain where it decreases hunger.  Starvation, on the other hand, increases triglycerides and blunts the effects of leptin.  People who IF are fasting, not starving, so, if anything, their hunger response decreases because of their substantially decreased triglyceride levels.

    Hope your fears are allayed.

    Cheers–

    MRE 

  13. This is an awesome article. After LC,LF for weeks, lost more , content, feel better, (Not like a sausage), and more energy than any eating plan with carbs. How is the poor girl making out, I wonder.
    As a nurse, I see obesity, and have my self, lived it, when over weight the carbs create a continuous horrible circle.
    Thank you so much for this, I will read more.
    What are your feelings of how the LC method of eating can effect (or not) some ones cholesterol etc ?

    Hi DLC–

    Type ‘cholesterol’ or ‘lipid’ or ‘lipid hypothesis’ in the search engine space for this blog, and you’ll find more than you probably ever wanted to know about my feelings on cholesterol and the low-carb diet.

    Cheers–

    MRE 

  14. thanks for the paul pottsian blast of clarity!

    btw, does booze raise triglycerides? I’m always a little extra hungry the day after an over-indulgence, I wondering if that’s due to this triglycerides-leptin thing?

    Hi mrfreddy–

    The idea that alcohol raises triglyceride levels is far from established.  Here is a link that gives a few references you might want to track down if you’re interested.

    Cheers–

    MRE 

  15. Dr. Mike, How about the effect of alcohol on testosterone levels? I’ve read that alcohol consumption lowers T-levels in the fitness/bodybuilding sites. Thank you for the great work you do. Any thought on publishing PPLP in Spanish? –Carlos

    Hi Carlos–

    I don’t know for sure without delving into it more, but I would suspect that alcohol causes an increase in testosterone-binding protein, which means that more testosterone is bound in an inactive form.

    No interest yet in Spanish publication of the PPLP.  Get a Spanish publisher interested, and I’m sure my publisher would love to hear from them.

    Cheers–

    MRE 

  16. Hi Mike,

    Excellent post. I just wanted to add, that there is variation within brain receptors to leptin and some individuals have leptin resistance similar to insulin resistance.

    Here is a URL that may be of interest, I though it was quite amusing.

    http://www.amazon.co.uk/gp/reader/1580401716/ref=sib_dp_pt/203-7566453-8409550#reader-link

    Why does the ADA just not get it! Stay on this diet and indeed if you are a diabetic soon you will have less of a functioning brain!

    Best,

    Tahir.

    Hi Tahir–

    You are right about the leptin resistance.  I’m not sure how much of it is at the receptor level and how much at the BBB, though.

    Great picture.  Thanks for posting.  And you’re on the money about the less functioning brain.  I wonder if they noticed?
    Cheers–

    MRE

  17. Have you seen this? Insulin resistance and elevated triglyceride in muscle: more important for survival than ‘thrifty’ genes?

    There seems to be more to it than my comprehension can grasp, but I think it says this: intramuscular triglycerides increase insulin resistance in muscles so that glucose is spared for the brain and other cells that need it. When muscles take up glucose from the blood, does that necessarily mean lower triglycerides in the blood, or is the level in the blood maintained by another factor? (You already mentioned that starvation increases it.) It makes sense that when muscles have energy on hand (the triglycerides), people would benefit by being less motivated by hunger to hunt food down, and that starvation would increase hunger.

    Hi Carly–

    Yep, I’ve seen the article.  I almost posted on it when it came out.

    In fact, after rereading it, I’m inspired to post on it again.

    Fat within the muscle cells produces insulin resistance at the level of the muscle…except for highly trained athletes, who have a lot of stored fat but not the insulin resistance.  The paper speculates as to why that should be the case.

