Saturday, January 16, 2010

The Body Fat Setpoint, Part II: Mechanisms of Fat Gain

The Timeline of Fat Gain

Modern humans are unusual mammals in that fat mass varies greatly between individuals. Some animals carry a large amount of fat for a specific purpose, such as hibernation or migration. But all individuals of the same sex and social position will carry approximately the same amount of fat at any given time of year. Likewise, in hunter-gatherer societies worldwide, there isn't much variation in body weight-- nearly everyone is lean. Not necessarily lean like Usain Bolt, but not overweight.

Although overweight and obesity occurred forty years ago in the U.S. and U.K., they were much less common than today, particularly in children. Here are data from the U.S. Centers for Disease Control NHANES surveys (from this post):

Together, this shows that a) leanness is the most natural condition for the human body, and b) something about our changing environment, not our genes, has caused our body fat to grow.

Fat Mass is Regulated by a Feedback Circuit Between Fat Tissue and the Brain

In the last post, I described how the body regulates fat mass, attempting to keep it within a narrow window or "setpoint". Body fat produces a hormone called leptin, which signals to the brain and other organs to decrease appetite, increase the metabolic rate and increase physical activity. More fat means more leptin, which then causes the extra fat to be burned. The little glitch is that some people become resistant to leptin, so that their brain doesn't hear the fat tissue screaming that it's already full. Leptin resistance nearly always accompanies obesity, because it's a precondition of significant fat gain. If a person weren't leptin resistant, he wouldn't have the ability to gain more than a few pounds of fat without heroic overeating (which is very very unpleasant when your brain is telling you to stop). Animal models of leptin resistance develop something that resembles human metabolic syndrome (abdominal obesity, blood lipid abnormalities, insulin resistance, high blood pressure).

The Role of the Hypothalamus


The hypothalamus is on the underside of the brain connected to the pituitary gland. It's the main site of leptin action in the brain, and it controls the majority of leptin's effects on appetite, energy expenditure and insulin sensitivity. Most of the known gene variations that are associated with overweight in humans influence the function of the hypothalamus in some way (1). Not surprisingly, leptin resistance in the hypothalamus has been proposed as a cause of obesity. It's been shown in rats and mice that hypothalamic leptin resistance occurs in diet-induced obesity, and it's almost certainly the case in humans as well. What's causing leptin resistance in the hypothalamus?

There are three leading explanations at this point that are not mutually exclusive. One is cellular stress in the endoplasmic reticulum, a structure inside the cell that's used for protein synthesis and folding. I've read the most recent paper on this in detail, and I found it unconvincing (2). I'm open to the idea, but it needs more rigorous support.

A second explanation is inflammation in the hypothalamus. Inflammation inhibits leptin and insulin signaling in a variety of cell types. At least two studies have shown that diet-induced obesity in rodents leads to inflammation in the hypothalamus (3, 4)*. [2013 update: several studies have shown that preventing hypothalamic inflammation attenuates fat gain in obesity models].  If leptin is getting to the hypothalamus, but the hypothalamus is insensitive to it, it will require more leptin to get the same signal, and fat mass will creep up until it reaches a higher setpoint.

The other possibility is that leptin simply isn't reaching the hypothalamus. The brain is a unique organ. It's enclosed by the blood-brain barrier (BBB), which greatly restricts what can enter and leave it. Both insulin and leptin are actively transported across the BBB. It's been known for a decade that obesity in rodents is associated with a lower rate of leptin transport across the BBB (5, 6).

What causes a decrease in leptin transport across the BBB? Triglycerides are a major factor. These are circulating fats going from the liver and the digestive tract to other tissues. They're one of the blood lipid measurements the doctor makes when he draws your blood. Several studies in rodents have shown that high triglycerides cause a reduction in leptin transport across the BBB, and reducing triglycerides allows greater leptin transport and fat loss (7, 8). In support of this theory, the triglyceride-reducing drug gemfibrozil also causes weight loss in humans (9)**. Low-carbohydrate diets, and avoiding sugar and refined carbohydrates in particular, reduce triglycerides and produce weight loss, although that doesn't necessarily mean one causes the other.

In the next post, I'll get more specific about what factors could be causing hypothalamic inflammation and/or reduced leptin transport across the BBB. I'll also discuss some ideas on how to reduce leptin resistance sustainably through diet and exercise.


* This is accomplished by feeding them sad little pellets that look like raw cookie dough. They're made up mostly of lard, soybean oil, casein, maltodextrin or cornstarch, sugar, vitamins and minerals (this is a link to the the most commonly used diet for inducing obesity in rodents). Food doesn't get any more refined than this stuff, and adding just about anything to it, from fiber to fruit extracts, makes it less damaging.

** Fibrates are PPAR agonists, so the weight loss could also be due to something besides the reduction in triglycerides.

74 comments:

Matt Stone said...

Thanks Stephan, can't wait to see what you come up with. All my studies have led me down the path to leptin. The question remaining is how to overcome leptin resistance. It seems like a really low-fructose diet would be optimal, but there are obviously more tricks that I haven't found yet. But that's where my sights are set. No question about it, especially after seeing the effect of increasing my leptin levels on my insulin sensitivity. Amazing.

Ned Kock said...

Very interesting post Stephan, thanks.

It may be that leptin resistance is more central to the metabolic syndrome than insulin resistance. I don’t know if this is where the data is taking you. It looks like.

Intermittent fasting (IF), with fasting windows longer than 12 hours, may increase leptin sensitivity. Leptin levels seem to take longer to go down than insulin levels, but do go down quite a lot after 12 hours.

This may be why we see some many improvements in health markers (e.g., link below) induced by IF, even though sometimes there is no actual calorie restriction going on.

http://healthcorrelator.blogspot.com/2010/01/intermittent-fasting-and-reduced.html

I wonder if leptin resistance is not the fundamental cause of diabetes, whether its own cause (of leptin resistance) is mostly genetic or environmental …

toddhargrove said...

What you said about healthy humans and animals all being about the same weight reminded me of a famous line from Tolstoy that says:

"Happy families are all alike; every unhappy family is unhappy in its own way."

Its the same with other kinds of health. There are fairly few manifestations of physical (or psychological) health, but an infinite variety of manifestations of poor health. Feed ten people the same crummy diet, one might balloon to 400 pounds, another might be skinny, another athletic and healthy, another might have bad teeth, another bad skin. Feed them all a good diet and they will all look pretty much the same.

Michael Kramer said...

Stephan,

Thanks for addressing this topic.

There is a lot of buzz about leptin resistance and endoplasmic reticulum stress.

Would you like to expand on what are the weaknesses of the article on stress in the endoplasmic reticulum?

Stephan said...

Hi Matt,

I agree, leptin seems central. I wish there was more information on how different factors affect it.

Hi Ned,

I'm interested in the idea of IF as a leptin sensitizer. I haven't come across any direct evidence to support it yet, but it wouldn't surprise me.

Todd,

That's very perceptive. I agree. Different people will express the consequences of an unhealthy lifestyle in different ways depending on their genetic makeup, upbringing, etc.

Hi Michael,

Here's an excerpt from an internal review I wrote on this paper last week:

"Overall, the paper contains several interesting findings. However, it did not fully accomplish what it intended to demonstrate: that ER stress is caused by diet-induced obesity, that ER stress causes leptin resistance in vivo, and that leptin resistance due to diet-induced obesity can be reversed using small molecule chaperones."

Basically, the paper suffered from flaws in experimental design and a liberal interpretation of the data throughout. Some of the Western blots almost made my eyes pop out they were so bad. I can get more specific if you have a molecular biology background and would like to hear about it.

Jim Purdy said...

Stephan, do you know if gluten plays a role in interfering with this process?

Nancy said...

I've got low triglycerides but I bet I'm leptin resistant. I'm going to have some tests done to see what's going on, fasting insulin, leptin, reverse T3 and a few others.

Michael Kramer said...

"I can get more specific if you have a molecular biology background and would like to hear about it."

Thanks for the offer, but I don't have the requisite background.

Much of my life I have been underweight. So, my interest in this issue is mostly intellectual.

I know of at least one overweight person, dissatisfied with her progress on a Kwasniewski-type LC diet, who is entering upon a regimen based on the conclusions of the Ozclan, et. al. article on endoplasmic reticulum stress.

Her regimen consists first of two months of Symlin, a drug with hormonal effects resembling leptin. Then she plans on taking a "chemical chaperone" UDCA, which is related to the TUDCA that is mentioned in the abstract of the article you cited.

