Thursday, January 31, 2013

Why Do We Eat? A Neurobiological Perspective. Part III

In the first post, I explained that all voluntary actions are driven by a central action selection system in the mesolimbic area (the reward system).  This is the part of you that makes the decision to act, or not to act.  This system determines your overall motivation to obtain food, based on a variety of internal and external factors, for example hunger, the effort required to obtain food, and the sensory qualities of food/drink.  These factors are recognized and processed by a number of specialized 'modules' in the brain, and forwarded to the reward system where the decision to eat, or not to eat, is made.  Researchers divide food intake into two categories: 1) eating from a true energy need by the body (homeostatic eating), e.g. hunger, and 2) eating for other reasons (non-homeostatic eating), e.g. eating for social reasons or because the food tastes really good.

In the second post of the series, we explored how the brain regulates food intake on a meal-to meal basis based on feedback from the digestive system, and how food properties can influence this process.  The integrated gut-brain system that accomplishes this can be called the satiety system.

In this post, we'll explore the energy homeostasis system, which regulates energy balance (energy in vs. energy out) and body fatness on a long term basis.

The Energy Homeostasis System

As we saw in the last post, food intake can vary considerably from day to day based on a variety of factors. If we compare the energy intake to the energy expenditure of an individual person on a particular day, the two often match up poorly (1).  Some days, a person eats hundreds of calories more than energy needs and sits on the couch, while other days a person exercises a lot and eats less than she needs to break even.  Yet if we look on a longer time scale, say a week, energy intake and expenditure match up fairly well.  If we look at an even longer time scale, say two weeks, the two usually line up precisely (2).  Even a modest persistent mismatch between intake and expenditure would lead to rapid changes in fat mass over time*, but in most people this doesn't occur.  This implies the existence of a system that matches intake with expenditure over a long time scale to maintain the stability of fat stores.

The first evidence for such a system came in 1840, when a German doctor named B. Mohr determined that a subset of his obese patients carried tumors in a part of the brain called the hypothalamus (B. Mohr. Wschr Heilkd, 6:565–574. 1840), which we now know cause obesity.  In the 172 years since then, an enormous body of research has accumulated in support of the idea that body fatness is regulated by the brain, and that the seat of this regulation lies primarily in the hypothalamus (4).  This makes sense, since the hypothalamus specializes in homeostatically regulating a variety of processes in the body, including body temperature, blood sugar, blood pressure, and electrolyte balance.  There is no other organ in the body that has been shown to regulate body fatness**.

Similar to the satiety system, the energy homeostasis system stabilizes body fat stores by measuring body fatness and adjusting food intake and energy expenditure accordingly***.  Only this time, the regulation happens over days, weeks and months rather than minutes and hours.  As with the satiety system, the "control center" of the energy homeostasis system resides in the brain, but not the brainstem.  The brain is able to modify calorie intake much more easily than calorie expenditure in humans, and so changes in food intake are the main way this system acts to 'defend' the size of fat stores.  It does this at least in part by influencing the satiety system, changing the degree of hunger and the desire for food at individual meals (5).  For example, if you haven't eaten for a week, you'll be very hungry and you'll be able to eat much more than usual before reaching fullness for a few days.  This reflects the energy homeostasis system influencing the satiety system to restore long-term energy balance.

As with a thermostat that measures temperature in order to adjust it, the hypothalamus measures body fatness in order to adjust it.  It does this by monitoring the circulating concentration of hormones that reflect body fat levels (6).  Chief among these is leptin****.  Leptin is secreted by fat tissue in proportion to its size.  The more fat, the more leptin in the circulation. Overeating and fat gain increase leptin levels, signaling to the brain to decrease subsequent food intake, and in some cases increase calorie use, to restore fat mass to its original level.  Conversely, undereating and fat loss lower leptin, which signals to the brain to increase hunger, increase interest in in food, and decrease calorie use in an attempt to recover the lost fat (7).  Replacing leptin to the pre-weight loss level attenuates these responses by tricking the brain into thinking that no fat was lost (8, 9).  This is the crux of why it's hard to lose fat: the brain 'defends' current fat stores against changes in the short/medium term, whether you're lean or obese.

Well Then How Does Anyone Gain Fat?