    Cheers–

    MRE 

  18. Excellent article, Dr. Mike! And the video of that dear little child (yes, she is, after all, just a little child) is enough to keep me on the straight and narrow, in my own quest to lose about 100 pounds.
    I have been back on the LC program for 3 and a half months, have lost 21 pounds, but I can’t seem to get past the fatigue hump, which seems to be getting worse. I’ve increased my potassium substantially, (veggies and NoSalt) eat no dairy or prepared foods of any sort, just proteins, (mostly free range), veggies,(lots), eggs, LC fruits, nuts, plenty of good fats. (Recent blood work was all normal except for slightly elevated aldosterone.) My question is, should the level of carbs. be calculated as an absolute, or percentage of calories consumed? I’m petite with a very slow metabolism, so I have to slash my calories to lose weight at all, even on a good LC diet. I’m always in mild to moderate ketosis in the morning. Could it be that I need to increase my carbs substantially to address the severe fatigue problem? My exercise is moderate- half an hour walk with the dogs, and 20 minutes on the stair stepper or the rebounder, at a slow pace. I’m too weak to do anything more than that.
    Thanks for your wonderful blog and informative article. Keep up the great work!
    Madeline Mason

    Hi Madeline–

    We always calculate carbs for ourselves and our patients as absolute grams, not percentages of intake.

    It’s beyond the scope of this blog to give specific medical advice in a situation such as yours.  In our practice we always put our patients on a potassium supplement to replace the potassium lost during the first phase of a low-carb diet.  A low potassium level is a frequent cause of fatigue. Simply increasing veggies and adding a little NoSalt generally doesn’t do the trick.  You might discuss with your physician the possibility of a potassium supplement for a couple of weeks.

    Best–

    MRE 

  19. Dr Mike,

    Great article!

    One of the hormone manipulation tricks CKDers employ is the “resetting of leptin levels” by weekend refeeds with lots of carbs. They claim that once a person gets down to a low body fat percentage, they hit a plateau and cannot continue losing body fat.

    When one has less body fat to burn, do leptin levels decrease to the point of metabolism slowing down, and those last few pounds to lose just sticking like glue? If one refeeds with carbs, would that not raise triglycerides to the point they will interrupt the passage of leptin across the BBB? And, if this is the case, would refeeds with more calories, instead of carbs, help accomplish the same goal of “resetting leptin levels”?

    Any light you can shed on this would be greatly appreciated.

    Thanks for this wonderful article.

    BTW… I’ve been eating close to zero carb for sometime now, and have no appetite at all. I have to remind/force myself to eat enough. Years ago, on a high carb/very low fat diet, I was constantly hungry!

    Dean

    Hi Dean–

    Thanks for the interesting feedback.

    Cheers–

    MRE

  20. First – another truly wonderful wonderful post!
    Second – Í’ve been on LC for the past one and a half year and I do find that I don’t get the hunger pangs with trembling hands and weak knees that I use to get. With a solid LC breakfast I can still go for a full jog at the end of the day (4 miles).
    Question – nowadays I seem to get better at holding my alchohol down. Use to be 2 cans of beer and I’m out. Does this have anything to do with me doing LC and the production of ketones which also produce an alchohol like substance as mentioned in your earlier post?

    Hi antnagir–

    I guess the short answer is that I don’t know.  I’ve had a number of people – myself included – who seem to be able to better tolerate alcohol since starting low-carb, but I’m not sure of the mechanism.

    Cheers–

    MRE 

  21. Hi, Mike,

    Appreciate your prompt feedback.

    Since time is fungible, I’d love to make clear: you conceive 24 hrs by short and optimum period for fasting, right? If so, does it mean then that people who fast for 3-10 days occasionally throw themselves into deep starvation wearing out their petite hypothalamus with futile ‘heeeey, down there, it’s time-to-eat’ cries?

    Hi Aine–

    At this point in the IF arena no one really knows what is optimal.  There just hasn’t been enough work yet to determine the optimal interval.  People who fast for a few days don’t really get into deep starvation mode, but would be pushing it by 10 days I would imagine.

    Cheers–

    MRE 

  22. Dr. Mike –

    People on different LC forums have reported that the day before a large weight loss (known as a “woosh”), they tend to be very hungry. Could this link between triglycerides and leptin explain that? Does losing body fat raise tryglycerides? I have heard that actively losing weight can temporarily raise your LDLs and triglycerides but don’t know if it is true.