Again, this is not something that I am considering doing. But I do see people taking this article, the conclusion of which you claim is not well-supported by the evidence, as a basis for treating human obesity.

Jack Cameron said...

Hi Stephen,

Reducing consumption of refined carbohydrates, particularly sugar and high fructose corn syrup, is certainly a major factor in reducing weight and triglyceride levels.

Another factor that will reduce TG and weight is increased consumption of long chain omega-3 fats which enhances mitochondrial function and improves NO production by eNOS thereby improving endothelial function which increases glucose and fatty acid metabolism. Reducing consumption of omega-6 fats to a reasonable level would further improve mitochondrial function and glucose metabolism.

Exercise, of course, reduces TG and results in weight loss, in part as a result of improved endothelial function which increases metabolism of glucose and fats.

I recall you mentioned in one post that your serum HDL cholesterol is over 100. I believe that all of the many dietary factors which resulted in your high serum HDL cholesterol level also contribute to reduced serum TG and a lean body.

kilton9 said...

Great post. I wonder if higher postprandial Trigs after a high-fat meal (http://heartscanblog.blogspot.com/2010/01/gretchens-postprandial-diet-experiment.html) can have a transient affect on leptin signaling.

hkay said...

There is a lot of mention that intermittent fasting affecting leptin resistance. I want to add a personal observation of mine: while growing up, I fasted the month of Ramadan every year with my family and there is a common saying by most people who fast: "after a few days, your stomach grows smaller, you eat less". Might be silly but it is sort of true, after a few initial days of fasting, one gets fuller on less food.

Naively I thought that the stomach did literally shrink and that's why it took less food for us to be full. The mention of the leptin resistance and the comment above about intermittent fasting might clear this one up. Insulin alone did not explain this phenomena because people ate nothing close to a low carbohydrate diet.

Razwell said...

Stephan

So guys like Lyle McDonald et al who subscribe to the calorie theory are wrong regarding fat loss?

I don't think they allow for the root causes of obesity. I believe there is clearly much. much more going on than calories in/calories out.

Your take?

Thanks

Raz

Markus said...
This comment has been removed by the author.
Markus said...

Raz,

Gary Taubes makes many good points in this talk:
http://www.dhslides.org/mgr/mgr060509f/f.htm

Some of them are:

1) Calories in and calories out aren't independent variables. They both affect each other.

2) "To 'explain' obesity by overeating is as illuminating a statement as an 'explanation' of alcoholism by chronic overdrinking." -- Jean Mayer, 1954

3) "We don't get fat because we overeat, we overeat because our fat tissue is accumulating excess fat."

Markus

Coach Jeff said...

The theory that triglycerides, in and of themselves, may make a significant contribution to leptin being unable to do it's job properly (via being less able to cross BBB) is truly a revelation.

Christina said...
This comment has been removed by the author.
Christina said...

Great post, this is a fascinating subject.

After learning more about fructose and how the US obesity epidemic has coincided with our drastic increase in fructose (from high fructose corn syrup in particular), I am convinced that this "leptin resistance" is due to leptin's inability to recognize fructose the way it recognizes other carbohydrates (like glucose).

In addition to leptin, fructose fails to stimulate normal insulin release. As a result of this dysregulation of both leptin and insulin, people to continue to feel hungry despite adequate calorie intake.

Robert Andrew Brown said...

Thanks Markus

The Gary Taubes lecture is highly though provoking.

Many thanks for posting the link.

Stephan said...

Hi Jim,

I'm speculating here, but I suspect it may play a role for many people due to its effects on the gut and inflammation.

Hi Michael,

I'll be interested to see how her experiment goes, but I'm rather skeptical based on the results of that TUDCA paper. They really didn't show that TUDCA has any effect on diet-induced obesity.

Hi Jack,

That could well be. Low trigs do associate with high HDL. I wonder what my trigs/HDL are like now that I eat more carb? I haven't put on an ounce of fat.

Hi Razwell,

Although I'm not very familiar with Lyle McDonald's writing, I think he acknowledges that there are metabolic adaptations to reducing calorie intake. That's why he recommends periodic "refeeds" during weight loss to keep leptin up.

Stephan said...

Hi Christina,

Nice to see you on the blog. Ali sent me a link to your blog the other day, looks interesting.

I think fructose likely plays a role in leptin resistance. I'll be touching on that in the next post.

Jim Purdy said...

Wow! Here's a blatantly self-serving campaign by fake-food giant Unilever to ban butter.

Of course Unilever makes chemical fake-butter blends like Country Crock and I Can't Believe It's Not Butter!

Unilever says Ban Butter? Let's ban Unilever's fake foods instead!

Markus said...

Jim,

Thanks for the link. Absolutely ridiculous.

"Mars UK announced yesterday it is to cut saturated fat levels in Mars bars, Snickers, Topic, Milky Way and Flyte products by the use of sunflower oil."

That will reduce production costs, right? If so, it is such a clever move. First, start a war on butter, then use cheap and deadly sunflower oil. And simultaneously, those "leading heart surgeons" will have lots of ruined hearts to make money with.

If only I was that smart.

Markus

Jane said...

Stephan, you are a mine of interesting information. I had no idea that leptin resistance is related to the unfolded protein response. You know, the UPR is closely linked to inflammation, the second of the proposed causes of leptin resistance (look up 'the unfolded protein response is an important regulator of inflammatory genes ..').

The UPR is also linked to insulin resistance. See 'Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes', Ozcan et al 2004, Science 306:457.

The UPR is even thought to be a normal component of the insulin-producing function of pancreatic beta cells. In other words, the UPR is implicated in the whole of the metabolic syndrome. If a cell can't fold its exported proteins properly, it can't function.

Protein folding in the endoplasmic reticulum is dependent on addition of sugars by glycosyltransferases, which are activated by manganese or magnesium. Folding also needs formation of disulfide bonds by the enzyme protein disulfide isomerase, which is a copper protein.

So arguably the pathological aspects of the UPR are related to deficiencies of manganese, magnesium and copper. The third proposed cause of leptin resistance, high triglycerides, can be caused by magnesium or copper deficiency.

Deficiencies of these three metals are what you'd expect from a diet high in meat and refined carbohydrate.

Talking of meat, try googling this scary title:
'Alzheimer's researchers find high protein diet shrinks brain'.

hkay said...

Just a thought:

I maybe mistaken but I understood that the proposed explanation is that the fat cells secrete leptin when they are full (half full?) to supress apetite.

As far as I understand, the actual fat/calories from a meal take a certain amount of time to reach the fat cells. How is it then that we can feel satiation within 10-20 minutes of starting a meal if digestion takes a lot longer?

Caira said...

Thanks, Stephen. I've been reading your blog for six months or so now, and am finding it fascinating.

hkay,

I'm sure that the leptin kicks in long before even half-full. I don't think 'full' is the right word even. (When is a balloon 'full'?) If we have a static number of fat cells, and it's possible to weigh 800 lbs, but ideally we should weigh around a sixth of that (depending on height and gender, of course), then I would conclude that leptin kicks in whenever it thinks the fat is at an appropriate level.

I think it's more general than "stop eating now" kind of full. How ravenous or moderate do you feel when you're filling your plate? How quick are you to go back for snacks, or no inclination to snack at all?

kilton9 said...

I've been thinking about this data along with that of the Kitavans, who have low leptin levels and higher trigs than the Swedes to which they were compared, and yet no obesity. How could this be? Well, looking at the Kitavan study (http://www.canibaisereis.com/download/cardio-risks-melanesia-kitava-study.pdf), the trigs don't seem all that high to me. They're below 120 in each age group.

Then, looking at the data in the leptin/BBB study (ref #7 in Stephan's post), it looks to me like leptin transport was impacted only when trigs were above 150. (Perhaps someone can validate this since my experience reading these studies is limited.)

So perhaps the Kitavans don't have "high" trigs afterall. Perhaps in the context of leptin, "high trigs" means over 150?

bob said...

FISH OIL SHOCKER!

unrefined fish oil increases belly fat and insulin resistance (in rats). refined fish oil didnt. they say its the pollution that did it

http://www.scientificamerican.com/article.cfm?id=obesity-insulin-resistance-organic-pollutants-fat-diet

Mark said...

Bob,

That is scary. That is the only thing about a high-fat diet that scares me. I have read that fire retardants are very common in meats and milk. Sigh.

Can one eat enough vegetables and take enough antioxidant supplements along with a high-fat diet to counteract environmental toxins? Or are we just stuck with them?

Dr. B G said...

Seafood killed my cats (endocrine disruptors, flame retardants, etc). Bob, good article.

Robert Andrew Brown said...

