Saturday, January 23, 2010

The Body Fat Setpoint, Part III: Dietary Causes of Obesity

[2013 update: I've edited this post to remove elements that I feel were poorly supported.  I now think that changes in the setpoint are at least partially secondary to passive overconsumption of calories, particularly low quality calories]

What Caused the Setpoint to Change?

We have two criteria to narrow our search for the cause of modern fat gain:
  1. It has to be new to the human environment
  2. At some point, it has to cause leptin resistance or otherwise disturb the setpoint
Although I believe that exercise is part of a healthy lifestyle, and can help prevent fat gain and to some degree treat overweight, it probably can't explain the recent increase in fat mass in modern nations. This is because exercise doesn't appear to have declined. There are various other possible explanations, such as industrial pollutants, a lack of sleep and psychological stress, which may play a role. But I feel that diet is likely to be the primary cause. When you're drinking 20 oz Cokes, bisphenol-A contamination is the least of your worries.

In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:
  • Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
  • Low-carbohydrate diets are somewhat effective for fat loss and lower triglycerides
  • Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
  • Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
Inflammation in the hypothalamus, with accompanying resistance to leptin signaling, has been reported in a number of animal studies of diet-induced obesity. I feel it's likely to occur in humans as well, although the dietary causes are probably different for humans. The hypothalamus is the primary site where leptin acts to regulate fat mass (3). Importantly, preventing inflammation in the brain prevents leptin resistance and obesity in diet-induced obese mice (3.1). The hypothalamus is likely to be the most important site of action. Research is underway on this.

The Role of Digestive Health

What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.

Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.

Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).

A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.

Overall, I think gut dysfunction could play a role in obesity and other modern metabolic problems.
Exiting the Niche

I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.

In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.

The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.


Robert Andrew Brown said...

Stephan many thanks for all your hard work.

I agree that excess Omega 6, lack of Omega 3, lack of vitamin D,and minerals, are key factors behind increasing levels of western illness for a wide variety of reasons.

Dr. Art Ayers said...

Stephan, thanks for the grand summary. I would just like to an another embellishment, the communication between gut and gut flora that alters the composition of both the gut flora (relative proportions of the numerous species) and also the components of the immune system, which resides predominantly in the lining of the GI tract.

Note this study of changes in gut flora based on dietary changes in humans:

Stephan Guyenet said...

Hi Art,

I agree that communication between the gut and gut bacteria probably plays a role as well (especially considering the phenotype of sterile mice). I don't subscribe to the theory that gut biota disturbances cause obesity because they allow us to extract more energy from food though. That should be irrelevant if the fat mass homeostasis mechanism is working correctly. But that doesn't preclude other effects through the immune and endocrine systems as you mentioned. I hope you continue writing about that in the future.

Robert Andrew Brown said...

You are what you digest. (-:

Excess Omega 6 is connected with gut dysfunction.

Poor digestion compounds nutrient depletion.

Tim G. said...

Hi Stephan,
I'm new to your website and wanted to say WOW! What a treasure trove you've put together here. Thank you for the all the time and effort you've put into this and making it available for all of us. I look forward to browsing through your back posts.

As a Naturopathic doctor with an emphasis in digestive health I have to agree that gut dysfunctions can cause a huge amount of suffering for people. I had seen the data implicating gut flora in obesity but had never considered hypothalamic leptin resistance as a possible mediator. Great to consider.

The idea of hormone resistance I think is still very new to most docs. Insulin resistance, sure. But I think most of us don't often consider other hormone resistances, such as thyroid hormone resistance, sex hormone resistances, and now, leptin resistance.

I look forward to your next post on this topic, and can say from my experience that normalizing GI health has an almost magical effect on people's overall health and well-being.

Greg said...

Great post! I would love to hear your thoughts on carbohydrate/fat ratios in the diet and why high fat often leads to immediate weight loss and there is less hunger on a high fat diet (as discussed in Good Calorie, Bad Calorie). Is high fat is a mechanism to help reset the set point?

Tim G. said...

Hi Greg,
If I understand the literature correctly and GCBC, aren't we looking at appetite suppression from a reduce carbohydrate high fat diet as a result of low insulin, stable blood sugars, and high ketones (not necessarily ketosis)?
Intuitively it makes sense that if the body and brain have enough fuel they won't signal to take in more food. If blood sugar can remain stable and sufficient through a low insulin and correspondingly sufficient glucagon and is being supplemented to brain tissue with a healthy supply of ketone bodies then there's no great need to signal for more food.
In contrast when someone is on the typical SAD diet, the high carbohydate, high glycemic load intake causes spikes of insulin and blood sugars surges in waves of high and low. And as anyone who has ever experienced or seen someone in a even a mild hypoglycemic crash they need to eat NOW.

My $.02. Don't know a lot about leptin and looking forward to Stephan filling in that piece of the puzzle.

Ilya said...

Inflammation there is, and an oxidative stress to accompany it, too. But that it reaches to the hippothalamus is a little bit of a stretch. However there is a direct association between the insulin levels and those of leptin in other words they are synced:
and interestingly they work through one and the same buffer mechanism which is instrumental in controlling body weight(and not only it) and this is the Brown Adipose Tissue Thermogenesis:
The Tipping of the "Body Set-Point" as you formulate it occurs whenever a dissonance between the innate acclimation pattern and the corresponding diet macronutrient content takes place. What is a this correspondence I'm talking about? It's very precisely, I would say, mathematically expressed through the Respiratory Quotient of Food at different temperatures i.e. High Carbohydrate Diet(RQ approx. 1)is characteristic for hot climate and temperatures that is for heat-acclimated populations. On the other hand, High Fat (RQ approx. 0.6 corresponds to temperate and cold climate acclimation. What happens if this correlation is toppled ? Increased oxidative stress,inflammation, obesity, diabetes... not necessary in that order. Regards, and take your time. said...

Stephan, do you recommend that we supplement our diets with oligofructose, and if so, how?

Anneatheart said...

Hi, I've been reading your blog for a few weeks and just wanted you to know that I'm anxiously awaiting your posts on this body fat set point topic.

I've been stuck at a specific weight for a long time- 7 years! (since my first child was born) Even though we've adopted the principles of Nourishing Traditions and Weston Price, my body is still stuck it seems. (of course, I've been pregnant off and on 5 times, which I'm sure has something to do with it)

Anyways, I'm trying desperately to connect all the dots to figure this out and find the magic key to unlock my once muscular and lean body out of this fat one!

Thanks so much for all the effort put into these posts. I greatly appreciate the information you're putting out there.

God bless,

zach said...

Thanks for the posts. I'm curious about the role of the fiber. Eliminating sugar and grains restored my health. Fiber from vegetable source doesn't seem to help or hurt me now, and this would be consistent with several traditional cultures that didn't get any fiber. What would you consider adequate dietary fiber?

You mentioned stress, and I think that plays a role. So many people today have their amygdala "set points" screwed up it seems logical that it would have some negative effects. Everyone knows chronic stress depresses their immune system and digestion, even if we don't know the exact mechanism.

Matt Stone said...

Do you think other bacterial agents can also trigger the release of LPS, or just the gram-negative bacteria in the gut?

The most interesting theory of obesity and insulin resistance I've come across is that of Russ Farris and Per Marin (Potbelly Syndrome). They believe that obesity and insulin resistance are caused by... heart disease.

There's no question that arterial lesions precede both, found in almost all autopsies of young children.

The question then becomes, what fosters chronic infection, bacterial overgrowth, and other sensible causes of chronic inflammation?

Your assessment is very good I think. The hypothermic effects of alcohol and potentially fructose may have a role in lowering resistance as well.

Still much to be left uncovered.

High-glycemic carbohydrates do not cause large rises in blood glucose unless you are insulin resistant - but I believe this can be overcome.

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

supplement with oligofructose. My triglycerides are 42. My HDL is 97. My C-RP is .6, my calcium scan is zero, I am no longer insulin resistant nor obese. I am 25 pounds overweight, after having lost 65 pounds while eating HF/LC steadily over two years. Kept it all off for years, but couldn't lose another ounce after having major surgery three years ago. In fact a year after surgery I gained 10 inexplicable pounds with no change whatsoever in diet.

I eat a high fat, modest protein, low carb diet that contains no processed food of any kind. My ratio of O3 to O6 (of which I have very little) is great. I eat grass-fed meat only. I am the poster child for your theory -- except that I am extremely leptin resistant as shown by my blood tests.

Those tests also revealed that the LR had caused me to become thyroid hormone resistant as well (thus explaining the ten pound gain), by pooling T3 in my blood and blocking it from my cell receptors by raising my RT3 -- which also caused incredibly high, outlier cholesterol. I fixed the TR problem by taking Cytomel, which caused a 120 point drop in my TC and my LDL in six weeks.

Thus I believe your theories about the cause of this problem are interesting but incorrect. My own research has led me to believe that LR is caused by stress to the endoplasmic reticulum (which can be caused by surgery, for instance) and that "curing" it -- or becoming more leptin sensitive will NOT be done by diet change but by medication. With my Endo's support I am currently doing an Experiment of One to see if this is in fact the case on and so far it it appears to be working.

Ilya said...

@awriter Sir, the link you posted doesn't seem to work. I'm quite interested in what you say about LR as I'm trying to reconcile it with my findings. Leptin, Insulin, Thyroid and Norepinephrine have one and the same focal point-Brown Adipose Tissue and they all incite Thermogenesis. Defects in BAT (and BAT thermogenesis) lead to a number of metabolic syndromes. I would be glad if I can contact you and have some more info about your Experiment of One. Thank you in advance.

Ned Kock said...

A problem so widespread as the metabolic syndrome may well have a genetic cause that evolved among one or more ancestor subpopulations.

As strange as it sounds, harmful traits do evolve, as genes compete among themselves. The unit of selection is the genotype (set of genes) coding for a trait, not the host.

This may be one of the causes of modern fat gain; other causes may well be bad dietary habits. These may interact and moderate each other.

It seems that the majority of us do not develop diabetes, even after years of heavy consumption of refined carbs and sugars.

Ned Kock said...

Note: My previous post is not an invitation to consume refined carbs and sugars. They are bad for us. What I mean to say is that a genetic predisposition may be a very strong factor, and that such genetic predisposition might have evolved among our ancestors (rather than being the result of spurious genetic mutations).

tooearly said...

I think that the social determinants of health, while the most difficult to study due to their inherent complexity , are the predominant causes of obesity. We need to get away from reductivist agendas: if you stop taking meals with your family (or even better, your community), you are probably likely to eat more fast food, eat it in a hurry, eat it without joy, and so forth.

awriter said...

Ilya wrote: @awriter Sir, the link you posted doesn't seem to work.

Sorry, I made group plural instead of singular. The link below should work now.

Robert Andrew Brown said...


I would guess you do but what is you view on exercise?

Many thanks

David said...

Masterful summary, Stephan. Given your conclusions regarding the influence of the gut in all of this, I wonder if the effects that vitamin D seems to have on weight (in the sources you cited as well as anecdotally) might also have something to do with its healing effect on tight junctions in the gut.


Ed said...