    Thanks.

    Hi Ryan–

    It’s iffy.  Fasting and low-carb dioeting reduce triglycerides.  Long term starvation raises them.

    Cheers–

    MRE 

  23. This explanation clears up so much for me in understanding one link in the whys and wherefores of LC appetite suppression. I had only a vague notion about “circulating” fats and ketosis and the beauty of appetite suppression before reading this. Thank you for helping us understand the science behind our diets.

    I’m glad you enjoyed it.

    MRE 

  24. I really enjoyed this, thank you…

    Triglycerides preventing leptin from crossing the BBB, a possible cause of garden variety obesity? Interesting… wouldn’t we observed a correlation between triglyceride level and perceptions of satiety (assuming leptin level kept constant)?

    Also, I had read that common obesity involves an acquired, somewhat reversible insensitivity to leptin. That is, when leptin levels begin to increase int he person predisposed to obesity (as a result of stimulating insulin, gaining fat, both of which independently make leptin)… the leptin receptors dull off. Possibly this may be a major component of the “famine” or “thrifty gene” (but that’s another discussion). Point is: controlling insulin controls leptin controls obesity.

    Also, one minor criticism: I really think you should emphasize the metabolic effects of leptin, as opposed to the effect on appetite & food intake behaviors. I appreciate that you “dumbed down” leptin so people reading wouldn’t get fouled up in details… but, leptin is a lot more important than an appetite suppressant (or, even an appetite/fat mass regulator). Leptin (or lack of it) mediates the whole starvation response, actually. If we took a leptin deficient human (say, someone who lost massive amounts of weight 😉 )… even if they managed to restrict their food intake sustained (fighting daily hunger), their physiology would be markedly different from a person who was not leptin-deficient but eating equal amounts.
    1) They would weigh more, with higher fat mass.
    2) They would have a state of functional hypothyroidism (less active thyroid hormone, slower metabolic rate, with symptoms of hypothyroidism)
    3) They would perceive cold abnormally (hypersensitive), because of reduced thermogenesis.
    4) Their vitals would be borderline abnormal (very low heart rate, BP, and respirations)… partially due to the hypothyroidism, but also because of how leptin directly regulates ventilation in the brain.
    5) They would have reduced fertility, possibly being totally infertile/amenorrhetic (suppressed GnRH, abnormal cortisol, LH amp reduced, LH sensitivity reduced, sex steroids bound).
    6)They would have a poorer response to glucose challenge, as leptin is essential for normal glucose tolerance through a lot of different mechanisms.

    I have a point, I promise, I’m getting to it :).

    My point is this: the fact is leptin works pretty much normally if one is controlling insulin, and has not changed their weight or food intake.
    Actually, leptin is most relevant in marginal weight / food intake states, or after extreme weight changes… because it is then when leptin starts to crap out on us, because we stop making enough to keep our physiology working the way we like it (equal to undieted people with no history of obesity).
    Organic leptin deficiency/insensitivity is just not that common… it is not as socially relevant as leptin deficiency in reduced body weight/food intake (i.e. dieting).

    My theory is that the relative leptin deficiency which occurs post weight loss in extreme obesity is a major reason people fail to maintain the weight loss they worked so hard to obtain. Besides hunger (especially for fatty/sugary foods)… there is all the changes in how the body functions listed above.

    … and, so often we look to psychology, or willpower, as to why people fail to keep off weight. Blame, truthfully. But, I think obesity involves some kind of acquired leptin resistance (possibly secondary to insulin resistance)… and, once you’ve achieved/maintained a certain level of obesity, the condition is semi-permanent (that is, weight level is increased as the body requires more fat mass to stimulate enough leptin to tell the brain “hey, our weight and nutrition is groovy”.)