Omega 6 20 carbon arachidonic acid and its derivative PGE2 appear to increase leptin.

Arachidonic acid pushes up insulin.
Insulin increases the conversion of Omega 6 linoleic acid to arachidonic acid. (A self reinforcing cycle?)

Insulin may increase leptin secretion http://ajpcell.physiology.org/cgi/content/full/283/1/C244

Insulin increases fat deposition, and in general terms it looks as if leptin is trying to head in the other direction.

Does excess Omega 6 linoleic acid in the diet contribute to leptin blocking?

Levels of arachidonic acid in the cell membranes are a function of the dietary intake of Omega 6 linoleic acid, the 18 carbon fat common in vegetable oils, with a ceiling of around 4% as previously posted by Stephan.

I did not manage to find any evidence Omega 6 arachidonic acid regulates leptin.

It is confusing (-:

For refs see 511-528

http://www.omegasixthedevilsfat.com/trial500_599.aspx

(new much improved better edited version with new title not too far off completion - hopefully)

Robert Andrew Brown said...

Bob,

Thanks for posting that. Did you find the link to the original paper by any chance.

Are wild fish as badly affected ?

Something to look into.

Scary )-:

Many thanks for sharing

bob said...

rob andrew brown,

i didnt find the original article (though in fairness i didnt do much looking!)

as for wild fish this is worth a read:

http://www.scientificamerican.com/article.cfm?id=salmon-to-blame-for-poisoned-killer-whales

this quite frankly chilled me to the bone as i eat a fair bit of salmon (especially as i thought salmon were among the 'safer' fish for pollutants compared to say tuna etc higher up the food chain). i just hope it doesnt come from the west coast of usa/canada!

malpaz said...

this has always interested me because in a starving person and in an obese person, leptin levels are screwed in both. what causes the leptin in a nourished once starving person not to bounce back?

love your work and recently added you to my blogroll if that's ok!
http://malpaz.wordpress.com/

Scott W said...

Bob, Dr. B.G., Robert Andrew Brown:

I've been considering switching to krill oil instead of fish oil. Krill are the bottom of the food chain. More expensive, but I see that Costco is carrying it now for less money. And it is supposed to be somehow more concentrated so you take less. Any thoughts on that?

Another point, I guess, would be that harvesting krill (which I understand to represent the largest biomass on the planet) would be more sustainable in the long run. And they are definitely grown "wild."

Just wondering.

Scott W

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Dr. B G said...

Krill oil is fine but the n-3 content is not sufficient I believe to outweigh or 'fix' dysfunctional n-6/n-3 in our cell membranes, which may have been damaged by DECADES long insults from the S.A.D. Krill oil works b/c it has cholines and astaxanthin, one of the most potent anti-inflammatory carotenoids ever discovered.

Fish oil molecularly distilled from small fish are typically sustaintable and free of ocean pollutants, I believe.

Jack Cameron said...

Robert Andrew Brown asked "Does excess omega-6 linoleic acid in diet contribute to leptin blocking?"

Apparently. See pubmed 17647039, "Linoleic acid decreases leptin and adiponectin secretion from primary rat adipocytes in the presence of insulin".

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ItsTheWooo said...

The idea that leptin prevents obesity and ought to terminate it, is false and outdated.

Leptin prevents starvation, it does not prevent obesity.

Fat people do not lose weight in spite of high leptin because leptin has nothing to do with preventing obesity. Leptin prevents starvation. It makes the body not work when it is not present. This does not mean to say having a lot of leptin ought to mean that you are going to be extremely thin. It doesn’t work that way.

It’s like protein. Not having it makes stuff break. Having it makes stuff work. Eating more than your requirement does nothing special at all (it is catabolized into glucose and fatty acids, used for fuel and nothing more).

Obesity is not an issue of leptin resistance, if it were, there would not be a dramatic change in appetite/satiety/eating behavior/energy when people reduced their insulin levels via low carbohydrate diets. Clearly leptin resistance cannot be a major factor if this is the case. Unless there is something about reducing insulin / glucose that also affects leptin, anyway. *

Now it is true that a lack of leptin can lead to obesity… but this is not the same as extra leptin preventing obesity. With no leptin signal to terminate anti-starvation genetic programs, obesity and metabolic disorder results, but this does not mean that extra leptin ought to make the metabolism work extra good/fast.

As pertaining to human obesity, leptin has very little role during the actively obese phase, and it has a major role in the post obese phase. It is consistently observed that dieted obese individuals have very low leptin and respond to leptin replacement therapy.

There is currently a sweeping fad to attribute obesity to leptin resistance, but I’m just not seeing it really.

I was a classic fatty, 300 pounds, PCOS, hypoglycemia… I lost weight with low carb. My body stopped working. I got a lab test, my leptin level was <2 (very deficient). I replaced the leptin. I feel great. I am not atypical, low leptin is common after weight loss in obesity, adipocyte hyperplasia and atrophy and avoiding insulin release etc.

I am quite skeptical of leptin resistance and doubt it is relevant at all. Inflammation is a metabolic problem, but this is mediated by a resulting insulin resistance/insulin release and not leptin resistance.

*I think it is very likely/possible that leptin transport across the BBB may be inhibited by high insulin/triglycerides, but this is not leptin resistance, this is simply hyperinsulinemia mediated fattening and the focus should be on lowering insulin. Sans high insulin leptin signaling is likely normal.

Speaking from personal experience, anyway. From what I’ve read, leptin deficiency is the norm not the exception after obesity.

http://www.bloomberg.com/apps/news?pid=20601124&sid=agme3MESlQ5k

Robert Andrew Brown said...

Jack
Many thanks Jack useful and interesting reference.

ScottW
Krill levels are not something I have looked into in depth but recall an article suggesting Emperor penguis were suffering due to falling Krill.

This article suggest Krill harvesting is a big environmental issue http://www.guardian.co.uk/environment/2008/mar/23/fishing.food
"Scientists believe krill have declined by 80 per cent since the 1970s, and the most likely cause is global warming. "

Loss of ice was also as factor as needed for some species to breed.

This paper also suggests stocks are falling.

http://www.nature.com/nature/journal/v432/n7013/full/nature02996.html

Refined fish oil is a useful source and makes use of the livers etc from fish. Modern refining is very efficient, but they take out most of the Vit D etc.

Farmed marine fish is a whole other issue because most are carnivorous and depend on fish meal made form small oily fish, and conversion rates are poor. It takes 4-5 tons of a very natural product to make one ton of a rather less natural product. At least fish oil production can use some of the 'waste'.

Bob

Thanks - scary indeed

Nigel Kinbrum BSc(Hons)Eng said...

ItsTheWooo said...
"I am quite skeptical of leptin resistance and doubt it is relevant at all. Inflammation is a metabolic problem, but this is mediated by a resulting insulin resistance/insulin release and not leptin resistance.

An analogy would be type 1 & type 2 diabetes. With type 1 diabetes, lack of insulin = body doesn't work. With type 2 diabetes, lack of sensitivity to insulin (insulin resistance) = body doesn't work.

So leptin resistance = body doesn't work.

Nige.

Stephan said...

Hi Itsthewoo,

What obese people have is not leptin deficiency. They have tons of leptin, much more than a lean person, that is rock-solid established at this point. See this paper:

http://content.nejm.org/cgi/content/abstract/334/5/292

What obese people have is a relative leptin deficiency, i.e. it's deficient relative to their sensitivity to it. In other words, they're leptin resistant.

Leptin plays a role in increasing energy expenditure during overfeeding, so yes it does actually regulate the response to overfeeding as well as starvation. It's exactly what you'd expect from a classic negative feedback loop.

ItsTheWooo said...

I'm not saying obese have leptin deficiency.

I'm saying high leptin in the obese:
1) Is not a sign of resistance at all, as there is no negative feedback inhibition of leptin...
2) Is rapidly correctable upon the adaptation of diet/lifestyle/drugs to reduce insulin levels and lose body fat...
3) That, contrary to the idea of "resistance", the obese individual AFTER weight loss is actual at a low level of leptin and functionally deficient.

My situation post weight loss is not rare, it is common.

I hope this clarifies things.

Stephan said...

Hi Itsthewoo,

1) Leptin is definitely a negative feedback signal on energy balance, because administering it to lean (i.e. leptin-sensitive) animals and humans decreases food intake and increases energy expenditure. It's only in the obese that it doesn't, because they're leptin resistant.

2) Yes, but these typically improve leptin sensitivity as well.

