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Why Hyperleptinaemia is Not Leptin Resistance

Yesterday, I posted about the presentation of Columbia University’s Rudy Leibel on how losing weight results in a hypometabolic and orexogenic response mediated largely by a fall in plasma leptin levels that, as a rule, accompany any attempt at reducing fat stores.

This post elicited a number of responses that I will try to address in this follow-up post.

Several readers wanted to know whether there is a way to readjust your ‘leptin sensitivity’ so that the brain no longer wants to restore body weight to pre-weight loss levels.

The short answer is ‘no’. Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done. The sad fact is that anyone, who has ever lost weight, has to continue with efforts to keep it off – this includes people who have had bariatric surgery, who if they ever decide to reverse their surgery – will rapidly gain their weight back (even after years of keeping it off). This, by the way, is why bariatric surgery has to be seen as a definitive and permanent solution and why temporary devices like gastric balloons, which have to be eventually removed, are not a permanent treatment for obesity.

Another reader wanted to know, that if this was true, why some people are successful in maintaining long-term weight loss.

The answer to this is that these individuals somehow manage to continue their efforts (whatever those may be) in the long-term. The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (upto 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. So, what the NWC participants actually demonstrate, is not so much that sustaining weight loss is possible but rather that this requires an almost ‘superhuman’ effort (some would say ‘obsession’) – indeed the NWC registrants represent a rare minority of people attempting to lose weight by diet and exercise alone (the NWC registry has a few thousand registrants compared to the tens of millions who try losing weight every year).

Finally, some readers wondered about ‘leptin resistance’, a term often used to describe the fact that obese people apparently need higher circulating levels of leptin (hyperleptinaemia) to suppress their appetite and burn more calories than lean people.

In his talk, Leibel made clear that ‘resistance’ may not be the best way to describe this phenomenon.

Rather, he preferred to refer to an elevated leptin ‘threshold’, implying that there is an upward shift in the levels of leptin required to suppress the orexogenic and hypometabolic response elicited by caloric restriction.

Leibel prefers the term threshold, because even in people with a high threshold (i.e. obesity), once you have administered enough leptin to restore baseline levels and suppress the orexogenic response that follows weight loss, there is no further decrease in appetite, even at higher leptin doses. This is why simply injecting additional leptin into a person who is at their usual weight (i.e. prior to weight loss) has little to no effect on appetite, which incidentally, is exactly why leptin does not produce weight loss and would not meet thergulatory criteria for as a weight-loss drug (the rare exception being in individuals who are born with a genetic lack of leptin).

Perhaps the difference between ‘resistance’ and ‘threshold’ can best be understood by comparing leptin to insulin. In people who are resistant to insulin (e.g. patients with type 2 diabetes), you can ‘overcome’ this resistance by simply injecting increasing amounts of insulin. Even in the most insulin-resistant individual, you can eventually lower blood glucose levels by injecting more insulin – if you inject too much, these individuals will experience hypoglycemia, i.e. experience the physiological impact of too much insulin.

In contrast, the hypometabolic and orexogenic state following weight loss will respond to leptin injections only up to a dose that is just high enough to restore pre-weight-loss levels (the threshold level) – adding additional leptin will not increase metabolism or suppress appetite further.

Thus, while people with insulin resistance will respond to increasing doses of insulin to the point of hypoglycemic shock, people with an elevated leptin threshold will achieve a maximum metabolic and anorexogenic response (albeit at higher levels than people with a lower threshold) beyond which leptin has no further effect.

This may seem like a ‘semantic’ distinction but from a treatment perspective (and the science behind it), this difference is substantial and explains why high doses of insulin can always be used to treat diabetes even in the most insulin-resistant individual whereas leptin only works upto the point where it restores levels to the respective (pre-weight loss) threshold.

Obviously, the key question is why some people have a higher leptin threshold or rather why this threshold (that can also be thought of as the famous ‘set point’) only seems to move in one direction (namely to higher levels) and then becomes permanent (unless it is moved to even higher levels by weight gain).

As Leibel explained, the reason that this leptin threshold appears permanent, may be due to the fact that it becomes ‘hardwired’ into the brain – a process that is essentially irreversible (perhaps with the exception of patients with cancer cachexia). It is therefore perhaps not surprising that it actually takes neurosurgery (in animal experiments) to ‘reverse’ this threshold – an approach that is clearly not feasible in humans.