The energy homeostasis system wasn't designed for super sized french fries, pizza, or 32 oz Slurpees that you can get in 5 minutes by jumping into a car or simply making a phone call.  It wasn't even really designed for a roasted leg of lamb with rosemary, garlic and salt that you can make easily in your own kitchen.  It was really designed for simple foods like raw fruits, plain meat cooked on a fire, and plain roasted nuts, with no added salt and few added fats, sweeteners or other flavorings-- foods that also required work to obtain and prepare.  It was designed for daily physical activity, sleep and sunlight.  In that environment, the energy homeostasis system doesn't have to work very hard to constrain body fatness because food intake isn't constantly being driven to excess by non-homeostatic factors such as easy availability, high palatability, liquid calories, and constant advertising.  Its main worry historically was preventing starvation, which it evolved to be very good at.  The energy homeostasis system can only do so much to constrain body fatness in the face of excessive eating pressure, and our ancient brain is simply no match for the modern food environment in which non-homeostatic factors strongly drive food intake beyond energy needs.

This energy homeostasis system is more robust in some people than in others.  In a fascinating experiment published in the journal Science in 1999, researchers overfed 16 non-obese young adults with an excess of 1,000 calories per day (beyond energy needs) for 8 weeks (10).  They found an amazing 10-fold difference in fat gain between individuals, ranging from 0.4 to 4.2 kg of fat mass.  Some people were able to burn off the excess calories without any increase in voluntary exercise*****, while others gained most of the excess calories as body fat.  This suggests that the energy homeostasis system is more robust in some people than in others, and those who inherited a weak system are much more prone to fat gain.  Keep in mind that this system doesn't have to defend against fat gain unless a person is overeating, so these individual differences are only relevant in the context of excess food intake.  In 2012, I believe most people in affluent nations frequently overeat due to our unnatural food environment, and those who have a less robust homeostatic system gain fat over time as a result.

Obesity in animals and humans is associated with a resistance to the actions of leptin (and other related signals) in the brain.  In other words, similar to insulin resistance, the brain can't 'hear' the leptin signal very well.  That means it takes a lot more leptin, and therefore a lot more fat mass, for the hypothalamus to be satisfied that a person isn't starving.  Consequently, the brain of an obese person 'defends' current fat stores as if the person were lean, initiating a starvation program if fat mass declines, even if the person still has twice as much total fat mass as a lean person (11).  As a result, a weight-stable obese person has a higher energy 'flux' than a lean person-- more energy leaves the body because obese people have a larger tissue mass to sustain, and therefore more calories must enter the body to maintain weight (12).  The brain maintains this situation by keeping food intake high-- an obese person has to eat more food on average to feel satisfied than a lean person, but the difference isn't very large-- only about 20 percent higher than the lean level for someone who is very obese (13).  The difference is even smaller for someone who is only moderately overweight. This difference is therefore neither immediately obvious nor easy to measure.

What Causes Leptin Resistance and an Increased Setpoint?

To understand why we hold on to the fat we gain, and why it's hard to lose fat, we must understand what causes resistance to leptin and other signals of body energy status.  In earlier posts, I speculated about a variety of factors that may contribute to leptin resistance and an increased 'setpoint' (14).  I believe that physical inactivity can increase the setpoint over time, and in some overweight people exercise can lower it, although for most people exercise alone isn't a very effective fat loss strategy.  The ability of exercise to prevent fat gain is well supported by animal studies, which suggest that exercise maintains leptin sensitivity (15, 16).  Certain drugs, such as atypical antipsychotics, can increase the setpoint, presumably by acting on brain circuits that regulate body fatness.  There is some evidence that the sensory qualities of food, in addition to promoting non-homeostatic eating, can also increase the setpoint (17, 18).  One of the most compelling hypotheses is that leptin resistance is caused by low-grade inflammation in the hypothalamus, since animals that can't develop this inflammation are partially protected against fat gain (19, 20, 21).  Yet we still don't know for sure what causes the inflammation, even though many people including myself are working on it.  There are other likely contributors to an increased setpoint that I won't get into here.

I think all of these things contribute, but I recently had a breakthrough, and I now believe there's something else at play, something bigger.  It's actually quite simple.

Something I've noticed over the years is that when you make an animal gain fat by giving it a fattening diet, and then return it to the original healthy diet, it will lose most of the excess fat but frequently retain a portion of it (22, 23).  Similarly, in human overfeeding studies, after subjects return to a normal diet, they'll spontaneously undereat for a while, lose most of the excess fat, but if you read the studies carefully you find that they often hang on to a fraction of the excess fat indefinitely (24, 25).  The piece of evidence that pushed me over the edge was a study showing that half of annual weight gain in the US occurs during the 6-week holiday period (26).  People gain weight during the holidays by voluntary (non-homeostatic) overeating, lose a little bit of it in January, but hang on to most of it indefinitely.