    It’s not that people CAN’T fight off the weight, white knuckle through the relative leptin deficiency…
    … it’s just that few can do it long term, because facts are facts: hunger sucks, being cold and lethargic sucks. The simple fact is, when you are maintaining some “goal weight” after beings uper morbidly obese, some degree of hunger and metabolic conservation is just the facts.

    Oh right, that point I was getting to :)
    My point is, leptin is a lot more than eating less.

    I think in the future, we will have a greater understanding as to why permanent weight loss is hard, for very physically real reasons, and those are related to changes in leptin associated with reducing carbohydrate, insulin, and body weight… ironically, the conditions which cause the weight loss, also cause the weight REGAIN.

    When obesity occurs, leptin levels increase abnormally, leptin resistance occurs, “set point” (for lack of a better term) increases, and “starvation symptoms” occur when weight is forced/altered from this favored spot (which may be obese, sometimes significantly so).

    Once doctors appreciate the crucial role of leptin in regulating body weight (and, that not all bodies necessarily view normal weight as normal, especially people who have become significantly obese…)
    … then maybe we can actually make a difference in curing, if not controlling obesity.

    Leptin doesn’t help people lose weight, so no miracle weight loss drug there.
    However, I would be willing to bet it sure as heck helps them to keep it off.
    I wish some doctor would be willing to try this with one of their patients who has lost massive amounts of weight…

    As I see it, having someone like me maintain weight without supplementing leptin (high weight 280, present weight 122, height 5’5.5)… it’s a bit cruel, kinda like denying morphine to a cancer patient eh? I mean I could do it without it, and I have for 4 years, but my fingernails probably wouldn’t be blue right now… and, I probably would get my period back, and… well, my body would work not as if it were at the margins of nutrition (effectively underweight), but if I were actually at a normal body weight for my height (which I AM, my brain/body just disagree!

    Hi ItsLikeWoo–

    You are right that leptin has multiple actions besides simply regulating hunger as I emphasized in this post.  And there are many other substances that play a role in the hunger response.

    I suspect that you’re also correct that a kind of screwed up leptin response is at the heart of much weight regain.  It would be interesting to put subjects who have lost large amounts of weight on leptin to see if it would help during maintenance.  I don’t know the answer to that question, but I would bet that it would.

    Are you following a low-carb diet as your maintenance diet?  If not, I would heartily recommend it.

    Cheers–

    MRE 

  25. Greetings Doctor and thank you for such an eye opening report on Leptin.

    My question is: What is the difference between the fat you eat and the fat in your belly? I don’t understand exactly why it is acceptable to eat fat.

    My second question. If I eat

    B: 2 eggs and 2-3 bacon
    L: 1 Chicken thigh or 2 legs or 3 winglets
    D: 1 protein shake

    Am I eating enough? I am a 56 year old female, weight 166 and want to get to around 150. I am 5′ 7″.

    Thank you ~ Patsy

    Hi Patsy–

    It depends on how much protein is in the protein shake. Other than the shake it looks like you’re getting about 40 grams of protein in the eggs, bacon and chicken, which probably isn’t enough all by itself. I don’t know how large you are, but you can go to the website, go on the forum, and someone will help you come up with your protein requirements.

    I’ve written entire books on why it’s okay to eat fat, so that discussion is beyond the scope of what can be dealt with in a comment. Read some of the archived posts – there is plenty of info there.

    Cheers–

    MRE

  26. Dr.,

    You say that high triglycerides prevent leptin signals from doing their job. I am currently
    on a high-fat (80%) very low-carb diet and am struggling with extreme hunger. (As I did on low-cal diets as well. Could the triglycerides in my dietary fat be doing this if, say, I am already leptin resistant?

    Most people I know notice a serious decrease in appetite, but mine is alway raging.

    Mollie

    Hi Mollie–

    I doubt that this is the problem.  Most high-fat, low-carb diets actually reduce serum triglyceride levels, not increase them.  The nice thing about a very low-carb, high-fat diet is that when you have hunger, you can eat to quell the hunger as long as what you eat is low-carb.