I'm curious your thoughts on weight gain caused by thyroid dysfunction, which might be widespread due to low iodine consumption or flouride insult?

Ed said...

Is oligofructose the same thing as inulin? The term sounds like it would be.

Mavis said...

Great post!

I've read that ibuprofen and soy also cause "leaky gut." There are three things that have exploded on the scene since 1980 - ibuprofen, soy, and high fructose corn syrup. Along with the other things you mention, do you think those factors could help account for the explosion in obesity in the past 30 years?

When I was a kid in the 1970s, we ate a lot of sugar and white flour, probably got little omega 3, and already were consuming a lot of industrial seed oils (though the low-saturated-fat dogma had not set in). Yet most of us were skinny kids. Kids aren't skinny anymore.

We did get more sun and more sleep than kids now. And there was not soy and HFCS in everything. And no ibuprofen, though that's not as much an issue for kids as for us womens and our migraines and our cramps (which are probably largely caused by the same inflammatory crap that causes all of this stuff).

It also seems kids did not have so many allergies back then, though I did.

awriter said...

Robert Andrew Brown asked: "I would guess you do but what is you view on exercise?"

While I was losing the 65 pounds I couldn't exercise at all because I couldn't walk. Now that I can, I work smarter, not harder. I do the Big Five weight lifting exercises from _Body By Science_ for about 8-10 minutes a time, once a week or ten days, depending on how long it takes me to recover. I have biceps so hard you can bounce a quarter off them. :)
Ed wrote: "weight gain caused by thyroid dysfunction, which might be widespread due to low iodine consumption or flouride insult?"

If only. Thyroid HORMONE dysfunction (as opposed to thyroid GLAND dysfunction) is generally caused by T4 converting to the metabolically inert Reverse T3 instead of the metabolically active T3. Thus, all thyroid 'tests' show normal function when in fact all T3 is pooling in the blood instead of reaching the cells. It's exactly like insulin resistance. And it's the hypothalamus that sends the T4 to T3 or the T4 to RT3 signal. My theory: that signal is based on the leptin signal to the hypothalamus -- or in the case of LR, no signal getting through. Turning down the metabolism heat via T4 to RT3 is the fastest, easiest way for the brain to conserve energy when it believes there's an insufficiency.
Ed asked: "Is oligofructose the same thing as inulin?"

It's not, but it's *extracted* from inulin. Unlike inulin (which I add when I make yogurt), oligofructose is sweet and can be used in part as a sugar replacement even though it's a fiber rather than an artificial sweetener. It gives dairy and chocolate the same 'mouth-feel' sugar does, and I use it whenever I make LC ice-cream.

Anonymous said...


I had a similar experience in childhood as well. Perhaps saturated fat prevents some of the damage caused by sugar and white flour? It should blunt the insulin effect of carbs (I think), but perhaps there are others things that saturated fat does as well.

I don't think saturated fat consumption is anywhere CLOSE to what is was in the 1970s. Toast is made with margarine...restaurants use cheap grease full of Omega-6 (they aren't spending money on butter!) food is corn oil. I've heard Dr. Oz and Dean Ornish exclaim that saturated fat consumption has increased in the past 30 years but I think that notion is totally insane.

Ed said...

Saturated fat intake has dropped over th last 40 years.

saturated fat is protective of the liver in the face of fructose and alcohol, look for the drinking mans diet and posts by Peter at Hyperlipid.

Neonomide said...

Obesity seems to possibly lower Vitamin D levels:

In a very recent RCT 1000 µg (+ 500 mg calcium/day) per week (n = 449) Vitamin D administered to obese people with no fat loss effect in 12 months:

Despite the impressive rise in 25(OH)D, I'll be first to admit that divided dose of 100 µg a day a day may not be enough for fat loss. Yet other studies also lead to same direction - no potato.

It might be that sunlight has some independent effect on bodyfat, as may be extrapolated from this Vitamin D Council's newsletter:

ItsTheWooo said...

Steven, I agree with most everything you wrote.

Most specifically, I agree with the idea that "obesity" is not caused by one thing, but by a complex interplay of low level nutrient and lifestyle deficiencies - not just dietary ones, but also lack of sunlight, lack of sleep, excess/abnormal exposure to stresses (too much psychological and not enough physiological).

Lack of sunlight will fatten any person vulnerable to it, no problem.

I've recently been researching the role of light in health, I am *amazed* to discover so many nebulous health conditions I have are light responsive.

Light is a nutrient, as essential as protein. Not seeing bright light, it's like being deficient of protein. It is really, really essential.

Sleep is huge for terminating stress response, and bolstering a proper immune system. People are fat when they don't sleep, this is consistently observed.

Sometimes, people just can't accept that perhaps we are fat not necessarily because we aren't eating organic beef and bean sprouts, but maybe we are fat because of something really basic like "not seeing the sun anymore" and "not sleeping 8-9 hours a night anymore".

Most of us will agree, but few of us will modify anything.

Why is that?

I think it is because, on some level, we don't believe that light/sleep matter that much. In reality, they matter a whole, whole lot.

In my opinion, sleep/sun deficiency accounts for a whole damn lot of why people are fat.

The rest is stuff like chemicals (plastic, hormone disruptors) and crappy, crappy, crappy ass food that simply was not as commonly eaten 40 years ago.

Matt Stone - saying HD causes obesity, is like saying kaposi's sarcoma causes toxoplasmosis (as pertaining to HIV and AIDS). I mean, those are two symptoms of a common related pathology. Inflammation/insulin/glucose causes HD, it also causes obesity. Unless there is data I don't know about, otherwise, HD and obesity are caused by similar underlying mechanisms which is why they often coexist (especially in diabetes).

Robert Andrew Brown said...


Thanks for those interesting links.

In simplistic terms does not more fat equate to greater storage space and so dilution of the available vitamin d in the blood.

It would have been great if they had looked at other markers as well.


It sounds as if you are making great progress.

Several papers seem to suggest that the loss of visceral fat in the overweight will not happen without exercise. Dieting alone was not sufficient.

I too need more exercise (-: and could do with doing some weights.

Helen said...

ItsTheWoo -

I'd have to agree with you. Whenever I've gained weight, and even when I'm skinny, I store fat in my belly. I noticed this first when I was 13 and pretty slim. I think I always have some baseline metabolic disorder because I have not been able to sleep well since I was 12, when there was a huge amount of stress in my family.

I think this is why I've noticed, more than a lot of other people I know, the ill effects of sugar on my mood and energy, and have tended to eat far less of it. I also knew I felt destroyed by all-carb meals and avoided eating that way long before I had much theory to back it up. I think these semi-instinctive habits are what's kept me among the living despite my constant sleep deprivation.

Mark - Dr. Ornish and Dr. Oz (where'd he come from suddenly, anyway?) are peddling a crock, of course. The only thing I can imagine might back up their claims that saturated fat intake has increased is if the fats they are referring to are hydrogenated oils, which replaced the dreaded "lard" and "butter." ("It's vegetable!") Of course, my mom, and all moms, deep-fried and baked with Crisco, even in the 1970s.

Jenny Light said...

As a child growing up (born in 1960), my Mom and Grandmothers all used corn oil, Crisco and margarine exclusively (the media had long informed them that butter was bad for the heart). My mom always had Hi-C and Kool Aid in the fridge, and just occasionally soda (up until about 1970 soda was made with sucrose). "Orange juice" was made from a powdered space age concoction called Tang. Our parents limited candy but not desserts. My sister and I were both thin, and I can remember only one kid in my elementary school class who was teased for being fat. In those days, we spent all of our free time playing outside.

In a nutshell, I believe obesity in today's children is being caused by: video games, sweetened beverages, snacking, and pre-packaged industrial foods (used almost daily by today's too busy parents). An important and often overlooked change from my childhood is genetically modified food additives (primarily corn and soy) that are found in just about EVERY commercially made food item found in the grocery store. I don’t think science yet knows how GM food products affect our bodies, both in the long and short term, but I’ll bet that allergies are just the tip of the iceberg.

awriter said...

Robert Andrew Brown said: "Several papers seem to suggest that the loss of visceral fat in the overweight will not happen without exercise. Dieting alone was not sufficient."

The Woo said: "Light is a nutrient, as essential as protein. Not seeing bright light, it's like being deficient of protein. It is really, really essential. Sleep is huge for terminating stress response, and bolstering a proper immune system. People are fat when they don't sleep, this is consistently observed."

The problem with confusing observation with causation is that it is but anecdote built on sand, since any hypothesis is only as good as the exception that disproves it.

First, I got fat while getting plenty of light and sleep and eating a low calorie (1100-1200 a day), low fat, high carb diet.

I got thin again (and reduced my visceral fat by a measured 75%) while being shut in due to a disability, getting zero exercise and with almost no sleep night after night due to the chronic pain that disability caused -- just by changing diet alone.

Since my surgery I get lots of sunlight and sleep like a teen for eight hours a night, every night. Yet this is precisely when I CANNOT lose an ounce of weight without pharmacological intervention.

If you have a metabolic disorder, I don't care what you eat, how much sun or exercise you get, or how little or much you eat: as long as your brain believes your body is starving, it will take every measure we know (and some we don't yet know) to ensure that energy is conserved despite any conscious effort.

Conversely, if you have a healthy metabolism, as does my very lean son and his father, you can do zip exercise, stay in the dark all day at the computer and eat all the pizza and pasta you like -- your body will ensure that nutrients are all handled and burned perfectly.

Ilya said...

@ awriter
I must admit you are right in your quest. Leptin resistance is related to the levels of GLP-1 as seen:
Anini et al.
and oligofructose supplementation is the way to go:
Delzenne et al.
Nice job. Please, keep me updated about that Experiment of One. I myself am in a such. I'm waiting the approval for the Yahoo Group so I can follow you there. BTW do you know that capsaicin also increases GLP-1? So how about some chilli peppers? And sorry for calling you "sir".

Anonymous said...


Yes, sleep is important, but I think the notion that a lack of it causes obesity is a bit far fetched. I believe the theory originally came from the fact that night shift workers are prone to obesity and they are also prone to poor sleeping habits. From this, it was thought that the liver operated on a circadian rhythm, but it has been discovered that this is not true. The liver responds to food intake at any time and night shift workers are prone to snacking and eating at odd times. Snacking on anything (even a healthy snack) confuses the liver, pushes up insulin, decreases leptin sensitivity, and prevents triglycerides from being cleared from the blood inbetween meals. Meal timing is *essential* to staying thin.


Sorry - I had to throw Dr. Oz in there because he seems to appear everywhere (Charlie Rose, Men's Health, etc.) throwing his 2 cents in about the obesity epidemic. My favorite was his argument with Gary Taubes on PBS where he said he didn't believe low carb worked. Then the moderator asked him what he ate during the day and Oz responded, "usually just walnuts or almonds."

Robert Andrew Brown said...


Thank you for explaining your experience.

Clearly the control of fat metabolism by the body is multifactoral.

Robert Andrew Brown said...

What if the role of leptin was primarily reproductive?

Oestrogen appears to stimulate leptin.

And Leptin may be able to induce ovulation.