I believe this is the missing piece to the puzzle of how the body fat setpoint gradually increases over time, leading to the 'defense' of a higher fat mass.  What increases the setpoint, in a susceptible person, is fat gain itself.  Each time a susceptible person eats more calories than necessary to meet calorie needs, the excess is stored as body fat.  Afterward, a portion of the excess fat is lost as the energy homeostasis system kicks in, but a portion of it remains and is 'defended' in addition to what was already there.  Over time, the setpoint gradually ratchets up in response to temporary periods of overeating.  How this happens on a cellular/molecular level, I don't know, but it must coincide with the incremental development of leptin resistance in the brain since that's what supports the elevated setpoint (along with resistance to other circulating factors).  This process may also tie in with inflammatory signals.  I want to be clear that there are probably multiple contributors to an increased body fat setpoint, and this particular one may not apply to everyone, but I've come to see it as the most likely primary driver in most people.

This is both exciting and sobering at the same time.  On one hand, it gives us a simple explanation for this frustrating phenomenon that has undermined the fat loss efforts of millions of people.  On the other hand, it suggests that there's no easy fix for an increased setpoint.  I wish it was just a nutrient deficiency, a lack of sleep, or some such 'secret', and fixing it would melt away the fat effortlessly, but that's simply not the case.  That being said, there are scientifically supported strategies that can cause durable fat loss without having to bean count calories, and some probably act by changing the setpoint.  I've researched these strategies and used them to design a fat loss program in collaboration with sleep and food intake researcher Dan Pardi and other scientists.  This program will be available through the Dan's Plan website in late December 2012.

The Updated Model

Here's the new version of the simplified model of food intake regulation.  As before, the colored shapes are brain 'modules', and the words outside them are the external and internal factors they respond to.  We're most of the way through.


* This doesn't mean that eating 50 extra calories per day more than you do now will lead to rapid fat gain.  Actually, fat gain will plateau at a modestly higher level because larger bodies expend more calories.  But if you continually eat 50 calories more than your body expends, thus continually increasing your calorie intake, you will gain fat rapidly.

** I'm using the word "regulate" in the true sense of the word here, as in something that controls a variable in a purposeful manner.  To influence a process is not the same as to regulate it.

*** It also regulates a number of other variables related to body fatness, including the release of fat from fat tissue.

**** There are others as well, including but not limited to insulin, ghrelin, and amylin.

***** Involuntary increases in non-exercise activity thermogenesis accounted for the differences in energy expenditure.

33 comments:

gunther gatherer said...

Hi Stephan,

There is also eating because a certain food is about to go rotten in your fridge or cupboard. This often happens to me when I buy fresh produce which you have to polish off within a few days.

I was always taught not to waste food (the "children are starving in China" syndrome), so to this day I feel guilty letting stuff go rotten.

Gretchen said...

Stephan, Good blogpost.

I agree with gunther's "no waste" problem and the "starving Armenians or Chinese" and the resulting guilt when leaving food on the plate.

When I was a child, my mother was always trying to get us to eat just a little more vegetable or potato because "there's not enough to put away." If we didn't, she'd eat it herself.

OK, a few extra green beans probably won't make you obese, but in a restaurant where portions are huge, that same "waste not" idea can make people consume a lot more than they need or want.

Tyler Tyburski said...

Great stuff Stephan!

The "no waste", "starving Chinese", or any other "guilt" associated eating response is a exactly what it is; a response. Those that have had those neurological adaptations (from say your mother telling you to eat more or restaurants portions sizes) will continue to eat more than they need because of the reward system telling them to do so. This is why I personally am so happy to see regulations such as NY's "no soda's bigger than 16oz's" ban at certain public places. 16oz's is still entirely too large but that's another conversation.

This sobering research is minimally disheartening to myself because I am in disease management and a big goal of mine for my participants is weight loss. I guess a change in perspective is needed from said goal of losing weight to focusing more on the benefits of eating healthy and exercising to decrease chronic inflammation, improve lipid profiles, glucose levels, etc. because as I interpret, once you are at that set body fat temperature it is extremely difficult to change.

Stephan, if you were a health coach counseling an individual on preventative health how would you portray this information to someone?

Thanks for your blog, it truly is one of the best research based informational blogs out there.

Tyler, RN

bentleyj74 said...

This is fascinating. I can't wait to see the expanded version.

Sarah said...