Several readers also asked whether leptin is available and whether it works in humans to help keep weight off – more on this topic tomorrow.

In the meantime, here is a link to a previous post on Leibels ‘Threshold Theory‘.

Edmonton, Alberta


  1. Given what you have said about leptin, IS THERE NO HOPE for people who have dropped weight and want to keep it off?

    You seem to imply we’re all condemned by the leptin hardwiring.

    Please explain what YOU would recommend for maintaining a weight loss?

    thanks so much


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  2. With all due respect to the NWCR, I am in my sixth year as a registrant with that organization. I think they’ve nailed our exercise, but they do NOT ask the right questions regarding our food intake. They only have one fill-in-the-dot-with-a-#2-pencil question regarding salad intake, for example, and most of us, I would guess, are crazy salad eaters — and some of those salads are meal sized, others are side-items, and they need to be part of the analysis. If other NWCR registrants are like me, they use sparing amounts of full-fat, home-made dressing, but we really don’t know that, because the NWCR isn’t asking. And yet, they have concluded that we eat a 1300-calorie, low fat diet. (Note: my research of the NWCR differs from yours by 100 kcal.)

    My daily kcal intake is closer to 1800 per day. The NWCR has NEVER asked how many calories I think I take in. They ask several pages of multiple choice questions and give limited response options, then deduce our calorie intake. They also don’t ask about the “quality” of our food — whether it’s organic, or whether we avoid other potential obesogens (microwaving in plastic, etc.). I’ve made several posts about the NWCR at my blog. Other maintainers have responded at how frustrated they get with the NWCR forms, too.

    Despite its weaknesses, I do want the NWCR to continue its work. I think it is useful, and I think it’s the only think tank that is studying the true “experts” (while others love to bloviate about us, knowing NOTHING). However, the NWCR is far from perfect. It needs to clean up its database (they don’t check out our contact people to weed out participants who may be stretching the truth), it needs to make its database available to empirical researchers (like Leibel), and, most importantly, it needs to adopt a more disinterested and scientific vantage point. It was founded in 1993 by weight-loss optimists with the goal of proving that weight loss maintenance was possible through persistent behavior modification. The fact that the database grew to about 6,000 people, then topped out and grew no more (those signing on are balanced by those dropping off) may be telling them that they have found a null answer to their hypothesis, and yet they aren’t acknowledging that possibility. Some of their scientists are more objective than others; however, some of their scientists speak publicly as maintenance promoters, not scholars. One of the two lead scientists, for example, last I checked her Vita, had a private contract with SlimFast in addition to her NWCR work. That’s a conflict of interest, in my book (and I hope she’s dropped it). A radio station was running a lengthy “interview” with her via podcast in which she was clearly promoting maintenance, not illuminating it.

    They have run fMRI tests on some participants, and concluded that we respond differently to food cues. That is the ONLY empirical research they’ve done, to my knowledge. (I would LOVE to be corrected on that score!) Everything else is survey based and in need of more fine tuning (IMHO), while empirical research is virtually nonexistent. Why are we not giving blood and urine samples? And most frustrating, why are we being used to advance the cultural mythology that it’s all just a zippy “lifestyle,” when 97 percent of people cannot do it. Yeesh.

    (Thank you for the opportunity to rant.)

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  3. A major change of lifestyle has been the major factor in my recovery from obesity. The major change has been to go to a Paleo style diet. No trans-fats, sugar, grains, seed oils, or manufactured eatable products would go a long way in cleaning up this obesity epidemic. Other issues like food addiction, hyperinsulinemia, and no impulse control would then be obvious. Eat real food that would be recognized 100 years ago. Fruit, mainly in local season.

    Some Paleos also exclude all or most dairy, and legumes. Reference: Loren Cordain

    There is a second way in dealing with hyperinsulinemia, and that is to cut insulinogenic foods: sugars, grains, seed oils, manufactured eatable products, dairy, legumes, and fruits. When we remove the excess insulin, we can see the leptin, and gain the leptin effect. Also chew a Vitamin C tablet after meals, as it aids in satiety and satiation.