What if high oestrogen plus high fat is just telling the body to stop thinking about food to and concentrate on sex instead.(-:

(This would make leptin about sex and reproduction rather than trying to regulate food consumption, even if the calorific effect is similar)

It is all clearly highly complex (-:

"Relationship between leptin and oestrogens in healthy women"

Leptin in Pregnancy: An Update

"Leptin influences satiety, adiposity, and metabolism and is associated with mechanisms regulating puberty onset, fertility, and pregnancy in various species."

Paradoxical Increase in Maternal Plasma Leptin Levels in Food-Restricted Gestation: Contribution by Placental and Adipose Tissue

Leptin induces ovulation in GnRH-deficient mice

Leptin induces ovulation in GnRH-deficient mice

Leptin Receptor (Ob-R) Expression in the Ovary and Uterus of the Wild Japanese Black Bear (Ursus thibetanus japonicus)

phanamere said...

@Jenny Light
Being approximately of your cohort, I totally identify with all of the “Leave it to Beaver” food imagery of your youth (Tang, Crisco, corn oil, margarine, Kool Aid). Let me add to that Hostess Twinkies, Howdy Doody jelly, Wonderbread (“builds strong bodies 12 ways”) and the astonishing “molded salad” – consisting of teeny marshmallows suspended in neon-tinted Jell-o which was seriously believed to be “food.” Yes, the kids were slim (in the 1960s) – exactly as you said. But with 40 years retrospective experience I am wondering if there was something more sinister going on. First of all, the 1960s were only the beginning of this high-sugar, refined-carbohydrate, hydrogenated fat-larded diet. This marked the start of a trajectory (in the U.S.) which has brought us to where we are today – the most obese and unhealthy among wealthy nations. Something that troubles me, on reflection, is the observation that within my mother’s immediate social sphere (bridge club, bowling club) 8 out of 10 women were diagnosed with and eventually died of Alzheimer’s disease – including her. I cannot claim a cause-and-effect relationship but I continue to find this observation ominous (I’ve consequently given up bridge and bowling).

Unknown said...


I wonder if you comment on this quote from Dr. Seyfried ( ketones v cancer and epilepsy )

"What exactly is so dangerous about unrestricted ketogenic eating?

The ketogenic diet contains large amounts of high caloric saturated fats. It is not healthy to eat large amounts of saturated fats. This will contribute to cardiovascular disease and diabetes. High blood glucose levels are associated with high fat consumption even when there are no carbohydrates in the diet. High blood glucose levels will accelerate tumor growth. The liver will synthesize glucose from the glycerol component of the triglycerides. Consequently, the KD should be consumed in restricted amounts, especially over prolonged periods. As I have clearly written in my articles, “more is not better” when it comes to eating the ketogenic diet for either epilepsy or brain cancer.

"Does this mean the only safe way to very low-carb is to engage in intermittent fasting or eat tiny meals?

Yes. People can prove this to themselves by simply measuring their blood glucose levels under these conditions."


Unknown said...


The question was based on Seyfried's comment that calorie restriction was necessary in addition to the ketogenic diet to work against cancer/epilepsy


Mrs. Ed said...

Great post!!! Isn't it interesting that the evidence you just presented for fat gain is almost identical to what I believe is also behind autoimmunity and a big contributor to autism and adhd? Some of us get fat, some of us get autoimmunity, some get ASD and some get it all. Remove essential nutrients and protective bacteria, then the LPS shedding bacteria and yeasts move in and voila. I heavily suspect our diet as the main culprit as well.

Mavis said...


LOL re: Dr. Oz everywhere. I know! WTF? I don't get it.

Henry North London 2.0 said...

I finally chucked out what ever corn oil I had in the house out. IN the bin Its not getting used here ever again

Inulin is an oligofructose Tap that in to google and this is what you get
Inulin consists of up to 90 monosaccharides (sugar building blocks). It is used as a reserve carbohydrate predominantly in plants like chicory, onions, artichokes and Jerusalem artichokes. Oligofructose is similar to inulin, but consists of shorter chains.

Inulin derived from chicory is the main raw material for industrial oligofructose production.

Inulin and oligofructose are increasingly being used as functional foods. They are dietary fibres that are not broken down in the stomach and intestine, rather, they first get broken down in the colon. Their breakdown products support the growth of desirable Lactobacilli bacteria and create an unfavourable environment for pathogenic microbes. “Prebiotics” such as inulin and oligofructose are thought to prevent digestive tract infections and support the immune system.

Both inulin and oligofructose are used in dairy products and drinks. They have a creamy consistency and despite their slightly sweet tastes, are very low in calories (1 kcal/g). In addition, they are thought to improve the uptake of calcium.

Scientists are now working on genetically modified chicory with stabilised inulin levels. Low temperatures lead to a natural degradation of inulin in chicory sprouts."

David said...

Aren't oligofructose and FOS one in the same?

Henry North London 2.0 said...

actually oligo fructose is less than 90 saccharides...

ItsTheWooo said...

awriter - The problem with your thinking, is you seem to be limited to assuming that a person's obesity must have a singular cause. At any given time, you are looking for "THE" reason behind your "metabolic disorders". I propose there is rarely a singular reason, and there are often several, and the majority cases of obesity are a complex lifestyle/genetic interaction. Some reasons are more important than other ones but there are usually multiple factors involve in obesity.

Regarding "confusing observation with causation", the mechanisms behind sunlight and sleep mediated metabolic dysfunction are well understood. It is not merely an observation I have made (that not seeing sunlight and not sleeping make me fat), but I have reserached it as well. Lack of sunlight results in neurotransmitter deficiency, causing lethargy, depressive mood, and metabolic disorder/weight gain (known as SAD/atypical depressive symptoms). Lack of sleep increases cortisol, decreases leptin, thereby contributing to metabolic dysfunction.

If there are other reasons why metabolism is disturbed, sleeping and seeing the sun are not going to help.

There is a logical failing here, people have a hard time understanding that the presence of a thing doesn't mean other things can't also come into effect, or that the outcome is decided based on presence/absence of any given thing. There are multiple factors here involved in determining metabolic state. It is RARELY just one thing.
For example, with the "leptin resistance" idea... just because leptin is elevated in obesity does not mean they are resisting it, as leptin does NOT prevent obesity. Leptin does very little beyond terminating anti-starvation genetic instructions. Low leptin is a problem, adequate leptin is good, high leptin does nothing much extra that adequate leptin won't do.

It's evident leptin has very little to do with obesity, and mostly is involved in regulating minimum bodyfat level. A person who is 300 pounds with a leptin level of 50 does not have a leptin problem. She may have a problem when she loses down to 140 and her leptin is abnormally low (common after weight loss), because leptin is only relevant in low body fat/weight loss situations and it has very little, NOTHING to do with obesity (with the rare exception of leptin deficiency mediated obesity, which is so extremely rare due to the fact it causes infertility and offers no advantage otherwise).

So, yes, a person can sleep a lot and get a lot of sun and still be obese, becuase there are numerous routes to hyperinsulinemia. So, so many ways to get there.

All I put fourth is that a very , very common route, an overlooked/underappreciated route, is the tendency of americans to sleep 6 hours a night and to never, ever see adequate full spectrum lighting.

I don't think any one thing is causing hyperinsulinemia (obesity), but, multiple factors are... many people can skirt sleep and sunlight and remain thin, but not many can, and I would argue that any person already vulnerable to hyperinsulinemia / obesity is going to be much fatter for doing so than they would otherwise have been.

Markus said...


You mentioned "adequate full spectrum lighting". Are full spectrum lights adequate in your opinion? Or is only the sun adequate?

Anonymous said...

The primary cause of abnormal gut flora, or dysbiosis, is not modern food but modern medicine.

The diysbiosis that results from poor diet is relatively mild and can be corrected by improved diet. The deep dysbiosis that can be brought about by antibiotics, particularly when used serially, is not so easily corrected.

Birth control pills are also a major cause of severe dysbiosis. If a mother gives birth while suffering from gut problems, the unhealthy gut flora will be passed to the baby during birth and during breast feeding.

There is a very strong correlation between gut dysbiosis and autism, and it has been found that the majority of those suffering from autism have severe gut problems. More often than not the mothers of autistic children also have abnormal gut flora.

Autistic children are more than twice as likely to be obese than children without such chronic diseases.

Unknown said...


Thank you for the info on the low leptin after weight loss... that's something that I'll have to keep in mind if/when I'm facing that.

re: the leptin issue though... I don't think that anyone has said that leptin has a negative feedback mechanism like insulin... (i.e. the pancreas secretes more insulin because it senses that the 'normal' amount isn't enough)... it's more that leptin is produced by adipose tissue... not in response to any signals of resistance from anywhere, but just b/c it exists... so if you have more fat, you'll secrete more leptin (which makes a lot of sense with respect to the hypothalamus response to leptin... decreasing appetite and increasing metabolism). And since leptin has been shown repeatedly to reduce appetite and increase metabolism, the question remains as to why that effect is not seen in obese people who invariably have more leptin... i.e. why doesn't the hypothalamus respond to the leptin by reducing appetite and increasing metabolism? There are many detailed studies showing that it does exist... the issue is what's causing it and how to fix it.

Anonymous said...

I just had a thought re: Omega-6. How much more Omega-6 are Americans consuming as a result of restaurants changing their food preparation techniques following the anti-saturated fat crusade of the 70s and 80s?

For example, anyone eating at McDonalds prior to (I think) 1980, would have eaten french fries cooked in lard or beef tallow rather than corn oil. I wonder what percentage of non-fast food restaurants also switched from butter/lard/tallow to corn or soybean oil for frying? 98%?

One result of my having adopted a diet extremely low in Omega-6 is that almost anytime I go to a restaurant I feel like I have been poisoned by vegetable oil. I wonder if this would have been different 50 years ago. And considering how much Americans eat out, Omega-6 consumption must have gone through the roof in the past 30 years.

Unknown said...

oh, and I just wanted to add that I agree there are many factors at work here, but that doesn't negate the idea that obese people are resistant the effect of the high leptin levels in their bodies. If the leptin response system was working properly to begin with, the body wouldn't gain that much weight in the first place. This doesn't diminish hyperinsulinemia's role, I think it's probablhy more of a self-reinforcing phenomena between the various actors. But there is SOME reason why the obese body doesn't respond to all of that insulin... even if the LR didn't cause the obesity, those high leptin levels should be getting through.

Robert Andrew Brown said...


HI I would be really grateful if you have some links to trials showing the relationship between plasma leptin and its effect on appetite.

Any thoughts on this trial which suggests 3 day tube feeding raised leptin but did not reduce hunger.

"The rise in circulating leptin concentrations, associated with tube feeding and the increase in total energy intake, failed to predict subsequent hunger or oral energy intake."


As ItsTheWoo suggested leptin is not an obvious obesity controller. It may affect metabolism but I do not feel that is its purpose.

Its role is a reproductive controller of some sort. Oestrogen increases leptin and testosterone reduces it, and it is significantly involved in reproduction.

My unfashioned off the wall musings are as follows;

Mammal behaviour in the wild suggests fat accumulation is good, and females need fat to breed.