Hello-
I am curious about the role blood sugar regulation plays in this. I have struggled with low blood sugar all my life and in the past have had to eat, even when not hungry--to get my blood sugar higher to avoid blacking out!

I suspect a diet of processed food as a child negatively impacted my blood sugar response. Anyway, my weight (and other people's in my family) tend to fluctuate a bit, and I wonder if our troubles with blood sugar are partly to blame.

I also wonder how the brain decides between blood sugar signals and leptin signals.

I'm curious if you can speak to this!
Thanks for writing
Sarah

Sanjeev said...

> if you were a health coach counseling an individual on preventative health how would you portray
_____
You know your clients best right?

My impact when asked advice has been maximal with a "this is how you work with your brain and body instead of fighting them and yourself"

Jane said...

'..Over time, the setpoint gradually ratchets up in response to temporary periods of overeating. How this happens on a cellular/molecular level, I don't know, but it must coincide with the incremental development of leptin resistance in the brain...'

'..One of the most compelling hypotheses is that leptin resistance is caused by low-grade inflammation in the hypothalamus... Yet we still don't know for sure what causes the inflammation...'

'..there's no easy fix for an increased setpoint. I wish it was just a nutrient deficiency...but that's simply not the case.'

If you don't know what's causing the inflammation, how do you know it isn't a response to unrepaired damage resulting from a nutrient deficiency?

JBG said...

"Each time a susceptible person eats more calories than necessary to meet calorie needs, the excess is stored as body fat. Afterward, a portion of the excess fat is lost as the energy homeostasis system kicks in, but a portion of it remains and is 'defended' in addition to what was already there. Over time, the setpoint gradually ratchets up in response to temporary periods of overeating."


By hypothesis, evolutionary humans commonly had periods of food plenty which they instinctively used to put on fat as insurance against times of food scarcity. But they did not experience the ratchet effect you describe, while modern experience indicates that loss of weight by drastic underfeeding does not lower the set point. How to explain the different outcomes?

JBG said...

From my earlier comment: "How to explain the different outcomes?"

One way is to observe that evolutionary humans were not exposed to candy, cake, ice cream, etc. But even disciplined modern folks have considerable difficulty maintaining weight loss when they accomplish it. It would seem that something basic is still missing.

JBG said...

A further thought - There have existed indigenous cultures living in conditions of reliable supply of quite tasty foods. Some Indians of the American northwest, for example, and some south sea islanders. But they remained lean.

Don said...

Is it possible that the holiday binge not only causes us to put on fat, but because we are eating lots of n-6 fats relative to n-3 fats, also results in a higher percentage of n-6 in our own body stores? This would lead to a higher overall state of inflammation and greater leptin resistance. So every holiday season, it gets a bit worse.

Tom said...

Very interesting post Stephan, one of your best for sure.

Joe Berne said...

Based on no science whatsoever other than self-experimentation I suspect that fat loss works in a similar way. I can lose some fat using fairly aggressive measures, but it gets progressively harder to lose more as I veer from my previous setpoint. If I can stay at that leaner point for a while, however (no hard data, but at least several weeks or months), then pursue more aggressive strategies again, the weight comes off, as if my setpoint had been re-set to a lower baseline. Purely anecdotal, but out of anecdotes hypotheses are born...

Travis Culp said...

I wonder if the body fatness high water mark may be attributable to adipocyte hyperplasia during fat gain periods. If the person then lost fat later but was stuck with more fat cells that were less full (compared to a person at the same weight/fatness with fewer fat cells that are more full) perhaps less leptin would be produced overall.

This is assuming that adipocytes don't secrete leptin in a strictly linear manner with increasing fat stores. It makes sense to me that a maxed out adipocyte would produce more leptin than two adipocytes at half capacity, or four at a quarter capacity. This also assumes that the person got fat enough to cause hyperplasia in the first place. My understanding of this is that gynoid deposition patterns lead to hyperplasia far more than android patterns, possibly explaining the greater difficulty with which women appear to lose fat. Pure speculation however.

Sarah: I too was plagued with reactive hypoglycemia for years that caused me to be about 30 pounds fatter than I am now. Getting that under control resulted in my weight stabilizing at a much lower level.

Kindke said...

"Over time, the setpoint gradually ratchets up in response to temporary periods of overeating. How this happens on a cellular/molecular level, I don't know, but it must coincide with the incremental development of leptin resistance in the brain..."