3) That definitely happens after weight loss due to calorie restriction, because leptin drops like a rock since it's a signal of energy balance. If you increase leptin sensitivity rather than just forcefully restricting calories however, you don't create a leptin deficiency. That's why I'm interested in the approach.

ItsTheWooo said...

Yes, leptin is a negative feedback signal of energy balance, but what I meant was that elevated leptin does not signify a failure to inhibit leptin release, i.e. resistance to it (because there is not "normal leptin range" in the same way as a "normal fasting insulin range"... there are leptin levels which are "normal" but the range is very wide, and there is a lot of individual variation).

I don't think you are understanding that leptin drops BELOW matched controls in weight reduced obese. Say, the normal fasting leptin of a 25 year old female with 25% bodyfat is 12... if you take a 25 year old female with 25% bodyfat who was previously morbidly obese, you can expect her leptin to be more along the lines of, say, 4 or 5.

So, weight loss causes an absolute leptin deficiency, not a relative deficiency (i.e. they are not resistant, they simply do not make enough).

Even when weight reduced individuals have been maintaining a long time (not in negative energy balance), the leptin deficiency remains.

Joan said...

Itsthewoo,
very interesting. when does the leptin go back to normal levels? are overweight people doomed to feel in starvation even when their bodyfat levels are normal again?
is there any research about what brings leptin to baseline?
or its even a thing that takes time and that low level becomes normal for that person?

Venkat said...

It is excellent post Stephan. You have researched and presented so well.

Thanks, Venkat

"Guppy" Honaker said...

I think an approach to fat gain measuring Leptin levels is way overdue. Thanks for blogging this information.

Keep up the good work on you blog. - David

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Stephan said...

Hi Itsthewoo,

Yes, calorie restriction reduces leptin levels in both obese and lean people. That's because it's a signal both of fat mass and feeding state.

But that does not imply that losing fat mass by other means will reduce leptin to below the level of a lean person, it just says that starvation reduces leptin. Furthermore, it has nothing to do with fat mass, as starvation will reduce leptin both in lean people and obese people.

ItsTheWooo said...

Joan - It never rebounds. It stays deficient. My hypothesis is that a previous history of hyperinsulinemia damages the fat organ by causing excessive adipocyte hyperplasia, so that minimum fat mass requirement is above normal. When fat people attempt to diet below this weight (i.e. to "normal body fat"), they are functionally starving (their white fat is hypotrophic) and so does not produce leptin normally, and won't produce leptin normally until fat cell becomes adequately replete with fat again.

An illustration:

A never obese 25 year old woman has x million fat cells. Her body contains 20 pounds of fat. Her fat cells are adequately sized and she produces leptin normally.

A previously hyperinsulinemic/morbidly obese 25 year old woman has 3x million fat cells (multiplication by 3 is as a result of chronic hyperinsulinemia). Her body contains 20 pounds of fat. Her fat cells are markedly atrophied and do not produce leptin normally. She is leptin deficient and has signs of it like very low LH, FSH, TSH and T3, anovulation, etc.
Her body will not produce adequate leptin until she has 60 pounds of fat on her body, which is sufficient to terminate the adipocyte hypotrophy.
This will make her appear heavy/overweight but it is the proper weight for her body (that is to say, it is the minimum amount of fat she can carry as a result of previous chronic hyperinsulinemia and grossly excessive fat cells being a result).

ItsTheWooo said...

Stephen - caloric restriction does not figure in. THe leptin deficiency remains even when the formerly obese are weight stable for many months.

My leptin deficiency persisted for years and years and never corrected itself in spite of stable weight and eating a decent caloric intake (1700 cal at 120 pounds).

Again... leptin deficiency after significant weight loss is rather common and it is a chronic condition that does not improve with increased caloric intake or continued maintenance. It does improve with caloric intake but usually only at an intake sufficient enough to cause insulin elevation and retention of body fat.

This hidden leptin deficiency is a MAJOR cause of weight loss recidivism, and if only people (dieters, scientists, physicians, nutritionists, i.e. the WORLD) realized this, there would be a hell of a lot more thin people out there.

They are finally starting to get it, though.

http://www.bloomberg.com/apps/news?pid=20601124&sid=agme3MESlQ5k
I've been working with C.M. for 2 years now in a leptin study... I like to believe his observance of my progress has made the leptin research focus shift toward "post obesity weight maintenance drug". When I joined the study, no one was thinking this, but since that time there have been several studies demonstrating that physiologic leptin replacement post weight loss is extremely helpful in normalizing appetite control and metabolic/endocrine function in the post obese state.

In the future, obesity will be treated with insulin control (via drugs and low carbohydrate / calorie intake) during the weight loss phases, and theraputic maintenance via hyperplastic fat cell excision (i.e. "skin surgery") and leptin replacement as needed to maintain normal endocrine/metabolic function.

In the future, people will understand that obesity is a symptom of hyperinsulinemia... and they will understand it is a permanent "scar" which cannot be dieted away because of the compensatory deficiency of leptin. Obesity can only be healthfully controlled via leptin replacement combined with fat cell removal while maintaining the low insulin state (drugs/diet/surgery).

Lowell said...

IsTheWoo-- weight loss does not always result in leptin deficiency in obese individuals. I know of at least one case where an individual has worked for years to implement the best real food, low carb (etc etc) diet and has lost large amounts of weight... but whose leptin levels are still very high (mid 30s). Weight is now stable, and it appears the only cause at this point is the remaining leptin resistance. Insulin, blood sugar, and all other levels are great and diet and exercise are optimal. However, weight is stable (there is still 40+ pounds to lose) and the only remaining culprit seems to be the very high leptin.

I think you may be over-broadly applying your own personal experience. Some individuals do not end up leptin deficient in the situations you are describing, but end up just the opposite-- with very high leptin and continued resistance.

Anyhow... I'm extremely interested in any additional information on how to resolve the leptin resistance issue. As best I can tell, at this point the original leptin resistance combined with the extra fat cells from the weight gain (this individual gained weight during adolescence, and ended up around 120 pounds overweight by the time she was mid-20s) has resulted in a deadlock condition wherein the original insulin/carb issues pushed her body so far outside normal evolutionary conditions that it doesn't appear to be self-correcting effectively. She's lost 70 pounds at this point, but remains with very high leptin and cannot lose the remaining 40+ pounds.

My thinking is that some individuals are able to restore leptin sensitivity, but others become so leptin insensitive that even when the original issues are resolved and the steps are taken that they don't manage to get "back to normal". I managed to lose all my extra weight (70 pounds) and my leptin appears back to normal myself, while others don't seem to overcome the leptin resistance effectively.

ItsTheWooo said...

Lowell - if significant obesity remains, leptin is not going to become low (although, it will be very low compared to other obese individuals who are not dieted....
e.g. if a 350 pound man goes down to 300 pounds, his leptin is going to be lower than a 300 pound man who never dieted at all).

I'm talking about weight reduced obese people who have actually achieved a normal or semi-normal body weight (normal, slight overweight).


Again, I am going to reiterate that elevated leptin does NOT imply resistance to leptin. There is no negative feedback inhibition of leptin; leptin is only as high (or as low) as one's fed status, (insulin levels, body fat) with other hormones/factors contributing (testosterone lowers, estrogen highers, dopamine & fatty acids lower, serotonin/melatonin & glucose highers... but the main drivers are body fat cell size and insulin levels).


This "leptin resistance" crowd is really uneducated about basic facts of leptin physiology.
Like the fact there is extreme sexual dimorphism. The healthy leptin of a lean man is nearly imperceptible - 2 or something. The healthy leptin of a lean estrogen replete woman is going to be a lot higher than that. Leptin is only partly a metabolic hormone, it is also partly a female hormone (evolutionarily speaking, this interrelationship makes sense, as pregnancy while starving is so fatal).

Leptin is also an immunological hormone and is often elevated in such conditions where there is immune system dysfunction/hyperactivity. Being sick and having chronic illnesses (eg COPD multiple sclerosis and such) means high leptin. Leptin RESULTS from inflammation.

But... and this really important because I don't htink people are getting this... Leptin release is not inhibited by signaling in the way of say, insulin or growth hormone or thyroxine or any of the other hormones which have autoreceptors or inhibit their own release so that they stay in a narrow physiologic range.


This means to say that elevated leptin IS NOT A SIGN OF LEPTIN RESISTANCE.
Unfortunately, this seems to be largely the pivotal point on which the leptin resistance castle is built.

Elevated leptin is like, having really eccentrically long hair or something. It doesn't imply that leptin isn't working, although it does imply something is wrong with you somehow :).