Males have their appetite suppressed in the rut when I suspect testosterone is high.

Norepinephrine and epineprine stress hormones, fight or flight, increase transport of leptin into the brain according to this paper.

This makes sense as fight and flight and lazy repasts are mutually exclusive.

IF the output of the fat cells is simply a function of their size, and fairly constant in the short term as fat cells do not change size overnight, circulating leptin will be short term determined by leptin uptake by the brain, reproductive organs (in women) and other organs (liver and or muscles ????), rather than fat cell output which is a short term constant.

If stress related messengers, stress hormones steroids, testosterone? increased uptake then this may reduce circulating leptin. Brain levels would rise shutting down appetite for fight flight or sex.

At a reproductive level leptin would be a fuel gauge, that assisted breeding in times of plenty and closed it down in times of famine. Women would be switched on to breed by high leptin, and their appetite increased or at least not reduced.

Males would be rutting singing and protecting territory, and not having much time to eat.

This would mean that plasma leptin would need looking at in the inverse maybe, or does not mean much as it is mix of the ability of the fat cells to produce it minus the rate of uptake.

You would then need to look at brain uptake v fat production to draw any worthwhile conclusions?

Robert Andrew Brown said...


This would also make leptin a behavioural controller.

It also follows that to get leptin in the brain would need things that raised stress, which might include exercise which a form a very quick goggle (as I really should be doing something else (-:) is increase by exercise.

Robert Andrew Brown said...


And leptin is maintained in women even if uptake by stress is increased as it is made by cells in the uterus or ovaries which explains this trial below.

High leptin would maintain appetite in women via their reproductive cycle / pregnancy.

Paradoxical Increase in Maternal Plasma Leptin Levels in Food-Restricted Gestation: Contribution by Placental and Adipose Tissue

awriter said...

Itsthewoo wrote:

awriter - "you seem to be limited to assuming that a person's obesity must have a singular cause."

Except that's not what I actually said. Let's start at the top: a person ingests nutrients. The body can burn them, store them, or do both in varying combinations. What drives the burn, or store, or both, are the nutrients themselves (fat, protein, carbs, etc. and in varied combination), and the person's given metabolism at that time. Variables such as cells being insulin resistant or sensitive will affect that, as will being thyroid hormone resistant or sensitive, etc. There are so many hormones and glands and enzymes that can affect the metabolism at any given time, it is hard to pinpoint specific storage vs. burn problems. Hard, but not impossible.

One thing we do know from Taubes: in order to become overweight, you must, a priori, have a metabolic fat accumulation disorder. And now we know that leptin is the absolute ruler of every hormone in the body without a single exception.

Therefore, IF by a blood serum test it is shown that you have an excess of leptin -- not a dearth of it, as you seem to believe -- you are leptin resistant. You have a lot of leptin in your bloodstream, which means you must, again a priori, have a lot of stored body fat -- but little or none is reaching the brain.

Therefore, the brain believes you are starving, despite (again, as per Taubes) any amount of nutrient you ingest. Therefore, to stave off starvation, the metabolism MUST be slowed down. Of course there may be dozens of mechanisms at play that do this. Not one problems but perhaps many. Remember what Taubes said: "People don't get fat because they eat too much and exercise too little. They eat too much and exercise too little BECAUSE they are fat. They have no way to access any of the nutrients they eat because they are all locked away in adipose fat tissue. They are starving amid abundance."

"Lack of sunlight results in neurotransmitter deficiency, causing lethargy, depressive mood, and metabolic disorder/weight gain (known as SAD/atypical depressive symptoms). Lack of sleep increases cortisol, ****decreases**** leptin, thereby contributing to metabolic dysfunction."

Well, there's your problem. Obese people aren't obese because they have too little leptin -- they are obese because they have too MUCH leptin. If my brain could 'see' how much leptin I actually have (which is a lot, because it is an accurate measurement of how much stored adipose fat I have, also a lot), it would immediately turn up my metabolism to burn off the excess fat and thus reduce my leptin amounts. Your theory about sunlight then, or lack of it, is completely backwards.

Far from doing 'very little beyond terminating anti-starvation genetic instructions' (which, even if true would be an inadequate explanation, since it's now believed that anti-starvation instructions depend more on epigenetics than genetics), leptin acts as a fat-based A1c for the brain. It carries information not only about the current number of adipose fat cells and their state (full, half-full, etc), and not only information about the energy composition of the last meal eaten, but also the history of several days to a week past of that information. Which then allows the hypothalamus to course correct via the metabolism (in a myriad of ways) to either store energy, or burn it.

If *my* hypothesis is correct, my pharmacological experiment to restore my leptin signaling will work, and the proof will be that without changing a single thing except the medication I take, my daytime temperature will rise, and my weight will fall until I am at a true normal weight for my height. And my leptin level will fall, not rise, and also be at a normal level for my height. If I am wrong, the medicine will do nothing and I will remain fat, with a too-high leptin level.

kilton said...

"And now we know that leptin is the absolute ruler of every hormone in the body without a single exception."

And any statement this categorical and absolute about something as complex as the human body has GOTTA be true. :-)

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

Dear kilton9:

ItsTheWooo said...

etmon - Again you seem to be assuming that the high leptin of obese people ought to prevent obesity. Leptin is an antistarvation hormone, it has very little to do with regulating weight outside of this role.

As I stated before, beyond that which is needed to suppress the anti-starvation programs of the body, leptin does very little. Leptin will not boost the metabolism and reduce the appetite as it gets progressively higher, this is only true to a point (a high physiologic range), but the supraphysiologic leptin levels of the obese have no additional benefit over a normal physiologic level.

The reason the obese are hungry and fat in spite of adequate leptin, is because something is making them hungry and fat in spite of adequate leptin.
It is totally illogical to conclude that leptin "does not work".

A leptin reisstance/receptor deficiency may be true in SOME forms of obesity. However, there is very little proof/evidence, and it seems rather unlikely as leptin signalling deficiency has a very specific "signature" which differs markedly from your garden variety obese (i.e. suppressed HPO axis leading to infertility, downregulated HPT axis, mildly upregulated HPA axis... this is the opposite of garden variety obesity which typically involves very high reproductive hormones and high thyroid output hallmarks of high insulin glucose/fat without deficient leptin signalling).

I don't know why people seem to have difficulty mentally conceptualizing that numerous factors are at play. It is possible to have very high appetite and fat retention in spite of adequate leptin, because a whole lot of things affect appetite and body fat storage other than leptin.
If fat people are hungry in spite of adequate leptin, all this means is that something other than leptin is responsible for the increased appetite and increased fat storage / retention of body fat associated with obesity.

Resistance to leptin / receptor deficiency may explain some cases, but probably not many of them (as I said, a leptin receptor deficiency has the opposite profile of typical obesity, with decreased thyroid/reproductive hormones).

I've been explaining this over and over but no one seems to get it.
High leptin does nothing beyond physiologic leptin.
Multiple factors affect metabolism, and an having "high leptin" does not negate the other factors which can go wrong. A high leptin is not insurance against ravenous hunger/lethargy/high fat storage, all high leptin does is suppress starvation adaptation, it does not do anything to stop weight gain.

ItsTheWooo said...

There are some fundamental logical errors being made here.

Leptin does not regulate weight, in the sense that leptin does not prevent weight gain.
Lack of leptin, however, will cause weight gain.
This is not illogical.
Lack of leptin causes weight gain, but gaining weight does not mean leptin is lacking, as multiple things can cause weight gain/dysruption of endocrine/metabolic function.

Additionally, just because it is true if leptin is adequate weight is not gained, does not mean that adequate leptin should protect against all forms of weight gain.

Don't worry, most people make this logical error regarding leptin. Even clinical researchers, who speak of leptin resistance in the obese as if it were even proven as real.

Senta said...

ItsTheWoo, please can you explain what you mean when you say that leptin is an anti-starvation hormone? How exactly does this work?

ItsTheWooo said...

When leptin is too low, several endocrine/metabolic functions change so as to maximize energy conservation and increase food interest/consumption. Growth slows, reproduction stops.

When leptin is adequate, these functions are suppressed, growth increases, reproduction continues.

Leptin is increased by adipocytes being full, and by insulin acting on the fat cell telling it to metabolize glucose.
Being sufficiently fat and having sufficiently high insulin make leptin adequate.

ItsTheWooo said...

RABrown - I think the abstract is as expected. Increased leptin beyond normal physiologic range does not suppress appetite or increase metabolism. A leptin of 2.82 is perfectly healthy for a lean young man w. adequate testosterone, so raising it much above this level is not going to have any tangible effect on metabolism (energy production/thyroid/sns/spontaneous activity) or brain function (appetite/feeding).

I agree with your belief that leptin is a reproductive controller, however this function is just a splinter function of its more generalized role as a anti-starvation hormone. The role of leptin is not so much reproductive specific, as it only seems to effect female fertility (estrogen increases, tesosterone suppresses; estrogen and leptin are interconnected in that one sensitizes the brain/increases the levels of the other).

Because the nature of female reproduction makes it so very, very fatal to reproduce during starvation (i.e. fetuses and their high energy need and such), it only makes sense that the anti-starvation hormone leptin grew vines around the female reproductive system. It has limited effects on male reproduction, inhibiting mainly drive/interest and not actual ability. On the other hand, female reproduction becomes completely impossible during leptin deficiency.

So, I don't think it is accurate to say leptin is a reproductive hormone. It is true, but this is only secondary to its effect as an antistarvation hormone. Leptin prevents fertility in females during stress and starvation and any indication thereof.

Stress actually suppresses leptin action in the brain.
By this mechanism, stress also suppresses reproduction and fertility in women.
Stress hormone cortisol generally blocks the effect of leptin on the brain, although cortisol does raise leptin production. Cortisol blocks leptin's effect on both appetite and fertility, which is why "psychogenic stress" will cause women to become infertile.

It makes good sense evolutionarily speaking that the brain associates stress with famine, as stress usually precedes famine. When stuff gets rough, it isn't long until yer starving... adapting to starvation preemptively (indicated by high cortisol) is a valuable genetic trait. Therefore, we evolved a brain that allows for stress signals (cortisol) to block prosperity signals (leptin).

Exercise does not increase leptin, it decreases it, as exercise causes a reduction in insulin, glucose, and a greater fatty acid efflux from cell all of which are very leptin suppressive. Exercise may or may not make one leptin sensitive, secondary to triglyceride reductions (perhaps, hypothetically), but either way, the reduction in leptin level should negate any increase in sensitivity.

Note that the stress effect on leptin (to block it) is NOT leptin resistance. This is a physiological adaptation to stress, and it is easily resolved by controlling the stressors.

Nicholson said...

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

awriter: and now we know leptin is the ruler of every single hormone in the body without exception

... um, we do?
Evidence plz?

awriter: Therefore, IF by a blood serum test it is shown that you have an excess of leptin -- not a dearth of it, as you seem to believe -- you are leptin resistant.

No. This is is illogical.