    Cheers–

    MRE 

  27. Poor little girl. The mouse practically brought tears to my eyes; so terrible to see the child. I hope it wont be a life sentence for her and her treatment works.
    H

  28. Dr. Eades,

    I have been reading many of your posts lately, you have some great information on this site. I have been reading a number of low-carb diets, such as the anabolic diet (& metabolic diet), atkins, and other moderate carb diets. As I understand it, when following a low-carb diet in addition to weight-lifting, there should be >36hr carb-reloading time-periods. As I have read, they do not sabotage the diet since the carbs go directly to empty glycogen stores, instead of being converted to and stored as fat, meanwhile the body continues to burn fat for energy. Also, as I have read, leptin is very responsive to carbs and after about 5 days of low-carbing, leptin levels drop 50%. Since leptin is the anti-starvation hormone (and thus prevents extreme energy/fat storing), the carb-reloading day seems important to reset the decreasing leptin levels, let the body know it is not starving and continue to burn fat at the original pace.

    What are your thoughts on carb-reloading days?

    Thanks

    Hi David–

    I’m of two minds about carb loading. I need to think about it a little more and do a little more literature research before I make a public statement.

    MRE

  29. I am so glad I found this web sight!!!!! It is so insightful!!!!! I am reading about protein and the amount needed. I understand that you should have 1 gram of protein pound of body weight. Is this true? and will this bring about a weight loss if I then lower my carbs along with this ratio? Will the supplement L-Carnitine aid in the building of muscles along with the protein and cause me to lose or gain weight.

    Hi Dana–

    We usually recommend anywhere from 0.6 gm to 1 gm of protein per pound of lean body mass, not total body weight. If you take in the required amount of good quality protein and keep your carbs below about 30 grams per day, you should lose weight fairly easily. And the L-carnitine should help.

    Cheers–

    MRE

  30. Dr. Mike:

    Have you had any further thoughts (since the September 7 post above) or conclusions regarding “carb cycling”, “re-feeding” or “carb loading”? It seems to me to possibly be the final missing piece of a low carb lifestyle but I can’t seem to find anyone outside the body building community that endorse it as a practice.

    BTW, occasional cycling seems to work for me. I either continue to lose weight, or, do not gain weight, after a day or two of higher carb intake. The amount of heat my body generates from the carbs is remarkable too.

    Today I am going to start cycling every 12 days. This translates to every other weekend which would be great socially when dining with friends or family.

    Any thoughts would be appreciated.
    Thanks

    I haven’t had many further thoughts, but there is a new book out that discusses the subject from a hard research perspective. The TNT Diet was written by Jeff Volek and Adam Campbell. Jeff is without doubt the leading low-carb researcher working today; Adam is the editor of Men’s Health magazine. I plan on a fuller review of the book in a later post, but I can tell you that it is terrific. It’s written from a male prospective for men to follow, and I can assure you that any recommendations have been fully tested by Jeff iin the lab. And on himself because Jeff is a bodybuilder. Pick it up and take a look.

    Cheers–

    MRE

  31. Here is what the AHA says:

    “People with high triglycerides may need to substitute monounsaturated and polyunsaturated fats —such as those found in canola oil, olive oil or liquid margarine — for saturated fats. ”

    They just won’t say too many carbohydrates, only too many calories and or saturated fats are the main concern for most people.

  32. If a morbidly obese person is eating gobs of carbs, mostly refined, and is hungry all the time with undiagnosed diabetes, how could this person have triglycerides under 150?

    Hard to figure.

  33. what do you think of carbohydrate cycling? I just started doing it and lost 11lbs what I do is 3 day low-carb, 4th day higher carb. On the low-carb days I limit my carb intake to 20 NET carbs and on the higher carb day is 100 Net carbs. In doing this it will keep your metabolism from dropping. the carbs i eat on low days are fibrous veggies and on hi days i eat complex carbs and i limit my calorie intake to 1200 daily and i eat six small meals a day.

    Some people report success with carb cycling. I’ve never been a big fan. In your case, the higher carb day isn’t all that high. Some people really go after the carbs on ‘carb’ days.