Perhaps this can be more easily explained by the simple growth of fat tissue ( angiogensis + fat cell multiplication )

Your "set-point" is nothing more than the total number of fat cells you have. If you consider one fat cell in isolation, it has a "set-point" that is mostly determined by insulin. You can neither make that fat cell too small because it becomes more insulin sensitive as it does,

nor can you make it too large because it becomes insulin resistant as it inflates, leaking FFA as it grows ever bigger.

If you cannot make a fat cell neither too big nor too small that implies its size hovers around a "set-point", So if one fat cell hovers around a "set-point" and we accept that a persons fat weight is the total sum of all his adipocytes ( obvious ), the implication is that this persons "set-point" weight is determined by the total number of adipocytes he has.



Kindke said...

Travis,

I think your "speculation" is actually spot on, from all the evidence I have seen that is exactly how I view the obesity model.

I.E. adipocyte hyperplasia is causing all the problems with "higher setpoint"

Travis Culp said...

Kindke:

It seems to me that the magic bullet, if such a thing exists, would be something (not necessarily a drug) that causes adipocyte apoptosis after weight is lost, thus bringing the person back to a correct number of adipocytes. Perhaps there is a nutrient deficiency affecting the adipocytes' mitochondria that is interfering with apoptosis or perhaps they are actually acting in a way that is consistent with their design. I would think it would be beneficial for a "fat memory" mechanism to keep track of a particular environment's maximum energy availability for a wild human.

The downside though is that seasonal fattening would cause constant discomfort via increased hunger throughout the year. We tend to evolve toward greater reproductive efficacy, not greater comfort though.

On the other hand, given how much harder hunter-gatherers have to work for energy acquisistion, it was probably quite rare for them to max out their adipocytes to the point that new ones would need to be manufactured.

Alana in Canada said...

I've always suspected that the weight loss plateau is indicative of the body "resetting" it's set-point. I wonder if there's any truth to it--and whther you could speak to that someday.

As well, I've noticed that my own weight gain was incremental--about 100 pounds in 15 years due to pregnancy (2x), sleep deprivation, stress, quitting smoking and too much ice cream. Thanks so much for this series.

Docww said...

Richard Johnson's new book "The Fat Switch" gives us some interesting insights as to why humans store excessive fat. Yes, it is complicated, yet the solution is simple. Don't eat like a typical modern human.

Jane said...

Travis & Kindke
Leptin-induced adipose apoptosis: Implications for body weight regulation
http://www.ncbi.nlm.nih.gov/pubmed/12815275

'...recent evidence indicates that leptin acts centrally to trigger an apoptotic process resulting in adipocyte deletion. ...Of all the peptides studied to date that affect food intake and body energy balance, leptin is unique in that it acts in the brain to induce loss of adipose tissue by apoptosis. ..'

What this suggests is that a raised set point is due to leptin resistance in the hypothalamus. This is what Stephan is saying, very cautiously. He wants it to be due to a nutrient deficiency but has given up hope that this is the case. I have not, and I think the problem may be deficiencies of copper and manganese, which activate antioxidant enzymes.

Stephan's group has found that switching rodents to an obesogenic high-fat diet induces inflammation in the hypothalamus within 24 hours. Saturated fat is reported to inhibit absorption of copper and manganese, and to promote absorption of (pro-oxidant) iron.

http://www.ncbi.nlm.nih.gov/pubmed/11697763
http://www.ncbi.nlm.nih.gov/pubmed/8618945

Kindke said...

Jane,

Thanks for that first paper, I found this line particularly interesting in it....

However, food restriction alone does not cause a decrease in adipocyte number.

Yet we still have millions of PhD's, doctors, and shills preaching "calorie restriction" as the holy grail for weight loss.

I probably need to re-consider my own thoughts on starvation induced apoptosis now aswell. Sigh.

Travis Culp said...

That's interesting, Jane. I've thought for a while that leptin resistance (and perhaps obesity itself) is caused by damage to the ANH by the ridiculous levels of free aspartate and glutamate in the modern diet.

Considering that MSG is used to create obese rats by blasting them during early development, it may be that a mother's diet could doom a child in the same way if it crosses the placenta. Some cursory research I did a while back indicated that the Taiwanese consume the most MSG per capita in Asia and are enduring an obesity epidemic of their own. Who knows, maybe it's something as simple as that. Incidentally, the timeline for the increase in obesity lines up pretty well with the spread of MSG/aspartame/etc. in the food supply.

Hopefully the hypothalamic lesions or whatever can regenerate if that is the cause.

Gys de Jongh said...