First of all, if you actually bothered to read what I was saying all along, I am well aware that the metabolic disorder of obesity produces symptomatic supraphysiologic leptin levels. Much in the way tuberculosis causes lots of coughing and bloody sputum, the metabolic disorder of obesity (lots of fat stuffed in fat cells, insulin acting on the fat cell to metabolize glucose0 also causes symptomatic high leptin.

Second of all, your reasoning is flawed. This is because the premises you base your conclusions upon are incorrect.
The pivotal point on which you base your reasoning is illogical. Your argument boils down to:
"If a lack of leptin causes weight gain, then weight gain must be caused by a lack of leptin [signaling]"
Indeed it is shown in studies that when leptin signaling is impaired or absent, mice and rats become grotesquely fat. And, indeed, fat people have very high leptin.

From this you deduce that obesity must be an issue of leptin resistance.

The flaw is that the first condition has no relation to the other;
yes, lack of leptin causes weight gain... but this does not at all suggest a case of weight gain has anything at *all* to do with leptin.

I don't know why people are having a hard time grasping this.

It's sorta like the "ostriches have two legs, humans have two legs, humans are ostriches" thing, I mean, you're making leaps of logic without sufficient evidence. Just because humans and ostriches have two legs each does not mean humans are ostriches. There is more involved int he state of being human, vs the state of being an ostrich, other than number of legs.
So is this situation similar. Yes, in studies, experimentally knocking out leptin receptors or congenital leptin deficiency will cause severe obesity. Yes, fat people have very high leptin and are fat.
This does not mean fat people are leptin resistant. THis is totally illogical.
Just because fat people have high leptin, does not mean they aren't responding to leptin properly, because evidence suggest leptin is primarily an anti-starvation hormone (thus, only prevents starvation, and does NOT prevent OBESITY/weight gain/too much fat accumulation).

Third, clinically, garden variety obesity does not LOOK like leptin deficiency. HPT axis is upregulated, HPO axis is upregulated, fat people generally are not food obsessed and will eat *anything*, etc. There is very little in common between garden variety fatties and leptin deficient/receptor deficient fatties.

I would also suggest to not quote taubes, as you are trying to give yourself credit in doing so, but taubes does not at all support the leptin resistance hypothesis (and, even if he *did*, taubes is merely a scientific journalist and hardly an authority).

I agree with taubes argument regarding obesity (as a disorder of fat accumulation, a metabolic/endocrinologically real phenomenon, unrelated to morality) but this does not transfer over to the "leptin resistance" Hypothesis, which as I have previously demonstrated, is founded upon lots of bad logic and unfounded leaps of reasoning.

Out of curiosity, can you please explain what your experiment entails?

Robert Andrew Brown said...


Thanks for the reply. Leptin is obviously a bit of a passion for you. I am learning a lot. Is this what you are saying ??

Famine = small fat cells = low leptin = switch off ability to breed, and lower metabolism.

So if you have very low leptin, but an adequate supply of food unusually low metabolism will result in a high rate of fat storage .

(Low Omega 3 and 6 has a similar effect and hence my particular interest)

I did not mean to imply leptin was purely a reproductive hormone, but that it was about control of ability to breed,interlinked with the minimum levels of stored body fat that are consistent with a reaasonable chance of successful pregancy. Leptin has some pretty fundamental effects like increasing cell migration.

As to exercise, will there not be a difference between the long and short term effects on brain and fat cell levels?

Short term regular exercise in the fat normal will reduce leptin production in the fat cells with a time delay.

Hormones produced in exercise are likely to have a more immediate effect on brain levels. "Epinephrine and norepinephrine enhance leptin transport across the BBB by about 2-3 fold."

Exercise in the fat depleted will have a more immediate effect on fat production by the fat cells.

Many thanks for all your efforts to educate us.

Robert Andrew Brown said...


And from the obesity perspective?

Somebody can make lots of leptin but if it does not cross the blood brain barrier, then the brain might think food was in short supply (to the extent this is not conflicted by other messages).

And to make any difference you would have to worry about getting the leptin across the BBB rather than putting more into the body?????

Unknown said...

itsthewoo said:
"Leptin will not boost the metabolism and reduce the appetite as it gets progressively higher, this is only true to a point (a high physiologic range), but the supraphysiologic leptin levels of the obese have no additional benefit over a normal physiologic level."

I feel like we're running around in circles here... nobody has said that leptin has some benefit at increased levels...just because something exists doesn't mean there has to be a benefit for it. The high leptin levels exist b/c there's a large amount of fat producing it. Our bodies did not evolve to have that much fat, so therefore we never would have developed a benefit for that. Obesity is a derangement of the system... not a benefit. There IS a benefit to keeping the body at a healthy weight through a set point system.

And I don't think anyone has said that it's progressive... i.e. if you have 5 times the normal leptin that you'll have 5 times the normal metabolism, or that you'll eat 5 times less... I think it that if everything had been working properly, that it would never have gotten to be 5 times normal to begin with.

Leptin most certainly does boost metabolism/energy expenditure once administered to deficient animals... many many studies have looked at this but here's one specifically looking at thermogenesis/mitochondria:

If leptin was only about anti-starvation (and reproduction), it doesn't make sense that it would have the effect of decreasing food intake and increasing thermogenesis. Why decrease food intake at all? Why not just conserve as much energy as possible so as not to starve? The fact is that leptin DOES do these things... the question is, how did the obese person get obese when their bodies (supposedly not resistant to leptin) were telling them to stop eating and be more active as their leptin levels were increasing as they gained weight?

There's also research (linked to this site) showing higher leptin levels precede high insulin levels and weight gain. So how are the leptin levels rising if the weight gain hasn't quite happened yet? THAT's an interesting question actually... if there isn't yet more fat to produce more leptin, why is there more leptin circulating? Of course that isn't to say that metabolic derangement can't start from other point in the endocrine system, but compelling, nonetheless.

There is abundant research going on looking at every possible signaling pathway and all of the ones I've seen so far have shown that if any of those signaling pathways is impaired then leptin's signal doesn't get through (also that when the signal is improved, lepin's effects are manifest). So there's plenty of leptin and the only thing that's changed is impairment of the signal.

This article and all of its referenced articles may be of interest.
Recent advances in understanding leptin signaling and leptin resistance

"The reason the obese are hungry and fat in spite of adequate leptin, is because something is making them hungry and fat in spite of adequate leptin."

Any ideas? You keep saying this but then you don't actually propose an alternative hypothesis. I certainly do not claim to be a leptin expert and I'm very open to all ideas, but you just keep saying that leptin resistance isn't the problem and somehow we're not able to think logically without an alternative explanation or evidence to the contrary. Seriously... I am very much interested in learning all I can about leptin and as time goes on I'm sure the picture will get clearer, but all of the evidence I've seen so far seems to show that leptin resistance does indeed exist. If you have some other evidence I would truly love to see it. All of us, including the entire scientific community are still trying to figure out leptin, so the more insight, the better.

Unknown said...


You said "yes, lack of leptin causes weight gain... but this does not at all suggest a case of weight gain has anything at *all* to do with leptin.".

But other than that, do you think it is true that the effect extra leptin has given to a healthy human is reduced appetite?

I have read studies showing that injecting normal lean mice leptin makes them eat less. It seems like a very potent way leptin can prevent weight gain and leptin resistance cause weight gain. The more fat you have, the less you eat, if leptin is working.

But.. switching sides for a sec


You wrote that the level of leptin in the brain of an obese person isn't typically much lower than the level of a thin person. You also said that this probably isn't caused by a defect in transport, but because the transport mechanism just can't transport more than the normal amount.

Does this sound like a problem? The mechanism by its nature can't transport much more leptin than what it would have to transport in a normal person. So the brain can't see more leptin above normal levels. Does this imply that leptin really is more of an anti-starvation hormone?

If the brain can only see normal levels of leptin because of the way the transport mechanism is designed, the hypothalamus cannot reduce appetite, because it doesn't know about the increased leptin levels. Therefore leptin can't prevent obesity.

Also, what about the studies showing that triglycerides do inhibit the transportation of leptin across the BBB?

Perhaps the theory that leptin resistance is caused by triglycerides inhibiting leptin transport is the best one?

Anonymous said...

INTHEWOO- i tried to comment on your blog but i dont have a google account...
okay i think i finally grasp the concept. So what would you suggest to a nonmensturating underweight female... you plenty talk about the obese and overweight. how about the underweight not releasing eggs. how is it fixed?

Unknown said...

itsthewoo: rereading my last post I just wanted to make sure my request for you ideas/hypothesis didn't come across as snarky... I think everyone is just trying to figure this out and trying to put the puzzle pieces together, therefore the more ideas to consider, the better.

Stephan Guyenet said...

Hi Andy,

There's a feedback loop that "defends" the current level of fat mass, as demonstrated by overfeeding studies, underfeeding studies and common sense. Leptin is the best candidate for the signal that's responsible for this effect, as it's secreted in fat mass and acts in parts of the body that regulate feeding and energy expenditure. Getting rid of it largely abolishes the homeostatic regulation of fat mass. There's no other known signal that fits the description, although that doesn't mean leptin is the only player.

Overfeeding studies have shown that energy expenditure increases when calorie intake greatly exceeds requirements. I'm not sure that's been directly demonstrated to be dependent on CNS leptin signaling. It could be leptin acting in the periphery (ex: there are leptin receptors in the thyroid gland, and leptin controls liver metabolism of thyroid hormones). Or it could be independent of leptin.

But regardless, leptin keeps fat mass in check, that much is 100% certain. Get rid of it in animals and humans, and morbid obesity results. Replace it, and most of the fat goes away rapidly. This shows that in the absence of leptin resistance, leptin keeps fat mass in check and is able to reduce high fat mass to a near-normal level. You can inject leptin into the periphery or brain of rodents, as you noted, and cause them to eat less. There's some question about whether this is physiological though. They usually give very high doses.

Obese people on average have more leptin in the cerebrospinal fluid than lean people. CSF leptin comes mostly from transport through the choroid plexus, so there could still be a transport defect in the vascular endothelium (BBB). But tissue-specific leptin resistance in the hypothalamus, possibly from inflammation, is a more compelling explanation in my opinion.

ItsTheWooo said...

RA Brown – “
Thanks for the reply. Leptin is obviously a bit of a passion for you. I am learning a lot. Is this what you are saying ??

Famine = small fat cells = low leptin = switch off ability to breed, and lower metabolism.

So if you have very low leptin, but an adequate supply of food unusually low metabolism will result in a high rate of fat storage .”

Yes, that is precisely what I am saying :D

“I did not mean to imply leptin was purely a reproductive hormone, but that it was about control of ability to breed,interlinked with the minimum levels of stored body fat that are consistent with a reaasonable chance of successful pregancy. Leptin has some pretty fundamental effects like increasing cell migration.”

I would completely agree with that assessment, yes.
I would also credit you with having a great capacity to think abstractly. You seem able to grasp and consider that which is not obvious – that a hormone famously associated with obesity might actually have major, essential non-weight related effects. Impressive, kudos.
I only have such an understanding because I am living it.
Researchers have an understanding because they are observing animals and humans living it.
You have an understanding without such observations and that is impressive. Indeed, leptin is intimately related to reproductive capacity, and it is currently hypothesized that leptin is THE trigger for puberty (thus, the problem of precocious puberty is related to supraphysiological leptin levels in children who are hyperinsulinemic and obese). Females are so leptin dependent as an evolutionary nod to the fatality of pregnancy during starvation (so, a starvation signal became intertwined with reproductive capacity particularly female reproductive capacity; leptin combined with cortisol are largely responsible for hypothalamic amenorrhea).