In the case of your friend, his 40 extra pounds and very elevated leptin suggests hyperinsulinemia/insulin resistance, or perhaps some other pathology (e.g. high estrogen? some other type of sickness/illness/inflammatory condition).

His high leptin is not the result of leptin resistance, as I stated leptin resistance will not cause elevated leptin, as leptin is not self regulating in this manner (that is, the body does not make "more" leptin when it doesn't detect it as working via receptors in the way of, say, insulin... this would defeat the primary evolutionary point of leptin which is to be a marker of food and body weight trends).



Oh, another leptin myth: that people are fat in spite of high leptin means the leptin doesn't work right. Problem with this idea is that leptin doesn't work as a metabolic thermostat to "crank it up". Leptin is like dietary protein. It only causes problems in absence. When you have a very high leptin, nothing special happens... but when you have too little leptin, a whole lot of shit goes really wrong.


And, again, this is not my own personal experience with weight loss, if you follow the link I posted, researchers are now recognizing that successful (complete) weight loss results in absolute leptin deficiency, almost all the time if not all the time. Particularly for women since women are more leptin dependent.

ItsTheWooo said...

If you don't read that previous response (understandably, it was long), here is a shorter, more helpful response.

Your friend's elevated leptin is not as ign of resistance, as there is no negative feedback inhibition of leptin.

This means to say that leptin production does not "terminate" by signalling/autoreceptors for leptin, in the way thyroxine / T4 will cause a termination of TSH production.

There is no such mechanism for leptin termination like this. Leptin is only as high as the conditions which produce leptin.

Now, to return to your friend. He is at *least* 40 pounds overweight (probably/possibly more, in my experience obese people tend to view heavier weights as "normal" weight). Okay, so that's one reason his leptin is high.
His insulin is normal. I doubt this, as it is very unlikely for a 40+ pound overweight man with a leptin level of 30 to have low insulin.

Did he actually get the numbers himself? Were they measured fasting, or after meals as well?

But, if it is true that his insulin is low, there are other reasons his leptin can be so high. SUch as:
1) Chronic illness (COPD, kidney, autoimmune disease/other diseases)
2) Endocrine disorder resulting in high estrogen and low tesosterone (a leptin level of 30 is not so abnormal in an overweight person with high estrogen)
3) The assay reading of his leptin level was improper, wrong, insensitive, etc. There is NO standardized leptin immunoassay. This means to say, there are wide variations between readings. If your friend has the test repeated, it might come back 10 or 15, which would be pretty normal.


But really the most important part of this all:

High leptin does not have anything to do with leptin sensitivity. There is no negative feedback inhibition of leptin.
People are sorta assuming that having a high leptin means the body isn't turning it off right (as with insulin), but this is totally false and is not how leptin works.

High leptin does indicate pathology somewhere, but it does NOT indicate leptin resistance.

Ewert said...

ItsTheWooo & Stephan:

I read over your comments and tried to figure out the reason for the views not matching up with you two. I think I spotted it.

ItsTheWooo, you are right in what you are saying, though a bit more explicit terms could be used so that it is more clear WHAT you are saying. Yes, there may (only added for clarifying that I do not know for sure) not be any leptin release inhibition by any negative feedback loop. But you are talking of leptin _release_ (you should be more clear of that). "Leptin resistance", as used generally, refers not to release but to lessened effects in target organs.

Stephan is right in the basis of the theories about leptin resistance possibly being a problem. The resistance isn't about any exact absolute leptin levels being "low", but relative resistance in the target organ (possibly due to BBB effects from TG/insulin, and inflammatory modulation from whichever sources).

The two views are not mutually exclusive. Leptin resistance does not mean that there is anything aphysiological (unphysiological? imphysiological? ungh .. I'll go with "a" :)) about leptin release. Post-massive-weight-loss absolute leptin deficiency neither means that leptin resistance could not be one of the main problems with getting obese in the first place. Your experience seems to indicate there can be absolute leptin deficiency after losing "too much" weight from fat stores, and thus leptin replacement can be a viable therapy for some cases. But also therapies aiming at leptin resistance are interesting possibilities due to the base theories underlying long term energy balance maintenance and leptin.

PS. For acute feeding and satiety, as some commenters asked/talked about, there is a host of other hormones and signaling going on. Leptin is more of a "long term" issue, for acute satiety look elsewhere...

Robert Andrew Brown said...

ItsTheWoo

I spent ages trying to figure out the links between leptin fructose insulin and Omega 3 and 6.

It is clear fructose and Omega 6 products both increase leptin, and in excess both promote obesity. Leptin v Omega 6 and fructose = potential conflict.

Could high Omega 6 and fructose in the skinny disturb leptin?

Beyond that, the mists set in, as I try to make sense of it all.

Andy said...

ItsTheWooo,

How sure are you that your low levels of leptin were caused by the idea that after losing weight your leptin stays low? You said you ate 1700 kcals. You dont weigh a lot but depending on your activity it might not have been enough. You might have had a stable weight, but maybe it was stable because you were actually eating too few calories and low leptin was compensating for it, making sure you don't get even further under optimal weight. Other than personal experience, are there some studies supporting this?

Also, you say that "High leptin does not have anything to do with leptin sensitivity."
I thought leptin levels were proportional to fat levels and the effects leptin has is to reduce appetite and increase activity and metabolic rate. If leptin works, you cant get fat, because the more you eat the less you want to eat and the more you burn off. But if you become leptin resistant, the effects of leptin become weaker, meaning your appetite will increase, making you gain fat, which will increase the levels of leptin. So leptin resistance should cause increased leptin levels, it seems to me.

You also said "Oh, another leptin myth: that people are fat in spite of high leptin means the leptin doesn't work right."
But how can you get fat if the fatter you are the less you eat and more you burn off? Unless of course, you dont eat less and burn more, because leptin isn't working.

"People are sorta assuming that having a high leptin means the body isn't turning it off right"
I have read that leptin levels are proportional to fat mass and they correlate pretty well. It's not that you aren't turning off the production, it's high because you have a lot of fat secreting it and you are not reacting to it.

"Your friend's elevated leptin is not as ign of resistance, as there is no negative feedback inhibition of leptin. "
How come there isn't? Lets say you are fat and have lots of leptin. Lets imagine you are not leptin resistant (would be hard to get fat like that). Leptin tells you to eat less and be more active. So you lose fat. Leptin is proportional to fat mass so leptin levels lower etc until you are at an equilibrium. Isn't that a negative feedback loop? Increased leptin causes lower leptin levels by reducing fat mass, if working properly.


On another note, I don't quite understand how leptin is also a signal of feeding state. Don't fat cells just secrete leptin based on how much fat they have? Doesn't starvation cause a drop in leptin levels because fat mass also drops or is there some other mechanism which further decreases leptin secretion?

Lowell said...

IsTheWoo-

Not saying leptin resistance causes high leptin... I'm saying it's the other way around. I agree that leptin release is tied to energy balance (intake and how much you have stored as fat, i.e. fat cell size and count). However, if someone has a leptin level in the 30s and can't lose weight despite extreme control of insulin and carb intake, it seems likely the issue is that the body isn't "listening" to the leptin effectively.

If there were no leptin resistance in these cases, how do you explain the lack of weight loss? A leptin level in the 30s should be clearly signaling to the the body that there is too much energy, and should favor increased expenditure and decreased intake. There is quite a bit of evidence that chronically high leptin levels, like from those of someone with chronically high insulin and blood glucose, cause changes in leptin transport across the BBB as well as leptin receptor count/behavior, which would certainly explain evident "leptin resistance".

If, as you state, elevated leptin is just a random characteristic, what else would you suggest would explain the lack of weight loss in individuals whose only issue appears to be very high levels of leptin? I think the leptin resistance explanation is far more likely in these cases, and has plausible biological mechanisms.

My (female-- which explains some of the leptin but not all of it) friend is not hyperinsulinemic, and we've ruled out all other causes. Hormone levels are fine, thyroid is fine, there's no illness or chronic underlying condition. Seriously... insulin is nice and low. I know it's hard for you to believe, but we've spent a long time now and a giant pile of cash running tests and searching for other explanations, trying various treatments and dietary changes, with no luck. We have a hard time believing it too-- that someone can be 40+ pounds overweight in this state. We've run countless tests, I assure you this is the case.

I still think you're over generalizing your own experience, and getting this backwards; I'm saying the high leptin level isn't producing the appropriate effect, not that the leptin resistance causes the high level of leptin. High leptin does signal that energy balance is highly positive, which inhibits hunger and promotes thermogenesis. If someone has high levels of leptin but exhibits the symptoms and behavior of someone with much lower levels, it seems more likely to me that they've saturated the blood-brain barrier and the hypothalamus isn't seeing the full extent of the leptin level, or that there is selective resistance due to cell receptor changes (as leptin levels rise, cell receptor counts can decrease, etc)...