  34. Dr. Eades,

    I am creating a website about leptin for my biochemistry class. I am posting to ask permission to use the above image (with the arcuate nucleus). I will disassemble the site after it has been graded in May.

    Sure. Go for it. I don’t even remember where I got it.

  35. Hi
    I find your review on this matter quite fascinating, since I just got a newsletter regarding leptin.
    Recently, a new e-book on how to lose weight by having an ‘overeating’ day pr. week has been released, where you consume mostly carbs on that one day, while staying on a low calorie diet with mostly protein, fat and complex carbs for the rest of the week. The idea is, that the ‘cheaing day’ will increase leptin levels and hence make you continue to lose weight, since the normal low calorie diet will make your leptin level decrease.
    As I understand your point, leptine levels do not decrease, even if you are on a low calorie diet and if that’s right, the ‘cheating day’ would be wasted, if I’m correct?
    I have tried to find as much info on this matter as possible but you review seem to be the best available, understandable one :) I don’t want to waste more energy on useless diets than is strictly necessary.

    /Anni

  36. Hi there!
    Here’s my issue, I am a personal trainer so I workout regularly and keep a daily food log. About 4 years ago, my body started holding on to weight. I went to 2 different nutritionists who weren’t able to do much for me since my diet is very clean. I tried the hi-carb & lo-carb cycling but didn’t see any results in weight loss. At the beginning of May ’09, I went to a medical clinic who did a blood panel. My Free T3 was 2.9, CRP was 3.13 (should be under 1.5 but, I worked out that day so that may have caused the inflammation), Reverse T3 was 340, and my Leptin level was 4.0. I was also told that I am insulin resistant. So, I was prescribed T3 (10 mcg to start, I’m now up to 40 mcg) and Byetta (5 mcg) which I inject twice daily prior to my meals. I’m on my 2nd month of Byetta. So far I’ve dropped 4 lbs. but don’t know if this is the best course of action or if there is something more I could be doing. Any advice?

    For medico-legal reasons, I can’t give personal advice over the internet to people who aren’t patients of mine. I’m not sure, however, that the labs you got indicate insulin resistance. And if I did think you were insulin resistant, I don’t think I would be giving you the Byetta, especially if I wanted to help you lose weight. But you need to work this out with your own physician.

  37. Would you speak to leptin levels and keeping carbs too low too long causing stalls?

    I’m trying to understand this whole leptin thing. But what I’ve read is that people on LC diets who think going lower is better eventually stall because carbs are too low. Something to do with leptin. If they gradually increased their carbs instead as recommended by Dr. Atkins until they reached the critical level for losing, they don’t stall because whatever too low a carb intake does to leptin doesn’t happen because carbs are adequate. This is where the “refeed” theory and “whoosh after a carb blow-out” discussions come in on many LC bulletin boards.

    Could you explain the biology/chemistry of all this in plain talk like you do so well?

    Thank you.

  38. Hi, I have a 13 yr old boy that has medical problems as wells as behavior , but as long as i can remember he has been over weight he weighted 24.6 at 4 mos old . I have done alot to correct this nothing works hes 297 pounds at 13 . My question is when doctors do blood work do they test for this leptin or do have to specify for the test.

  39. My issues seem to be a little different than others. I have no appetite, food nauseates me and has for the last 9 months. I basically force myself to eat dinner – meat & veggies. Yet, have gained 30 lbs during this time period. I have recently purchased some desccicated liver tabs and am using them in place of meals. I am being treated w/ armour thyroid, 4 grains & cortef 30 mg, divided into 4 doses daily. My weight has not budged. I now weigh 175, my most comfortable weight is 145. I did weigh 260 in 1995 and lost it over a year with low carb and have maintained that regimen for all these years, so I do understand how it works. I did have the reverse t3 test done and it is quite high. Any ideas, suggestions out there would sure be appreciated.

  40. Hi Dr. Eades,

    This blog post is going in the “best of” section in my bookmarks for your blog.