Re: exercise… The problem with the idea that exercise (and physical stress) sensitizes the brain to leptin, is that it defies the observation that greater exercise is associated with worsening of fertility / thyroid / hunger / leptin deficiency signs in lean women.

There is indeed a difference between short and long term exercise… long term exercise affects leptin more than short term, because long term exercise often affects energy balance (greater fat efflux w/o sufficient compensation of food intake).

That epi & norepi cause a greater transport of leptin across the BBB is very interesting. Any references? Would like to read more, as another hobby/interest of mine is understanding catecholaminergic mediated hyperactivity/anorexia (which I’ve experienced and find it all very fascinating).

The first link provided suggests that type 2 diabetics have a greater leptin adaptive decrease to exercise than those who are not. I suppose this makes sense, given that diabetes is a condition of hyperinsulinemia/excessive glucose production/metabolism, which in turn causes pathological hyperleptinemia… short term exercise, in this population, is normalizing glucose use in their body and reducing insulin levels thereby ameliorating the symptom of hyperleptinemia. In a population without a glucose/insulin pathology I would expect exercise to have very little effect on leptin in the short term.

The finding that anoretics respond to exercise with immediate leptin reduction whereas controls do not is also interesting, and I would assume this is true because the anoretics are running on a fat based metabolism, and this suppresses leptin (fatty acid efflux suppresses leptin; glucose oxidation by fat cells raises it after all). This is all conjecture, though.

ItsTheWooo said...

RA Brown –
Regarding the possibility that obesity involves diminished leptin transport across BBB, causing similar signs as if leptin were not present…
I suspect it might be true that there is a functional sort of leptin signaling suppression in obesity – indeed high cortisol can suppress some of leptin’s effects, and cortisol causes metabolic dysfunction/obesity. And creating fat in the liver (triglyceride elevation) also seems to block leptin, not coincidence I’m sure but probably evolutionarily intended (capitalizing on seasonal excesses, perhaps?)
But I don’t think this is leptin resistance. It seems rather functional.
And I would argue that it is unlikely this effect is extreme enough to produce obesity, at best it might just make things a bit worse.

Speaking personally, leptin deficiency hunger has little resemblance to the sort of hunger associated with obesity. Having experienced both kinds, the leptin deficiency type is much more extreme. You feel starving.
Research in states of deficient leptin signaling suggests people behave the same as starving people – becoming aggressive and possessive of food, orienting their lives around food, etc. The hunger is painful, extreme, chronic, occupies your thoughts. This doesn’t happen in garden variety obesity. Garden variety obesity is more of a deficiency to ever feel truly full and to want to stop eating like “normal” people. Garden variety obesity it isn’t an issue of extreme, painful appetite like leptin mediated obesity (e.g. receptor knockout, or leptin deficiency).

This is a subtle difference, but, yes, leptin mediated hunger is a lot more extreme than the type seen in obesity.

OH, and on a related note... anyone hypothesizing they have a leptin resistance? Unless you have chronic and extreme hunger, think rotten lettuce is appetizing, and otherwise behave like a starving person, it's unlikely you've deficient leptin signaling.

ItsTheWooo said...

Etmon – No snarkiness taken. I quite enjoy this discussion, I just hope I’m not boring anyone too much ;)

So, if you agree that elevated leptin doesn’t necessarily increase metabolism, and that beyond a normal level shouldn’t have significant benefits, why are you keen on the idea that resisting leptin is the reason people are obese? If leptin doesn’t increase metabolism / decrease appetite in proportion to its level, why should it stop obesity?
IT seems to me if you agree with this, you must logically also agree that leptin does not “regulate setpoint” in that it does not specifically stop obesity (but merely causes weight gain if deficient, a very different thing). Leptin regulates set point in the sense that it prevents weight going too low, but there isn’t any evidence it does the opposite – prevent weight getting too high. Other disease processes cause obesity, unrelated to leptin directly.

“I think it that if everything had been working properly, that it would never have gotten to be 5 times normal to begin with.”
Agree, but this is not evidence of leptin resistance. Things can be not working properly, and not have anything to do with leptin (directly, anyway).

“If leptin was only about anti-starvation (and reproduction), it doesn't make sense that it would have the effect of decreasing food intake and increasing thermogenesis.”

This is a glass half empty/half full thing… it is a matter of perspective. Rather than assume leptin increases thermogenesis, I think it is more accurate to say that leptin deficiency causes decreased thermogenesis (which is then corrected/functional when leptin is present again). I think my view is more accurate because thermogenesis does not increase in a linear fashion with leptin – beyond high physiologic leptin there is no further increases.
Similarly, you are assuming leptin suppresses food intake, I tend to think a lack of leptin increases food intake.
People do not become anorexic and emaciated if you give them very high leptin levels, as occurs with a stimulant.
Think about this in reverse… perhaps leptin doesn’t *suppress* appetite and *increase* energy, but perhaps a lack of leptin causes hunger and lethargy?

“The fact is that leptin DOES do these things... the question is, how did the obese person get obese when their bodies (supposedly not resistant to leptin) were telling them to stop eating and be more active as their leptin levels were increasing as they gained weight?”

To repeat myself redundantly again… the fact that obese people gain weight in spite of adequate serum leptin does NOT mean leptin resistance is the reason.
This is a leap in logic that is not supported.

Okay, let me try another anaology.
You have a bank account. Your balance is 2000 dollars. You’ve a direct deposit of 3000 dollars a month from your job. You’ve automatic bills withdrawing 1000 dollars from your account every month. You predict that your balance ought to be 26,000 at the end of the year (woo hoo!)
However, at the end of the year, you discover your balance is only 5,000 dollars.
Rather than assume other, unconsidered expenses are behind this disparity in expected and actual outcome (e.g. leisure, food, rent)… you insist that your bank account is “resisting” the direct deposit, and ignore the possibility that other factors are involved in the unexpected outcome.

ItsTheWooo said...

(continued response to etmon)

“There's also research (linked to this site) showing higher leptin levels precede high insulin levels and weight gain. “
I’ve already argued that in the previous discussion. Elevated leptin is an early sign of IR/glucose metabolism dysfunction. More glucose oxidized by fat and less by skeletal muscle is going to result in symptomatic leptin elevation. Besides, I thought we already established that there is no negative feedback inhibition of leptin (so an elevation of leptin is NOT a sign of leptin resistance, thus this finding has absolutely no relation at all to the leptin resistance hypothesis). The previous discussion I think I argued this point well and offered evidence that insulin and glucose metabolism in fat cells causes leptin to increase.

“There is abundant research going on looking at every possible signaling pathway and all of the ones I've seen so far have shown that if any of those signaling pathways is impaired then leptin's signal doesn't get through (also that when the signal is improved, lepin's effects are manifest). So there's plenty of leptin and the only thing that's changed is impairment of the signal.”

This does not offer evidence of leptin resistance, BTW. Specific examples are appreciated.

The link you gave me re: leptin signaling/resistance is interesting, but the problem is the authors write as if leptin resistance were proven when it is still hypothetical at this point and it is far from a majority opinion that the obese are actually leptin resistant. I would be interested to know if anyone has actually demonstrated leptin resistence in free occurring obesity. I really doubt it exists, maybe sometimes it does, but probably not particularly often.

“Any ideas? You keep saying this but then you don't actually propose an alternative hypothesis.”
Why people get fat? Oh, that’s easy, most of the time it is hyperinsulinemia secondary to cellular-level deficits in using glucose and fat for energy, which in turn is related to genetic abnormalities and lifestyle interaction (high carb diet with high sugar intake, deficient micronutrients, sunlight, stress, sleep, large portions of energy dense food that set one up for a hyperinsulinemic reaction that becomes a cycle, lack of any natural famine or activity which promote glucose/fat uptake and reduce insulin, etc).

I can’t say with certainty that every cause of obesity is the same, I don’t think there is “one cause”, but most of the time, it’s as described above.
My POV is actually more hopeful, because if you control insulin then you can control obesity. Leptin resistance, as far as I know, has no real treatment or cure. Insulin can be controlled by doing a low carb high fat diet, taking certain supplements and drugs, getting adequate sunlight and sleep, reducing stress, being more active and the like.

Even if I lacked an alternative hypothesis, this doesn’t mean that the leptin one is valid.

awriter said...

Itsthewoo opines: "If leptin doesn't increase metabolism / decrease appetite in proportion to its level, why should it stop obesity?"

For the zillionth time -- it DOESN'T stop obesity. The only thing that will stop obesity in the leptin resistant is when:

1: UPR caused by endoplasmic reticulum stress is reduced, thus allowing
2: Leptin to be properly folded once more into the exact shape required for it to cross the BB barrier, so that
3: The hypothalamus, previously under the assumption that leptin levels were low (and thus assuming starvation conditions), finally understands that far from being low, they are too high, and
4: Sends the proper signal to various metabolic regulators -- like thyroid hormones produced in peripheral tissue like the liver for instance -- to turn up the metabolism. This is easily done by having more T4 convert to T3 rather than the metabolically inert Reverse T3, such that
5: Excess fat begins to be burned rather than stored.

Another Wooism: "anyone hypothesizing they have a leptin resistance? Unless you have chronic and extreme's unlikely you've deficient leptin signaling." And: "Elevated leptin is an early sign of IR/glucose metabolism dysfunction"

Based on what research other than . . . "Because I say so"? My blood tests, for instance, say precisely the opposite. I am severely leptin resistant and have zero IR/glucose metabolism dysfunction. But hey, don't let an inconvenient fact or two get in the way of your theories. :)

ItsTheWooo said...

malpaz - For the underweight amenorrhetic female, the solution is simple: eat more, exercise less. Gain weight. Sleep more. Reduce stress.

Mostly, eat more, exercise less, gain weight.

This should result in a natural production of leptin and a termination of amenorrhea/starvation symptoms.

ItsTheWooo said...

Awriter: please explain to me how you have proven you have a hypothetical disease based on labworks? Having elevated leptin and not reaching your goal weight is far from sufficient evidence you have leptin resistance. Having elevated leptin and not reaching your goal weight is only evidence that you are not losing weight, which for all I know is because you are eating a lot of calories/carbs. Once we get into the normal weight ranges, it’s no longer effortless to lose, it usually requires a bit of hunger and effort.

Out of curiosity, what is your leptin level?

Robert Andrew Brown said...


Thanks for the compliment that is very kind of you and appreciated . My overview such as it is just stems from being a nerd on a mission with access to the internet (-:, and my understanding of leptin has been greatly improved by this thought provoking thread.