Andy- leptin is also released in response to meals, not just by fat cells. In a thin person, the majority of leptin may even come from non-fat cell sources.

To quote: "In addition to white adipose tissue—the major source of leptin—it can also be produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver."

ItsTheWooo said...

Ewert – My belief in leptin deficiency after successful weight loss is not mutually exclusive with the “leptin resistance” idea, true. However, part of my view is that leptin resistance does not really exist much if at all as a cause of obesity.

My experience and studies leptin seems to be a passive actor in obesity, secondary to insulin and body fat trends. Leptin does not work correctly and is very elevated but this is secondary to hyperinsulinemia and abnormal use of energy secondary to hyperinsulinemia/resistance (this is to say elevated triglycerides during glucose excess causing central hypoleptinemia so as to facilitate seasonal fattening, evolutionarily speaking).

If leptin resistance were a part of obesity, the low carbohydrate diet would not be effective at all to change appetite/energy, when evidence suggests it is very effective for the majority of people with insulin/glucose mediated obesity. The difficult part of low carb dieting is adherence and motivation to do it. If people actually stick to it, they lose weight pretty easily. And once leptin deficiency sets in (after successful 100% complete weight loss, the weight of a “healthy” never obese person), at that point maintenance of the diet becomes a physical difficulty as well as the body is pushing you back to a mildly/moderately overweight size through leptin deficiency.


Robert AB – The link between fatty acids and leptin is inflammation mediated hyperinsulinemia.

Anti-inflammatory omega 3 is going to reduce insulin, which then causes symptomatic leptin reduction (leptin responds rapidly to insulin reduction). Proinflammatory omega 6 will increase insulin, which also increases leptin.
Fructose causes liver disorder which then causes insulin excess and thus leptin excess.

Leptin is largely reactive to insulin, it’s almost always true whenever you see an elevation of leptin, you can predict that the preceding condition also results in an increase in insulin (and, when you see an increase in insulin, you can safely predict their leptin levels are going to increase too).

ItsTheWooo said...

Andy –
1) How am I sure? Leptin is consistently observed to be lower in weight reduced obese when compared to matched controls who have not lost weight. This is true even if maintaining for many months. This has been studied, but the leptin resistance crowd ignores that data.

2) How do I know I’m eating enough? I do not exercise at all, and at 120 pounds, 1700 cals is not markedly deficient at all. At best I am looking at a deficit of a few hundred calories….which should not result in profound hypoleptinemia (a 25 year old woman with a level <2).

3) Leptin does not prevent obesity. This is another false, pivotal point the leptin resistance idea is built on. The fact that the obese can become so in spite of high leptin is taken as evidence that they are resistant to leptin, but this is a false conception of leptin’s physiological role. Leptin evolved as an anti-starvation hormone. The body had no need to evolve an anti-obesity hormone. Adequate leptin represents adequate health/nutrition, and so adequate leptin merely allows the body to work properly and suppresses anti-starvation genetic programs which would otherwise come into effect without its presence (e.g. upregulation of HPA axis, downregulation of HPO and HPT, higher glucose output from liver, lower SNS, so on all of which occur when leptin is below normal).

While it is true leptin terminates starvation genetic programs, it does nothing beyond this. Meaning to say, a woman with a leptin of 2 is going to have a lot of problems, but a woman with a leptin of 50 is not any better off than a woman with a leptin of 10 or 15. Nothing special happens when leptin goes “above normal”. There is a ceiling, a threshold, after which extra leptin has no further effect. There is a physiological range – someone with low normal leptin will be hungrier/more fatigued than someone with high normal leptin – but normal is normal and when leptin goes above this, there is no benefit in metabolism.

I don’t know how many ways I can say this. Leptin has nothing to do with preventing obesity, leptin only has a role to terminate energy conservation/starvation adaptation.

Again, to use the dietary protein analogy: if you don’t eat enough protein, bad things happen. Your immune system fails due to lack of substrate for immune factors. Your reproductive system fails. Your muscles waste away. Your IGF levels fall off. A whole lot goes wrong. If you eat adequate protein, this is corrected. But, if you eat a super high protein diet, nothing special happens. You get the benefits of adequate protein, but nothing more… and the extra protein is just converted to energy.

ItsTheWooo said...

(continued response to andy)



4) Re: lack of inhibition of leptin…
Obesity is most commonly a disorder of insulin excess/inflammation. Changes in leptin level mirror this, as leptin is increased by over-full fat cells and insulin that is constantly acting on the fat cell.

Hyperinsulinemia prevents leptin from working properly. Transport of leptin across the BBB is reduced by triglycerides, which are the byproducts of creating fat in the liver, secondary to glucose / fat excess.
http://www.healthy-heart-guide.com/lowering-triglycerides.html
Too much glucose & fat -> glycogen. Too much glycogen -> glucose goes to the liver into triglycerides which are stored as fat.
When triglycerides are elevated, leptin does not work in the brain. This is functional, and it is correctable by fixing the problem with insulin and fat storage. Much in the way glucagon & glucose suppression suppression by insulin is functional, leptin suppression by high triglycerides (making/storing fat) is also functional. If insulin is too high, then you have pathological triglyceride elevation, pathological central leptin suppression, pathological glucose suppression/hypoglycemia, etc.

When insulin (glucose/fat) is controlled, leptin will work properly. Triglycerides will drop and leptin can cross the BBB to work as intended.

So, even though leptin levels are adequate, the obese person with high insulin/high triglycerides actively gaining fat is centrally leptin deficient. This is NOT leptin resistance, this is evolutionarily conserved mechanism to store fat during seasonal food excess. The way to correct it is by addressing the high insulin and high triglycerides which prevent leptin from working properly. You do not fix this problem by focusing on leptin, you fix it by focusing on insulin and glucose.

Peripherally, the obese person has more than adequate leptin – elevated SNS, free thyroid, free reproductive hormones, all suggests high leptin and high insulin.

5) Re: the regulation of leptin
No, leptin release is determined by numerous factors other than fat cell size. The most important / common ones are fat cell size, insulin level, and estrogen level (all of these increase leptin). Insulin is a powerful controller of leptin release, almost as much as fat cell size.

You can predict changes in insulin by observing changes in leptin, and you can predict changes in leptin by observing changes in insulin. Here is a list of factors that control leptin level:

1) Fat cell size (not to be confused with “body fat weight”, this in conjunction with insulin is a major determinant of leptin)
2) Insulin level acting on the fat cell (the second major determinant of leptin)
3) Estrogen (markedly increases)
4) Testosterone (markedly suppresses leptin, together with estrogen this is the third most important regulator of leptin)
5) Fatty acids and dopamine (suppress by suppressing glucose metabolism and increasing fat release)
6) Glucose and serotonin/melatonin (increase by enhancing glucose metabolism and decreasing fat release
7) Inflammation/chronic illnesses (increase, leptin is an immunomodulatory/bolstering hormone)
Sleep/stress (these decrease leptin, as increased stresses, decreased sleep, are part of the reduced inflammation/debilitated immunity associated with hypercortisolemic conditions)

Stephan said...

Hi itsthewoo,

I disagree that leptin is largely controlled by insulin. If you knock out leptin receptors in the CNS, you get massive obesity. If you knock out insulin receptors in the CNS, you only get modest overweight. Knock IR out in muscle, liver, fat, any other tissue, you don't get obesity, only slightly higher fat mass in some cases. Knocking out the insulin receptor in the liver doesn't affect leptin sensitivity:

http://www.jbc.org/content/early/2007/06/07/jbc.M704053200.full.pdf

Increased serum leptin comes before elevated serum insulin and insulin resistance in humans:

http://www.ncbi.nlm.nih.gov/pubmed/16129731

Rosiglitazone (Avandia), a drug that increases insulin sensitivity and reduces serum insulin, causes weight gain, not weight loss. If you put rodents on this stuff they get massive. I've seen the abdominal cavity of mice on this drug, they're full of huge gobs of fat.

Leptin interacts with insulin signaling, but if anything insulin is mostly secondary to leptin signaling. Disrupt leptin sensitivity and you get hyperinsulinemia and diabetes, just like the Zucker rats, the ob/ob mice and the db/db mice.

ItsTheWooo said...