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  4. From the article
    “The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (up to 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. ”

    In my humble opinion, I think the last sentence clearly is the “magic pill” to lose weight and keep it off, you MUST completely change your life. I have worked with small changes over the last six months (with the help of the wonderful people at Weightwise) and slowly these changes have become like second nature. It is only when the changes become your new lifestyle permanently that you “may” be able to maintain your lower weight.

    When I began this effort last year, I was short of breath on walking any distance and could not walk up stairs normally. I did not believe I could change. I have lost weight very slowly, less than one pound a week, and have increased my physical activity equally as slowly. I have lost close to 30 pounds and am no longer getting short of breath and can walk up one flight of stairs normally. The benefits of my lifestyle changes have made exercise easier (and fun) and saying no to extra servings and high calorie foods and finding a more healthy alternative a common choice for me now. These results fuel my motivation to continue. I believe in myself now. This mindset is crucial in making my lifestyle changes permanent. Its not a diet anymore. Its a new way of living my life.

    Thanks for listening
    Rosemary 🙂

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  5. I correct myself: Rena Wing not only promotes maintenance, but pushes for weight loss:

    I believe this interview happened in 2007, but it remains on the Lifespan website. Please, tell me that’s not her decision, that she’s waking up now and this interview embarrasses her.

    Her financial connection to SlimFast may be old — 2001 — though she promotes the product in the above sited interview in 2007.

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  6. so why aren’t all women toddling around at term pregnancy weight?

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  7. This information needs to be as widely publicized as the connection between smoking and lung cancer.

    People need to know that they are not merely adding uncomfortable and unfashionable bulk when they gain weight, they are damaging their metabolisms – and the metabolic damage is permanent.

    Weight gain is sneaky. It is easy to put on a couple of pounds and rationalize that you can lose them “later”, and those pounds just keep sneaking on, a few imperceptible ounces at a time.

    PREVENTION is key now that we know damage is permanent. Doctors should warn patients (especially those a little overweight) to carefully monitor weight, and avoid ever becoming obese, making very clear the permanent damage caused by obesity and the many health consequences.

    Of course, there will be complaints that we shouldn’t focus on “ideal” weight, or that BMI isn’t a good measure, or that “health” is important and weight is irrelevant … etc, etc, – any excuse to not control weight.

    Maybe the Obesity Network could develop information pamphlets explicitly detailing the medical problems of overweight for doctors to give to patients. The pamphlets could be in waiting rooms along with the other info pamphlets on everything from diabetes to STD’s to flu shots, etc.

    Here in NS there’s a campaign on now to get tested for colo-rectal cancer by sending stool samples to be tested. There should be a similar campaign to promote self-testing for weight control – and, wonder of wonders, no high tech lab is required – the bathroom scale, and a consultation with one’s doctor to determine a good weight to maintain, and we have a simple early warning system for a medically serious problem.

    Monitoring weight and being warned of trouble is as important as testing for colo-rectal cancer. The campaign to monitor and control weight for medical reasons should have just the same public profile – clever TV ads, signs on busses, newspaper ads.

    The weight chart for my group (5’4″ women) allows for a 30 lb range of healthy weight. That’s plenty of room for individual variation, so a medical warning level can allow for that. There is a point at which overweight becomes a medical problem, and a public campaign is needed to make that as serious as other medical problems. (There are still people who think overweight is just an image or fashion or discrimination problem.)

    Maybe as well as a yearly flu shot campaign, we can have a yearly weight control campaign. There’s a month for many diseases, surely a problem with the ramifications of the obesity epidemic deserves its time in the spotlight!

    The goal could be not on weight loss, but on knowing your weight, knowing whether or not it’s healthy, and planning to check in during next year’s campaign to see if your medical situation has changed. Ads can emphasize the variation in healthy weight in individuals while being clear and graphic about the damage obesity does to health. Of course the campaign would have to offer good advice to people who want to take the lesson to heart and improve their health, so the Obesity Network would have to have evidence-based approaches ready to offer.

    (The Canada Food Guide should include calories. Otherwise the yearly weight control campaign would have to state that the food guide is inadequate for weight control, and the campaign could provide proper food plans to control weight by taking calories etc into account.)

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  8. Anonymous, you are really determined to lay blame, aren’t you? You’re just convinced that fat people are lazy and self indulgent.