You said:

"Speaking personally, leptin deficiency hunger has little resemblance to the sort of hunger associated with obesity. Having experienced both kinds, the leptin deficiency type is much more extreme. You feel starving.
Research in states of deficient leptin signaling suggests people behave the same as starving people – becoming aggressive and possessive of food, orienting their lives around food, etc. The hunger is painful, extreme, chronic, occupies your thoughts. This doesn’t happen in garden variety obesity. Garden variety obesity is more of a deficiency to ever feel truly full and to want to stop eating like “normal” people. Garden variety obesity it isn’t an issue of extreme, painful appetite like leptin mediated obesity (e.g. receptor knockout, or leptin deficiency)."

Thanks for you description of low letpin hunger. It is graphic, and explains why low leptin is a factor in obesity.

It seems to me there are three main 'mechanisms' of leptin effect:

The brain - The brain responds to leptin, (irrespective as to whether the body takes any notice of the signals that are being sent)

The body - leptin has brain independent effects on body function.

Signalling between the brain and body - Leptin has to get into the brain to have any effect and signals have to get out of the brain and be registered by the body.

It also seems that we need to define what we mean by 'leptin resistance.'

The body is not not responding to leptin?

The brain is not responding to leptin?

The leptin brain body communication in either direction is blocked?

It seems to me that any of the above could cause leptin 'resistance'.

Can you please clarify your definition. Maybe you and Awriter are not so far apart.

You suggest leptin is the controller of puberty. I would argue that Omega 6 (and excess calories) ultimately control puberty.

Yes leptin has a role in fertility and logically puberty too, given the need for a minimum fat mass, function of leptin etc, but Omega 6 and calories are *external* factors, whereas letpin is an *internal* signal.

The occurrence of Omega 6 in the food chain is a reflection of the fecundity of nature.

Omega 6 ultimately controls the production of hormones.

Omega 6 and fructose also battle with leptin, and Omega 3 assists it, which is where my interest in leptin came from.

(I make this argument in my book
Omega Six The Devils Fat.
It is poorly edited but the science is OK. I am currently getting towards the end of a total rewrite, expansion, and professional edit. The new version contains more bits in the Omega 3:6 jigsaw, more refs 2200 plus, and hopefully is better written. It will hopefully be available toward the middle of the year.)

Carl said...

News about a Leptin Pill

Robert Andrew Brown said...

Thanks Carl

More to chew on so to speak.(-:

Cooperative Activation of Cultured Vagal Afferent
Neurons by Leptin and Cholecystokinin

"Although the total amount
of leptin present in stomach is small ( 1.4 ng) and suggested
to be insufficient to influence circulating leptin levels significantly,
a local paracrine action of leptin, coupled with the
actions of other vagal stimuli, such as CCK, suggest that this
source of leptin could have a significant physiological role in
controlling vagally mediated physiological responses, such
as satiation, gastrointestinal motility, and secretion."

it is possible that leptin sensitizes the satiation signals
via its actions in the brain (30), our present work contributes
to a growing body of evidence suggesting that leptin may
influence satiation via an action directly on visceral afferents
that participate in satiation through their monitoring of mechanical
and humoral signals from the gastrointestinal tract."



"In lean animals, leptin mRNA levels decrease in fasting conditions and increase rapidly with a short period of food intake. Obese Zucker rats also overdisplay stomach leptin levels. Feeding acutely stimulates leptin secretion by the stomach in lean, and to a lesser extent, in obese rats."

Robert Andrew Brown said...


So many questions

"Leptin and Ob-Rb were expressed in hyperplastic polyps, adenoma, and adenocarcinoma. In the gastric adenocarcinoma, leptin was expressed significantly less in the poorly differentiated and diffuse-type groups than in the well-differentiated and moderately differentiated groups or in the intestinal type. Based upon our findings, we suggest the possibility that leptin expression can have a pathophysiologic role about the differentiation or growth pattern of gastric adenocarcinoma. A further series of experiments is necessary to elucidate the pathophysiological role of leptin in the differentiation of gastric adenocarcinoma."

PositiveThinker said...

Great information. Looking forward your next post

Mavis said...


If you're still reading...

I know you aren't considering environmental toxins a big player in the rise in obesity, but from bits and pieces I've read, they seem to have a measurable impact. Do you think a possible scenario could be a synergistic effect?

For instance, an animal could be somewhat affected by bromides/phthalates/BPA, and somewhat affected by refined fructose and vegetable seed oils, and somewhat affected by gut-disrupting substances (BTW - have you checked sucralose?), and somewhat affected by disturbances in normal patterns of light/dark/sleep, but put two to four of these factors together and you have a perfect storm?

It seems that we live in a metabolic chamber of horrors.

TedHutchinson said...

@ Mark
sleep is important, but I think the notion that a lack of it causes obesity is a bit far fetched.
& Helen
affected by disturbances in normal patterns of light/dark/sleep,

interesting series of 30minute talks here
enter MELATONIN in searchbar and you'll find
Basic science of circadian rhythms, melatonin and melatonin receptors

Pancreatic Melatonin Receptors: From Fiction to Function

The genetics of the melatonin receptor 1B in type 2 diabetes

donny said...

Speaking of leptin and melatonin...

"Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity."

Orexin is sort of an alert-making hormone, helpful in consolidating the sleep and awake periods. People with narcolepsy have disrupted orexin, rodents bred to lack orexin are narcoleptic.

Tryptophan restriction increases rat lifespan, and delays sexual maturity. Refed tryptophan, rats breed at an age at which they would normally be dead. One theory is that low serotonin levels explain both the delayed maturation and longevity.

"Differential effect of orexins (hypocretins) on serotonin release in the dorsal and median raphe nuclei of freely behaving rats"

Mice that over-produce orexin generate lots of amyloid plaque and end up with mouse-alzheimer's.

One more thing... fasting and long term calorie restriction decrease leptin levels, but increase orexin.

Malpaz, this may be a long shot, but what are your sleep patterns like?

Stephan Guyenet said...

Hi Helen,

I think it's entirely possible.

Robert Andrew Brown said...


Thanks for the link, that was useful and interesting.

On weight and sleep there are a number of factors that could explain the links between sleep and obesity.

Thanks to a thought provoked by your comment I just found this which helps add to the argument.

Visceral fat content has been suggested to link to a number of western conditions.

A trial suggests melatonin administration in middle aged rates suppressed visceral fat accumulation.

Every thing it seems is interlinked at some level.

Robert Andrew Brown said...


Thanks for those thoughts.

Do you have a link for the rat / tryptophan trial.

In terms of puberty signalling I am not sure that you can equate animals and humans.

I suspect melatonin is involved here some where, and it seems that there are interesting differences between species.

Nocturnal activity is going to complicate comparisons.

Robert Andrew Brown said...

Re the melatonin trial above Fig 3 suggests leptin rises with age, and melatonin supplementation is associated with a significant reduction in leptin levels back down towards the leptin levels of youthful rats.

Robert Andrew Brown said...

^ Re the above on leptin cell migration and cancer.

Delicate and complex dances of intertwined paths we tread it seems.

"Additionally, epidemiological studies underline that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined."

"Functional leptin receptors are found to be expressed on diverse cancer cells derived from different tissues such as breast, colon or prostate [26-30]. The breast cancer cell lines HTB-26 and ZR75-1 [27], the prostate cancer cell lines DU145 and PC-3 [30], and various colon carcinoma cell lines such as LS174T and HM7 [29] as well as SW480, SW620 and HCT116 [26] all express OB-Ra and OB-Rb. In breast cancer cell lines and in human primary breast carcinoma leptin receptor has been demonstrated to occur in combination with leptin. Therein, leptin is able to induce the growth of these cells via different pathways, can mediate angiogenesis by inducing the expression of VEGF, and promotes invasion and migration by transactivation of the epidermal growth factor receptor (EGFR) [15]. A bidirectional crosstalk between leptin and insulin-like growth factor-I (IGF-I) signaling was also shown to stimulate invasion and migration of breast cancer cells [31]."

ItsTheWooo said...

I'm disappointed awriter never returned. I was curious as to what her leptin level actually was.

I suspect it is probably between 10-15, which isn't terribly high at all, and is actually rather low for a 145 pound woman.

Reading more about awriter's experiments, it seems as if she is taking pure T3, which thereby resulted in improved energy and reduced cholesterol levels. For some reason she thinks this is becuase of reduced leptin resistance, which makes very little sense, as it is well known low energy and high cholesterol are a result of low thyroid function.

Her low thyroid may be because of leptin resistance, but it could be many things. It might even be hypoleptinemia (awriter seems to think that a leptin >10 is high, this is very false when applied to females, and for a female, a leptin of 10 is actually on the low end of normal).
Or, the thyroid thing might not have anything to do with leptin. Eating an extremely low carb/calorie diet can also cause functional hypothyroidism (decreased conversion of t4 to t3).

Lots of leaps of logic going on here.

Robert Andrew Brown said...


You were pondering why nature would want an insulin resistance mechanism.

I found this as usual looking for something else.

In pregnancy prolactin appears to block the effect of leptin in the brain.

This makes sense as women ideally need to put no weight in pregnancy to provide an insurance reserve and prepare for the energy demands of lactation.

And at the same time there is a make more leptin message, which if leptin is essential to pregnancy would make sense too.

Induction of Central Leptin Resistance in Hyperphagic Pseudopregnant Rats by Chronic Prolactin Infusion

But at the same time may increase letpin secretion by adipose tissue

Prolactin Stimulates Leptin Secretion by Rat White Adipose Tissue

ItsTheWooo said...

RA Brown
Hi, I never pondered why nature would create an insulin resistance mechanism.

From my point of view, most forms of insulin resistance fall into one of two categories. "Physiological" insulin resistance, the sort that happens during stress, starvation, and seasonal weight gain... and "pathological" insulin resistance, the sort inducted by damage to mitochondria, major mitochondrial genetic defects, or genetic/inducted defects in secondary systems (e.g. profound hypoleptinemia secondary to fat cell depletion will cause pathological insulin resistance, diabetes, very high cholesterol and such).

The relationship between impaired leptin signaling and prolactin is expected, and it is not leptin resistance. This is physiological and corrected when prolactin is adjusted to a normal range (sufficient dopamine, no excess of serotonin, not post partum).

Robert Andrew Brown said...


I said

"You were pondering why nature would want an insulin resistance mechanism."

I meant to say leptin not insulin. (-:

Indeed I do not recall you pondering on insulin resistance, but do recall a comment on leptin resistance.

Is leptin resistance in pregnancy not a form of leptin resistance? Does it not depend how you define leptin resistance? (-:

How do you define leptin resistance, or perceive other define it.

donny said...

I thought I'd read a full article on that tryptophan/serotonin thing, but all I can find now are abstracts.