In October this year there was a similar series in nature Neuroscience :

Nature Neuroscience Vol 15, Issue 10 October 2012

Focus on neural control of feeding
We present a special focus that highlights research on the role of the CNS in the regulation of feeding behavior and how disruption of such regulation can lead to obesity.

Nat Neurosci. 2012 Oct;15(10):1330-5
The drive to eat: comparisons and distinctions between mechanisms of food reward and drug addiction
PMID: 23007187

Nat Neurosci. 2012 Oct;15(10):1336-42
Synaptic plasticity in neuronal circuits regulating energy balance.
PMID: 23007188

Nat Neurosci. 2012 Oct;15(10):1343-9.
Unraveling the brain regulation of appetite: lessons from genetics.
PMID: 23007189

Nat Neurosci. 2012 Oct;15(10):1350-5.
From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior.
PMID: 23007190

I saw several experiments where intranasal insulin is used to reduce food intake. Might be a simple and practicle way. Here is the last one :

Diabetes. 2012 Sep;61(9):2261-8.
Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans.
Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising
PMID: 22586589

Jane said...

@Kindke
Yes! That line leapt out at me too.

@Travis
Interesting. You know glutamate is detoxified by a manganese-dependent enzyme (glutamine synthetase). Modern meat-and-refined-carbs type diets are very low in manganese, and I suppose it's just those diets that need a lot of MSG because otherwise they don't taste of anything.

Yes I think the hypothalamic lesions can regenerate, and manganese is very interesting here too. I imagine you've come across the 'master growth regulator' known as mTOR. Well mTOR works together with another enzyme of the same family called Vps34 (Class III PI3 kinase) which controls autophagy. Together this pair of enzymes seems to constitute a master switch between synthesis of cell constituents and their breakdown. Cells apparently cycle between the two states, and if they don't, they end up with accumulations of damaged proteins and dysfunctional mitochondria.

The enzymes are kinases, meaning they need magnesium-ATP. Except that magnesium doesn't work. In vitro at least, they can only be activated by manganese. Nobody thinks this is important because very high Mn concentrations are needed. However it was found recently that mTOR moves to lysosomes when it's activated, and that's where Vps34 is. Lysosomes accumulate manganese!

Other members of the same enzyme family control DNA repair (ATM, ATR and DNA-PK). They all like manganese. So it could be that the entire maintenance-and-repair system is dependent on a metal nobody thinks is important and that gets removed from a large part of our food and thrown away.

Dave said...

If the number of fat cells has anything to do with set point, why doesn't liposuction lower set point?

Kirk said...

In regards to the concept of the body defending a higher setpoint, I keep thinking about the following passage from the book, "Don't Sleep, There are Snakes":

Often after a visit to the city of three to six weeks, a Piraha will return as much as thirty pounds overweight to the village, rolls of fat on their belly and thighs. But within a month or less, they're back to normal weight. . . . They are lean and tough.

mary li said...

I feel hungry now.

Sara said...

@Joe, many physiological systems operate by increasing sensitivity when levels of 'something' are low: for example, the cells start expressing receptor proteins for that hormone or nutrient. It's quite well known also that in excess, sensitivity decreases. So maybe your period of fatloss is causing a corresponding increase in leptin sensitivity over time? Who knows really? I think I saw also on this site that lectin overload messes with leptin sensitivity. Did I see that here?

Madhu shree said...
This comment has been removed by the author.
Mrs. D said...

Stephan, do you have any thoughts on how this might apply to the special case of weight gain during pregnancy? Of course a lot of pregnancy weight gain is the baby as well as fluid increases, but then there're the "enhanced" fat stores as well. If your correct-sounding thoughts apply, it sounds like a mom is fighting an upward battle against long-term weight gain with each child she has even though the fat gains of pregnancy are healthy in the short term. :(

Leo said...

Anyone else read "The Fat Switch"?

henrydrn said...

Hello Stephan,

Do you believe there is a lower glucose intolerance in formerly obese, lean people in comparison with those who have always been lean?

Enjoying the series.

thanks,

orkidea ilona said...

And then we have the weight and the aging process, if you are 80 years old, 10 pounds overweight and you live an active life, should`t you be content?

I have a question, i think health is also written in DNA and RNA, i had a grandmother, who was not overweight at all, she lived an active life, but she suffered all her life from high blood pressure and osteoporosis and my uncle is slender and he is physically active and he suffers also from high blood pressure? Some humans follow all the correct recommendations and they get sick anyway.