Hi again Lowell

1) If your friend is at least 40 pounds overweight (likely more) and female, her leptin level of 30 is absolutely normal. If someone told her that her leptin is too high, that person is wrong. That’s sorta what a 40+ pound overweight woman who is estrogen replete can expect.

2) Her body appears to be resisting fat loss. If a female is 40 pounds overweight with a leptin of 30, it is extremely unlikely that her insulin is “normal”.

Thyroid is an unlikely explanation as hypothyroidism involves low leptin (reduced metabolism of glucose, means reduces production of leptin as well).

Adrenal is also an unlikely explanation, as stress states suppress leptin too (sleep deprivation and stress slashes leptin production).

Whenever obesity occurs with high leptin, it’s almost certainly mediated by IR and elevated insulin, it is a fundamental abnormality in using energy properly.

Again if I were your friend I would totally question the finding that her insulin/glucose was “normal”, it seems really unlikely given her situation.

Has her insulin been measured after meals? If she is overproducing insulin to food, but her basal insulin is normal, that can be the problem.

Your friend isn't on any drugs (psychiatric, OCPS) is she?

It is important to realize leptin is produce by insulin acting on the fat cell. Anyone with a leptin that high VERY likely also has elevated insulin as well. Perhaps she is not extremely hyperinsulinemic, but she definitely doesn't have low insulin.

Seeing as fatty acid efflux suppresses leptin, and glucose metabolism/influx raises it, it might simply be that your friend's lack of weight loss and high leptin is simply evidence of itself.

Leptin is high when fat is not leaving the fat cell. Leptin is high when insulin is pushing glucose to be metabolized in the fat cell.
Leptin is low when fat is leaving the fat cell. Leptin is low when glucose is not entering the fat cell to be metabolized.

The obesity of your friend and her high leptin is just evidence of the obvious - she isn't losing weight, her fat is not leaving fat cells, etc.

Reasons why this may occur are as diverse as the nebulous physiological processes in our bodies. Who knows, she could have some rare genetic abnormality which causes fat loss resistance. *shrug*
But, for the majority of people with her profile, the #1 reason is going to be HYPERINSULINEMIA mediated, secondary to diet/nutrient/lifestyle deficiency.

Lowell said...

IsTheWoo-- I'm not saying her leptin levels aren't normal or expected. And you're wrong about her insulin levels-- they are normal. Insulin is no longer the issue here.

Your response is somewhat troubling to me. You seem to start from a set of assumptions, and when faced with an example that calls those assumptions into question, you fall back on stating that the insulin tests must be wrong, or the leptin tests are wrong... or there is some other "nebulous" cause. This is not a reasonable way to approach a problem, and not productive.

I agree that in the vast majority of people resolving the hyperinsulinemia is sufficient to resolve any leptin resistance which has developed, and things largely go back to normal (in terms of weight). However, I think some individuals develop enough leptin resistance that resolving the insulin issues is not sufficient to resolve the leptin problems which have been caused. I think these cases are the minority, but my friend appears to be one of them. I have numerous other individuals I've worked with who have lost all their weight with no issues by simply resolving the insulin problems. The friend in question here has not experienced that same thing.

Just because most people have their high leptin levels return to normal when they resolve their insulin issues doesn't mean that leptin resistance does not exist. It means that, for most people, leptin resistance is not permanent and can be resolved by correcting insulin. That in no way proves that, for others, leptin resistance can reach a level wherein it does not reverse itself simply by fixing insulin levels. For these individuals, their leptin resistance is high enough and their fat cell size/count (i.e. leptin levels) high enough that the strictest insulin and calorie controls are not enough to reverse the condition.

This seems far more plausible than a mysterious unknown cause, or repeated bad test results. We've been working on this for a long time, and have run and re-run huge numbers of tests. The only issue right now appears to be high leptin in the absence of the expected symptoms of high leptin. The body is behaving like leptin levels are normal, when they are not. If that isn't leptin resistance... well, you haven't offered another reasonable explanation.

High leptin can be a problem. Yes, it is the correct and normal physiological response to extreme positive energy balance (via obesity). However, that doesn't mean there are no negative effects associated with it. As the blood brain barrier is saturated and leptin receptors are affected the high levels stop having as much of an effect. For some time this is likely reversible... in much the way that insulin resistance is typically reversible. But in the same way that insulin resistance eventually develops into diabetes, and eventually results in beta cell burnout and other permanent damage, I'm suggesting that the initial reversible leptin resistance can increase to levels that are harder to reverse. How much and how I'm still learning. But there is plenty of evidence that it exists at some level. It's caused by chronic high leptin (not the other way around).

ItsTheWooo said...

Hi Stephan
1) Leptin is controlled by insulin in the sense that leptin production in fat cells is increased by insulin mediated glucose metabolism in them.

Yes, leptin receptor knockout in the brain is going to produce massive obesity, of course. As I said, a lack of leptin causes genetic anti-starvation programs to run unsuppressed. In an environment which is food replete, this is a recipe for extreme obesity. The body and mind behaves starved, but food is freely available… you can imagine what happens.

I expect frank insulin resistance to occur last in the cascade of metabolic disorder; that is a late finding (obesity is mostly an issue of hyperinsulinemia, not resistance to it… resistance is more of a diabetes thing).

Re; the study that finds leptin elevation as a predictor of metabolic syndrome…
This shift toward higher leptin represents early insulin resistance, possibly occurring before any “statistically significant” change in insulin level or glucose use or OGTT result. Early leptin elevation represents a shift of glucose oxidation away from skeletal muscle and toward adipocytes. This occurs before insulin level becomes pathologically abnormal, or before OGTT results become markedly abnormal.
Since leptin is reactive to glucose oxidation in fat cells, a slight rise in leptin will mirror a change in how glucose is being used (more by fat, less by muscle). This is part and parcel of early metabolic syndrome. Skeletal muscle IR comes before fat cell IR. Slight leptin increase is a sign of that.

http://endo.endojournals.org/cgi/content/abstract/139/2/551
Evidence That Glucose Metabolism Regulates Leptin Secretion from Cultured Rat Adipocytes
“We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. “


2) Re: avandia. I am not too familiar with this drug, but if it “increases insulin sensitivity and reduces insulin level”, it probably does so in a really physiologically abnormal way, possibly by making fat cells suck up fat/retain fat, which in turn would cause obesity but might hypothetically improve IR and reduce insulin level.

This was my first guess, and a quick google suggest this is precisely how avandia/ TZD works. It causes an increase in adipocyte differentiation (i.e. growing more fat cells, a tumor of fat tissue), which increases insulin sensitivity by offering a vesicle for excessive fatty acids/glucose secondary to metabolic dysfunction. It basically causes obesity but temporarily ameliorates diabetes.

If you’ve noticed, the super morbidly obese are rarely diabetic (and if they are, it is mild), whereas those who are badly type II diabetic are usually only slightly fat (comparatively speaking).
As peter from hyperlipid once said … “Being fat is bad when you stop”.

Even if avandia were an example of leptin-mediated obesity, the mechanism is by leptin suppression (possibly because the PPAR receptor is responsive to fatty acids, and fatty acids suppres leptin as it indicates fat loss).

http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0008196
“We found that treatment [with TZD] leads to [adipocyte] hypertrophy that leads to an approximately linear rate of cell diameter increase (2 mcm/day), and that the hyperplasia evident in treated animals occurs largely within the first eight days of treatment. The availability of additional lipid storage due to treatment may alleviate lipotoxicity and thereby promote insulin sensitivity. The hypothesis that a TZD regimen involving repeated treatments of limited duration may suffice for improvements in insulin sensitivity merits further investigation.



3) Leptin does control insulin, but only while deficient… and leptin deficiency only ever occurs when insulin is also deficient (cogenital leptin deficiency/receptor abnormality being very rare conditions)… otherwise, insulin controls leptin.

ItsTheWooo said...

Lowell –
I said: If your friend is 40 pounds overweight, the most LIKELY reason is high insulin. Which is the only reason I questioned your assertion her insulin is normal… it’s very unlikely for someone to be 40 pounds overweight, with elevated leptin, yet normal insulin. That’s not likely. It rarely happens. Very rarely. It happens so infrequently, it might as well be considered impossible.

I question the finding not out of a dogmatic belief on my behalf, but simply because high insulin is the most common reason someone is fat with high leptin.

It’s like if you said “My friend has low T4, low T3, hair loss, a hoarse voice, low body temp, sleeps a lot, thinks slow, but her TSH is normal”.
It is understandable that I would question your statement that her TSH is normal. This clinical picture described above USUALLY also goes along with a slight or significant increase in TSH (although, not always).