Growth-retarded rats fed a tryptophan deficient diet at 21 days for periods of 6-22 months were shown to reach normal body weight when subsequently fed Purina Rat Chow. They demonstrated an increased ability over similar aged controls to recover from hypothermia induced by 3-minute whole-body ice water immersion, were able to bear litters at 17--28 months of age, showed a delay in the age of onset of visible tumors, and indicated an increase in their average lifespan at late ages. Animals fed on this diet from 3 months of age revealed a similar ability to reproduce at advanced ages, but not as marked as those placed on the diet earlier. The average lifespan (in months +/- the standard error of the mean) of the rats recovering from the long-term tryptophan-deficient diets was 36.31 +/- 2.26 while the control rats survived an average of 30.5 +/- 1.90 months. The last of 8 rats surviving the period of tryptophan-deficiency died at 45.50 months (1387 days) while the last of 14 control rats died at 41.75 months (1266 days). It is hypothesized that some kind of subtle mechanism exerts its influence on the rats during the period of tryptophan deficiency which caused an accelerated morbidity and mortality as they approached senescence approximately 1 to 2 years after refeeding. This is parallel to the situation with immature animals subjected to long-term caloric restriction and then fed on normal diets.

I was just reading an excerpt on googlebooks that claimed that tryptophan restriction caused voluntary calorie restriction in rats, and that it was this rather than any effect on serotonin that was the cause of the longevity. I think you get in trouble looking for first causes. If serotonin is involved in the pleasure received when eating carbohydrate, tryptophan restriction might decrease appetite, especially for carbohydrate. Methionine might have a similar effect; after eating glucose, protein synthesis increases, pulling competing amino acids out of the blood stream, which increases the transport of tryptophan across the blood brain barrier. Restricting a growth-limiting amino acid such as methionine might leave a greater ratio of these competing amino acids in the bloodstream, decreasing tryptophan transport in a manner similar to tryptophan restriction itself. I can't seem to find much about that last so far, although there is a case study of serotonin syndrome involving a serotonin reuptake blocker used in conjunction with SAMe-- but that could be caused by the reuptake blocker by itself.

donny said...

That gut bacteria thing... I can't imagine a change in diet that wouldn't have profound effects on gut bacteria. Resveratrol, extra glycine, potassium, sodium, high fat, low fat...olestra, polyunsaturated fat (bacteria that cope well with omega 6 might be nastier than those that cope well with omega 3...)

Bitter compounds might cause rodents to eat less... or it might make their bacteria behave.

lorentide said...

I just found your blog, and I like it very much. I'm a celiac that eats paleo, and was a biochemisty/genetics student for a few years. rock on!

donny said...

For full disclosure, all I've read is the first line;

"Background: Hyperprolactinemia is associated with obesity. Furthermore, in human adipose tissue cultured in vitro, prolactin (PRL) inhibited lipoprotein lipase (LPL) activity via functional PRL receptors."

Lipolysis inhibits leptin secretion. Prolactin decreases lipolysis in adipose tissue. This should increase leptin levels. If the hyperprolactin state is chronic, body fat might increase. Anything that chronically shuts down lipolysis should increase both leptin levels and fat levels. This would tend to cause increased levels of leptin with obesity, is this necessarily leptin resistance?

The rat pseudopregnancy study;

"Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance."

The assumption there is that non-central administration of prolactin caused central leptin resistance. Communication between the hypothalamus and the rest of the body is hardly one-way.

Induced hyperleptinism in non-obese rats causes decrease in appetite, and depletion in fat mass. Once the fat is gone, leptin's affect on appetite decreases. The rats continue to have little desire for carbohydrate, but the appetite for protein increases.

This is when the rats are offered self-selected diets of carb, protein, fat. How could they prefer protein over carb if their food is offered in pellet-form? For some, butter and potatoes-- to taste-- might not be fattening, where french fries might. Any study of leptin "resistance" where the subjects can't self-select among the macronutrients is highly suspect.

"Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test. Despite these dramatic differences in macronutrient selection, total daily caloric intake did not differ between groups except on day 2. Thus controls of food intake related to ongoing metabolic and nutritional requirements may supersede the negative feedback signals related to body fat stores."

That last part is what makes me suspect that the more important work done by leptin is permissive, rather than prohibitive; encouraging the use of fat for energy rather than inhibiting its storage. Rather than inhibiting hunger, satisfying it.

Robert Andrew Brown said...

^ Thanks Dony

Conflicting results ?
Any thoughts ?

"In this study we found that severely obese women, following major weight reduction as a consequence of malabsorptive bariatric surgery, had a significant lowering of plasma PRL levels during the whole day."

Basal PRL levels were neither significantly correlated with the BMI of the subjects (r = −0.05, P = 0.77) nor with any other of the assessed variables (all r < 0.16, P  > 0.06) even after adjusting for the influence of sex. After massive surgically induced weight loss that on average almost approached 50 kg, basal serum PRL levels remained completely unchanged (before vs. after, 9.1 ± 6.0 vs. 9.2 ± 4.6 μg/l, P = 0.86).

donny said...

Okay, this is why you shouldn't just read the first line of a study. In my own defense,

"Hyperprolactinemia is associated with obesity. Furthermore, in human adipose tissue cultured in vitro, prolactin (PRL) inhibited lipoprotein lipase (LPL) activity via functional PRL receptors."

I assumed the inhibition of lpl activity was within the cell, decreasing breakdown of already stored fat. I guess I have to read up on how fat is broken down in the fat cell itself, I only assumed lpl was involved because of the context of that quote.
Insulin is the primary hormone acting by increasing lipogenesis. Both insulin and PRL (36) enhance the differentiation of fibroblasts and preadipocytes into mature adipocytes. Therefore, the reduction in PRL plasma levels is likely dependent on the lowering of insulin plasma concentration which, in turn, produces the reduction in LPL adipose tissue expression. On the other hand, the large increase in insulin sensitivity did not influence PRL secretion, whereas insulin secretion did.

In conclusion, lipid malabsorption but normal calorie intake rather than reduced calorie intake in severe obesity might be related to the net improvement in PRL secretion after weight loss, which became similar to the values reported in the literature for healthy women (15), even in the face of persistence of a frank obesity. Furthermore, the reduced expression of LPL in the adipose tissue observed after bariatric surgery, being significantly correlated with the decrease in insulin and PRL, suggests a role of hyperinsulinemia and hyperprolactinemia in inducing and maintaining obesity

At this point, although I'm as green as it gets when it comes to prolactin, my guess is that the drop in insulin is the obvious cause of the drop in lipoprotein lipase.

The subjects in this study went through bilio-pancreatic surgery, a more severe form of gastric bypass causing extreme malabsorption of fat.

"Discussion: The restriction of lipid metabolizable energy rather than weight loss seems to be responsible for both reduction in PRL circulating levels and normalization of its secretion rhythm after bariatric surgery."

The other study you posted, Robert, may have involved a gentler form of bariatric surgery more friendly to fat absorption.

Robert Andrew Brown said...


No defense required.

I am totally green as far as most of this is concerned, but fascinated.

This is interesting. Prolactin was expressed in early peradipocyte differentiation.

And in adipose and visceral tissue,

"In addition to being a circulating hormone of pituitary origin, PRL in humans is produced by nonpituitary sites, including the endometrium, decidua, lymphocytes, brain, breast, and prostate, where it acts as a cytokine"

Ed Clements said...

Stephen I've been following your blog for a while and find it very interesting.

I've noticed that recently you've changed your stance on dietary fiber and now recommend prebiotic fiber such as FOS, inulin and resistant starch as important for modifying the gut flora.

I followed this approach a couple of years ago and my health declined.

Recently, having heard the new wave of buzz about inulin, started taking 10 grams a day, and then upped to 15.

I felt fine and my digestion may have slightly improved but my sex drive, which is normally high, dropped way down.

It's well known that high soluble fibre diets reduce testosterone levels and I believe a high dose of inulin will do the same.

Given low T levels correlate with low insulin sensitivity is it really a great idea to increase fiber greatly?

Also it's worth noting that low amounts of inulin, like 1 gram, which you can get from one half onion have been shown to positively alter gut flora, and this amount would not lower sex hormone levels.

This amount probably would not reduce the ph of the colon like high doses would though and would not create very high levels of butyrate.

In previous posts you note that the Japanese only eat small amounts of fibre but are very healthy. Clearly these people dont have high levels of butyrate yet are still healthy?

I'm interested in this because I can see all the potential benefits to taking inulin but am not sure that it will help everyone's health...

Chris Kresser said...

Hi everyone,

A new study was just published in Science linking intestinal bacteria to obesity. The researchers found that Increased appetite and insulin resistance can be transferred from one mouse to another via intestinal bacteria.

Looks like the theory that gut dysbiosis is at least partially responsible for obesity is gaining ground.


robrob said...

lots of good comments by people. I was thinking when reading about sleep, I think we have it backwards people sleep poorly because they are sick not sick because of poor sleep.

healthy people naturally sleep enough and properly for the most part.tho the number of truly healthy people seems to be falling.

also if a persons fat cells are insulin resistant that cell cannot make enough leptin (how do the doctors know what amount you should have in blood based on fat cells status?)it needs glucose to stimulate leptin prodution.

high leptin levels means your leptin resistant in that the leptin is remaining in the blood and not reaching the brain, otherwise you leptin levels would rise and fall in a normal fashion.

wonder what affects this high leptin has on the organs like liver and adrenals and heart if they remain too high, like high insulin does when it remains in the blood at high levels too long.

anything in excess can cause harm to the organs I am sure, just like high adrenalin for too long causes diseases too. high cortisol too these hormones must remain in a flux to avoid poisening itself.

poor liver ends up being overloaded with detoxifying these hormones not to mention all the poisens in our enviroment too.

no wonder we are all having hard time getting and maintaining good vibrant health.

isn't our skin the biggest immune organ? doesn't it protect us first, then our gut? then our sinus or sinus first then gut?

when I used to read about leaky gut I thought ridiculous. not I understand what they meant.

as for omega 6, I don't think it is totally the culprit here, I think it the fact people are eating rancid rotted oils, those oils on the shelf have been burned and are dead oil that is rotting, like eating rotten meat that has been spiced to cover over the bad taste and smell. oxidized oils as it were, polyunsaturated fats cannot be cooked or burned or heated, after all healthy omega polys come from cold water fish cold climate nuts, that won't freeze in winter and have mild summers.

if you look at hot weather fats they get more saturated as the climate gets warmer. saturated fats are stable in hot weather where polyunsaturated fats break down. moderate climate that don't get very cold are the monos like peanuts grown in georgia, or olives grown in semi tropical climiates.

so it's type of fat is determined by the climate it grows in. so maybe if we all live in tropical we should only consume saturated fats that are natural not the processed hydrogenated crap they try to pass off as saturated fats or confused with sat fats from natural sources.

by the way dr oz and his brother, are just in it for the money. they advocate whatever they are paid for, after all they are probably making more money doing a tv show then being real doctors at a hospital.

I saw them slamming saturated fat as causing heart disease, if they are reading the same stuff I am then they know that aint true, but who is paying them to say that? if they are talking about manmade sat fat from oils and don't tell others that is what they mean they are guilty of fraudulent concealment.

he has right to say what he wants, but he must take responsiblity for how it affects others, he has a md by his name and people put faith in him, so he has a higher responsiblity to watch what he says. regular joe says the same things they won't take it as seriously guess that is why they are willing to pay these doctors so much to say what they want to give the info strong credibility.

wonder how many people have died of heart disease because they replaced good sat fat with rancid veggies oils touted as better than sat fats per doctors recommendations? or ate low fat and more carbs, that died from same?