    Some of our bodies are naturally much heavier than average. I was raised with a weight loss “lifestyle” and became fat in spite of it. I wore a size 20 in seventh grade. Are you saying that primary school me or the thin, health nut mom who raised me were responsible for the fact that I was heavy? No, I don’t think so. My dad and his siblings all have maximum weights well over 300 pounds (although the previous, non-dieting generation in that family was my size). Being heavier than average isn’t always about “letting yourself go.” Some of us were never thin. And, you can’t necessarily keep someone who’s predisposed to be heavy from gaining weight. Believe me, my mom tried.

    I don’t think I damaged my metabolism. I think I started out with a body that thought it was supposed to weigh around 200 pounds and was willing to make whatever adjustments it had to in order to enforce that. And luckily for me, although my body won’t maintain anything under 180 pounds, it also has no interest in weighing more than 220. I’m pretty sure that when I get close to 220, my metabolism speeds up and I stop absorbing all the calories from the food I eat. My body actually resists weight gain when it’s near the top of its set range. (and maybe that’s the phenomenon that scientists should be looking at if they want to make everyone thin – weight gain resistance rather than weight loss resistance)

    That 30-pound “healthy weight range” does NOT provide enough room for individual variation, and weight is not hard-wired to health or level of fitness, so I don’t think there’s a need to define a universal “healthy weight range” at all. It may be true that people each tend to have a 30-pound healthy weight range, but it varies widely by individual and may also change over time. The only thing BMI is good for is looking at population-level risks. It doesn’t say anything about an individual.

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  9. Oh – and obviously the discussion about the role of leptin in preventing weight gain is exactly what this post is about. But, there’s more to it than leptin. Leptin may help prevent the panic reaction that take place when bodies lose fat stores. However, what is it that makes bodies resist weight gain? A lot of thin people’s bodies do resist weight gain, and fat people with stable weight ranges (like me) experience the same thing. However, I think it’s safe to assume that most of the patients that consult a obesity specialist have never experienced this, and so obesity specialists may not even be aware that it exists. My advice: study the thin people who have trouble gaining weight and see how they differ from people who have to work to prevent weight gain.

    I’m convinced that this hasn’t been studied because very few people are willing to acknowledge how important individual biological differences (as opposed to eating habits) are in weight variation.

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  10. “Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done.”

    I would definitely agree with this statement.

    But there is some literature demonstrating that increases in insulin can increase leptin ( My guess is that in the popular literature the assertion is that carbs will increase insulin and this will increase leptin which leads to the concept of refeeds.

    While there is currently no evidence to support the concept of refeeds, does this mean that they are not effective or that they simply have not been studied?

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  11. I believe Leibel’s Threshold Theory is seriously flawed. Leptin is a hormone and like all the other hormones, there is “cross talk” feedback amongst them. Meaning, there are multiple pathways to get the message delivered. Research shows that there are links between Leptin, Insulin, Cortisol, Estrogen, Vitamin D and other hormones. Trying to control only one, without finding a balance amongst all the others makes no sense. That is why there is no single pill to lose weight.

    I will shortly reach my 8th year of keeping 70 pounds off, I am no longer obese and have a healthy BMI of 21-22 with a 25% body fat content. I eat 1600 -2200 calories a day based on my activity level. I stay active, but don’t live in a gym. I have learned over the years which starchy carbs give me problems and which foods to eat to reduce the effects of stress. I am not diabetic, but still have a low thyroid, which is turning around.

    Yes there are lifestyle changes to be made, like getting enough sleep, eating breakfast, finding your own carb/protein/fat intake balance, consuming more fiber, staying active, drinking more water…all the things we are told to do to lose weight. It is a process, it does take time, and as one ages and life events occur, what one eats and how much also changes.

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  12. I don’t know if you will see this Holly, but I want to say thanks so much for posting… I need to lose about 50-60 lbs and after reading this article was ready to throw in the towel.

    I have been following a Paleo way of eating as described above for 3.5 mos and have lost only 7 lbs. I just had extensive blood work done and am working with a medical group that specializes in hormone balancing.

    My leptin is 34 and my RT3 is 24… I am hypothyroid (given that I first became overweight at 7 yo, I have probably been hypothy most of my life)… I have lost wt three or four times in my life… usually by using stimulants or by extreme amounts of exercise (as a geologist, I used to do field work all day and that did the trick…. + stims)… however, for the past 20 yrs I reached my set point level of around 240… I never seem to go any higher than that.