In the same way, being 40+ pounds overweight, having trouble losing weight, having high normal leptin *rarely* goes along with a normal insulin level. It just rarely happens, because elevated insulin is the most common reason for her symptoms (weight loss difficulty, fatty acids staying in the fat cell, high glucose metabolism in fat cell, leading to elevated leptin).

However, I do accept it is possible, and it has happened before. In the case of your friend, it probably represents that which is already self evident – it represents an inability to lose more body fat – fat is not leaving her fat cell, her fat cells are continuing to metabolize a high rate of glucose, etc. The most common reason for this is high insulin and high glucose, but it is not impossible for genetic abnormality/atypicality to also cause it. You are saying leptin resistance is causing her problems, but there is zero proof of this. There are a *lot* of reasons fat stays inside a fat cell driving up leptin other than leptin resistance.

Lowell said...

Just to clarify in as brief a way as possible, I'm suggesting that hyperinsulinemia is the cause of obesity. However, simply removing the cause isn't necessarily enough to reverse the condition, once developed. For some, this is sufficient, and the process goes like this (chronologically, and obviously oversimplified):

1. Hyperinsulinemia
2. Obesity, and corresponding high leptin levels
3. Mild to moderate Leptin resistance
4. Hyperinsulinemia is resolved
5. Leptin resistance isn't enough to prevent decrease in adipose mass
6. As weight is lost, leptin levels decrease, and leptin sensitivity increases
7. Normal weight is obtained, leptin and insulin sensitivity return to normal as well

For others, it goes like this:

1. Hyperinsulinemia
2. Obesity, and corresponding high leptin levels
3. Leptin resistance - severe (likely a combination of duration of obesity, degree of obesity, and possible genetic factors)
4. Hyperinsulinemia is resolved
5. Leptin resistance is severe enough that the reduction in insulin is not enough to reduce fat cell mass and leptin levels and start the cascade that eventually restores leptin sensitivity.
6. Stuck!


I think it may be misguided to try and decide which of leptin and insulin are the "master" hormone and which one is the only one that matters. They're each important. From what I've learned, insulin seems to be the primary culprit as a causitive factor for obesity. That doesn't mean it's the only important thing in resolving and reversing obesity for everyone. For some people, the damage done by obesity may extend beyond simple insulin stabilization and normalization. Leptin resistance is a plausible mechanism for this, and is currently the only available hypothesis for my friend. Trust me, I'm looking for other explanations. We'd like to resolve this as soon as we can, of course.

Lowell said...

IsTheWoo-- looks like we both posted at the same time... let me quick reply to your most recent post.

Understood-- it's just a bit tiring to have to go through the same long series of questions from people and challenges. No one is willing to believe me when I share my friend's information. Saying "It happens so infrequently, it might as well be considered impossible" is something I hear a lot, trust me.

That being said, we've tried to find explanations and prove that it is impossible, but it is what it is. It is possible, and that's the situation. Telling me it's impossible is to deny the evidence presented. I understand it's hard to know if you can trust my evidence, so no hard feelings for questioning that. However, I can assure you, I've gone to great lengths to try and question all the evidence, and it all checks out.

So... that basically leaves us with you saying it's genetic, and there's nothing that can be done. I don't think that's likely... and certainly isn't helpful in resolving the condition ;-).

I don't agree with your assertion that there is no evidence for leptin resistance. There is evidence for receptor modulation, and for blood brain barrier saturation.

Razwell said...

Stephan

I think Gary Taubes is 100 % correct in attacking the energy balance hypothesis. It is a hypothesis born of logic alone and completely ignores the data.

We now have a worldwide epidemic of obese 6 month olds, we have obesity and malnutrition strongly linked. The classic caloric model of obesity completely ignores these facts.

Gary Taubes' only fault is that he has not yet satisfied a complete alternative hypothesis of obesity .

Taubes is ignoring his own data in the photos he shows of the victims of lipodystrophy.

The blood insulin level is the same everywhere in the body, so insulin cannot explain why they are morbidly obese in the lower body and rail thin in the upper body and vice versa.

No one really to date has provided an alternative hypothesis . Science is moving forward very slowly on this matter. The industry LOVES the energy balance hypothesis because it blames the individual.


Take care

Razwell

Neonomide said...

Very recent Princeton Study seems to confirm that HFCS really IS the main culprit, at least in rats:

http://www.princeton.edu/main/news/archive/S26/91/22K07/


Similar calorie intake and big differences in weight gain -> awesome stuff.

Seems that the obesity mystery may be solved, What do you think ?

robrob said...

I think maybe leptin is only a signal of the amount of fat storage. the brain decides the setpoint. if leptin is higher than the setpoint the body increases energy output and decreases appetite.

when you lose fat naturally leptin will fall, but if it falls below setpoint that the brain has set then your appetite will increase. insulin is a appetite hormone, makes you ravenous if high, if cells are resistant then that is the problem not high insulin. so if you force your body to lose by undereating, then naturally leptin falls but the weight setpoint has not come down so weight rebound via ravenous hunger.

which caused it high insulin or resistance? chicken or egg question.

setpoint is determined by food quantity and food quality. if you have a diet history weight loss via hypocaloire (less than maintence cal intake) then your body remembers that and responds accordingly. the brain has a long memory for survival threats like dieting. so you can have perfect parameters, but if your setpoint is high you will remain fat.

the health problems with obesity such as high insulin or leptin resistance high triglycerides and the like are only survival mechnisms responding to bad eating practices (low cal or poor quality over long term)malnutrition as it were.

I wouldn't be surprised if they put stuff in our food to make us eat more via insulin resistance, leptin resistance etc. profit and all being more important than health.

famines cause insulin resistance, high triglycerides etc, whether that family is quantity (not enough caloires even if high quality) or just low quality like junk. thrify gene only determines how famine sensitive you are and how you respond to undereating, crap eating or malnutrition or overexercising or drugs or even chemical addictives.

lets face it we all should avoid high glycemic poor quality stuff regardless if we have a weight problem or not, thin people need to eat well too not just the obese. it is okay occassionally but not normal fare.

I read that high triglycerides is a safty mechnism in enviroment of insulin resistance as high sugar is more damaging then fat and the cells can't use the glucose fast enough or can't use it at all, and still need energy and to conserve glucose that is there for brain the cells of body need fat, and to have it readily and protected they accumulate it within itself, fatty liver, for the liver's own use, fat heart for heart only, (fat attracts bacteria to live hence immune response and plaque build up and the like). not fat itself but what it attracts. fat inside muscles for muscle use only. this is only shorten form to explain it.

RRR

Sonya said...

I'm a little late to this party, but this is what I was looking for! Both the post and the comments. I can stop emailing you for a bit now, Stephan, as I catch up on all your "hyperphagia" posts. :)

But the way, I'm surprised you weren't aware that obese people do in fact become leptin deficient upon weight loss -- it's a huge reason why we gain the weight back, or their hunger gets more intense as our weight loss progresses. We lose as much as 50% of circulating leptin when losing only 10% of fat mass.

Now whether it falls lower than lean people, I don't know, but the endocrinology textbooks I've read agree that leptin falling is a much stronger signal to eat than high levels are to stop eating. Lean people's leptin levels are much more stable than obese people's.

Paul said...

Leptin signaling occurs primarily in the hypothalamus. MSG injected into new born rats damages the hypothalamus and obesity results. So perhaps leptin resistance is caused by damage to the hypothalamus.

''Hypothalamic lesion induced by injection of monosodium glutamate in suckling period and subsequent development of obesity.'' Tanaka K, Chimaera M, Nakamura K Kusunoki. Exp Neural. 1978 Oct.

(I'm not suggesting eating food rich in MSG or other type of free glutamate cause obesity. I just cite this source as a reference to a hypothalamic trauma-obesity link. I suspect there are many ways to damage the hypothalamus either temporarily or permanently)

Unknown said...

Hi,
I just discovered your blog and am trying to catch up, reading everything from your first post! So good!!! Thanks!
My two questions - sorry if you already answered those or if it seems uncoordinated, I'm trying to link all the information, but right now it seems too much for my level of knowledge:
1) Supposing leptin resistance is linked to high triglycerides in the blood, going on a very low carb diet would help the brain listening leptin back and making a person to lose weight...but not helping reset their setpoint, since people going on Atkins-like diets go back to their original (over)weight if they stop dieting. Does it make sense or am I missing something?
2) Take a keto-adapted person who is not losing weight anymore and is overweight. Would something like CarbNite function as hormesis and help lowering their setpoint?

Sorry about the long questions!! :)

Best regards,
Nic