    If people really want to lose weight, the key is to make it as easy as possible for leptin to cross the BBB. And to do that, decrease triglycerides. To reduce triglycerides, cut out all unnecessary carbs like foods high in starch as well as anything with sugar.

    The above paragraph I wrote (I feel) summarizes what you’re trying to communicate and is something that doctors should tell their patients (especially the obese ones) WORD FOR WORD.

    About my weightloss: I realized in January 2011 that I had put on over 30 pounds since college, so I went back on a low-carb diet. I cut my carb intake at first to 20-30 grams per day. Now my maximum (in italics) intake is 40 grams a day. I have not been doing any kind of exercise since then, mainly because I’m lazy but I do think it has its benefits. Despite the fact that I didn’t exercise, I have lost 23 pounds. I’m 5’9 and my goal weight is at least 145. I’ve got 8 more pounds to lose and they’re steadily coming off with barely any effort on my part :-)

    I haven’t been following any specific low-carb plan, but I think your book PPLP was extremely helpful. Especially the chapter on insulin. The first LC book I ever read was Atkins New Diet Revolution in high school and he had a chapter on insulin as well, but your version was more in depth. PPLP is on my book shelf and I’ll probably give it a second read. It is that good.

  41. Dr. Eades, as a college nutrition instructor, I do appreciate the article. I myself am an unabashed fan of lower carb diets, but even after reading (and frequently touting) Gary Taubes’ two books on weight, I am not convinced that lower carb diets are for every body. Certainly, many people do successfully maintain their weight on a 50% kcals from carbohydrates diet.

    The first question I would ask is – can we identify those who successfully respond to a low carb diet? Would you guestimate that fasting triglycerides (without a genetic propensity for elevated triglycerides) might be that marker?

    Secondly, having seen my TG’s fall to ~ 50 mg/dL after taking fish oil for 6 mos. (to raise my HDL from 39 to 50 mg/dL), would omega-3 fats provide a means by which the obese could more greatly respond to their circulating levels of leptin? (via omega-3 reductions in TGs).

    Thanks,

    John P

    PS Off to go teach nutrition to a class full of Gatorade sipping undergrads!

  42. Hi, thanks for the very informative article. I have a question. Do you know what a healthy child’s leptin level should be? (more specifically a 4 year old) I had my daughter’s tested and it was a 9.9. I read online that it should be around 2.2. Any answers would be greatly appreciated. Thanks again :)

  43. I may be one of the few people who would benefit from Leptin therapy. I am obese but have a circulating Leptin level close to zero. As a result, I have type 2 diabetes and metabolic syndrome.

    It’s not the typical situation with obese people where they have plenty of circulating Leptin but triglycerides prevent absorption of it. For some reason, I don’t produce it at all. Wouldn’t you think Metreleptin would help?

  44. Great info Dr. Eades. We know that the overweight/obese person has leptin resistance. There are recent claims that hCG unblocks leptin to be released in the bloodstream. This claim has no scientific merit. What are your thoughts?

  45. I’m a 63 yr old female, I have been eating low carb for 4 weeks. I measure, and ate less than 20 carbs the first two weeks; now I keep carbs under 40. I’m hungry a lot! I have 24 G whey protein drink in the morning, along w a boiled egg and a small piece of flax bread that I bake. Lunch is beef and veggies– broccoli or salad (no dressing) and dinner is the same. I eat mozorella cheese sticks for snacks, or flax bread or a boiled egg. I usually get hungry after I eat. And I am jittery a lot ( never prior to LC) . I am sometimes in ketosis per the keto stick s
    But not always. In 4 weeks, I have lost two!! Pounds. I am small
    Boned, and weigh 113. I’m just trying to lose belly fat. In general, I don’t eat sugar, but I used to eat home baked whole wheat bread. I don’t bake now. I eat no bread. No potatoes, no junk. Help! Why am I hungry so much? How can I get this extra on my stomach gone?

  46. I’m wondering what might be done with a leptin antagonist.

    Also, the 63YO on the minimal diet with belly fat issues should get a thyroid panel done.