    I eat less than my thin friends… they always remark on that… and my thin boyfriend years ago also observed that “you don’t eat very much.” I have never been a binger or really an overeater at all. When I was younger, I probably did consume too many refined carbohydrates… but don’t eat them at all now.

    All that to say that I am trying so hard to reverse the weight gain and not wind up like my poor morbidly obese mom who had an autoimmune thyroid disease and then was not given proper medication and subsequently she became quite obese… if I only knew then what I have learned in the last 2 mos. she would have had a much better life (by having proper thyroid meds and probably adrenal hormones as well.)

    I have just been prescribed time release T3 as well as other supplements and adrenal support supplements to turn my situation around.

    I came to this site because of a search for leptin resistance treatment… and was thoroughly depressed… so thanks again Holly for your post…. it gives me hope.

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  13. I’m not certain the place you are getting your information, but good topic. I needs to spend a while studying more or figuring out more. Thank you for great info I was on the lookout for this info for my mission.

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  14. Amаzing! Its really awesome ρiece of ωriting, I havе got
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  15. This research really illustrates how the field of medicine simply does not yet understand why humans gain (or fail to lose) weight. The old “calories in/calories out” model is simply not supported by the evidence. In addition, as this research suggests, we only have a shaky understanding of the interrelatedness of metabolism, hormones, and weight gain/loss.

    For this reason, I think it is the responsibility of knowledgeable members of the medical profession to no longer allow medical research to support larger social prejudice against people who are fat. Medical professionals who now see that fat has many more causes than gluttony or sloth should be speaking out on behalf of a class of people who have been maligned and mistreated for too long. Eugenics was the medical representation of social fears against race and class in the early 20th century. “Obesity research” is the eugenics of our time.

    I speak as a woman who gains weight at 1200 calories a day with a half hour of vigorous exercise. I must eat around 400 calories a day to lose any substantial amounts of weight over the long term. To maintain my weight I must eat around 800 calories a day (no carbs, lots of veggies, lean protein, no fat). No doctor will believe me. And, by the way, my thyroid levels are relatively normal.

    If I weighed 100 pounds, the DSM would classify me as anorexic. Because I weigh nearly double that, I am told by doctors I should go on a diet. It’s exhausting, quite literally.

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  16. This is interesting.

    I have been overweight in the past but for for very long so I suspect whether you can keep the weight off or not is dependant on how long you’ve been overweight for.

    I had a BMI of 26.5 and initially lost weight using low carb diet and maintained a healthy weight for about a year. I then developed anorexia nervosa. I got to a BMI of 17.5 eating 1500kCal per day and exercising intensively, so much so I became injured and could no longer exercise so cut to under 1000 but was overestimating so the real figure was lower. I got to a BMI of 16.5 on that intake, very quickly and felt cold tired and weak.

    In recovery I went through a period of binge eating but I didn’t become overweight again. My body resisted the weight gain when I was eating a lot, probably as much as 8000 per day. I began to feel very hot all the time. I did not become overweight again though, my appetite normalised when my BMI got to the middle of the healthy range and I’m now eating without restriction and my weight seems to be stable.

    I still have a little too much abdominal fat but the body tends to put the fat around the internal organs to protect them which is normal after starvation. I intend maintaining my weight because if I tried to loose, I wouldn’t be able to stop and malnutrition is far more unhealthy than my current weight.

    What interests me is someone who has a high leptin threshold and is maintaining a lower weight, typically employs similar methods as someone with anorexia nervosa to maintain a lower weight. There also seems to be psychological and behavioural parallels too: preoccupation with food, restricting calories or cutting out food groups, purging excess calories with intensive exercise and occasional periods of binge eating. This is can’t be good for ones mental health so yes you can maintain a lower weight but is it worth the physiological problems that come with it?

    Surely gastric bypass surgery or (hopefully if it becomes accepted) leptin supplementation are more healthy and sustainable alternatives?

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  17. Don’t believe this balderdash that if you gain weight the damage is permanent and there is nothing you can do. This is what the pharma medical industrial complex wants you to believe so that the only solutions are those that make them lots of money like gastric bypass and numerous drugs.

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