Monday, June 25, 2012

What Puts Fat Into Fat Cells, and What Takes it Out?

Body fatness at its most basic level is determined by the rate of fat going into vs. out of fat cells. This in/out cycle occurs regardless of conditions outside the cell, but the balance between in and out is influenced by a variety of external factors.  One of the arguments that has been made in the popular media about obesity goes something like this:  

A number of factors can promote the release of fat from fat cells, including:
Epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), glucagon, thyroid-stimulating hormone, melanocyte-stimulating hormone, vasopressin, and growth hormone
 But only two promote fat storage:
Insulin, and acylation-stimulating protein (ASP)*
Therefore if we want to understand body fat accumulation, we should focus on the latter category, because that's what puts fat inside fat cells.  Simple, right?

Can you spot the logical error in this argument?

To illustrate the problem with this argument, I'll use an analogy.  When you eat food, your brain has to have a way of knowing how much has entered the body-- a feedback mechanism to keep you from overeating.  The gut secretes a variety of substances that perform this task.  These are called "satiety peptides" because they're secreted when you eat food, and they make you feel full.

Important processes like this tend to be redundant; in other words, the body does not rely on one signal to perform important tasks because if something goes wrong with that signal, you've got a problem.  There are a number of known or suspected substances that contribute to satiety, including CCK, GLP-1, amylin, PYY, glucagon, enterostatin, and others (1).  But there's one single peptide that stands out from all the others: ghrelin.  Ghrelin is the only known gut peptide that promotes food intake instead of limiting it.  When you administer ghrelin to animals or humans, they eat more and eventually gain fat** (2, 3).

But the interesting thing is that if you consider ghrelin in the proper biological context, it performs the same function as the satiety peptides: it constrains food intake***.  How is that possible?  Simple: it's regulated in a reciprocal manner to the others.  After you eat a meal, satiety peptides go up, while ghrelin plummets.  Both of these act to limit food intake.  So these two types of signals have similar effects on food intake, but they accomplish it in a reciprocal manner.

The main point I want to make here is that factors that accelerate the removal of fat from fat cells can still promote fat accumulation if they decrease, and vice versa.  All of the factors I listed at the beginning of this post can either promote or oppose fat accumulation by fat cells, depending on how they're regulated.  When you think about it that way, the picture of fatty acid trafficking in and out of fat cells suddenly becomes a lot more complicated.  You'd almost think we were complex biological systems evolved to regulate fat mass in a sophisticated and redundant manner!

One of the main control points for fatty acid trafficking is nerve terminals that enter fat tissue and release norepinephrine (nor = nerve, epinephrine = adrenaline).  Depending on the receptors expressed by fat cells, this either causes them to release or store fatty acids (most often release).  Norepinephrine is one of the dominant factors in fatty acid trafficking in/out of fat cells, and this has been universally recognized in the research community for more than half a century.

The brain is the main physiological control center of the body, and it communicates in both directions with almost every organ.  It regulates the pulse rate of the heart, breathing rate via the diaphragm, blood pressure via the blood vessel walls and kidneys, regulates temperature by controlling sweat glands, hair follicles and capillaries in the skin, regulates various aspects of digestion, bone metabolism, glucose production by the liver, insulin production by the pancreas, and many other functions.  So it's not much of a surprise that it also controls fatty acids moving into and out of fat tissue.  Nerve terminals that release norepinephrine onto fat cells are indirectly hooked up to the brain (and ultimately the hypothalamus), and it's clear at this point that the brain exerts a powerful influence on fatty acid release and storage in fat cells via these nerves (4, 5, 6). Cutting the nerves to a specific fat depot increases its size (7).  Dr. Timothy Bartness has done quite a bit of research and writing on this.

The second main point I want to make here is that the brain not only controls energy intake and energy expenditure-- factors that are obviously important determinants of fat mass-- it also influences how much fat is moving into and out of fat tissue from the circulation by acting directly on fat cells.  Viewed from this perspective, it's no wonder that the brain has consistently been an important focus of obesity research over the last 150 years, and has almost universally been recognized as the central regulator of body fat mass since the 1980s.  It's also no surprise that genetic studies have consistently turned up obesity risk factors in genes related to brain function, and the leptin signaling pathway in particular (8, 9).  And that most if not all obesity drugs act in the brain (10). 

If we want to understand the accumulation of fat in fat cells, first we have to acknowledge the complexity of the system we're dealing with.  Then, we have to look beyond the proximal factors that influence fatty acid trafficking in/out of fat cells, and look for the ultimate factors that regulate these proximal factors (i.e., what originally set the ball in motion).  Researchers understand this and have consequently been studying these ultimate factors for at least 150 years, and by far the most productive line of investigation to date has been the role of the brain.  The role of the brain in obesity is my research specialty, and I chose this field very deliberately because I recognized how important it was.  I hope to be able to convey some of this research on my blog, because not only is it fascinating, it will inoculate people against some of the odd claims circulating in the popular media. 

So as for the question I posed in the title, the answer is "a lot of things".  If it were simple, there wouldn't be thousands of people studying it full time.  Under normal conditions****, you can't just measure one factor and predict what will happen to fat cells in an intact living organism.

* Typically ASP is ignored or downplayed in these arguments, but I'm not going to open that can of worms right now. 

** Ghrelin also acts in the hypothalamus.

*** Although one could make a good argument that it's important, ghrelin's role in satiety is actually not firmly established in my opinion.  One of the main reasons is that the ghrelin receptor knockout mouse has a normal meal structure.  This may be because 1) the satiety system is so redundant that knocking out one element has no effect (this phenomenon is commonly observed in knockout animals), or 2) ghrelin really doesn't play an important role in meal termination.  I favor explanation #1, but the jury is still out.

**** With the exception of extreme cases.  For example, giving someone a shot of epinephrine, a type 1 diabetic who secretes very little insulin, a nerve to fat tissue being cut, or injecting a concentrated dose of insulin into the same fat depot for 10 years.


Mike Kabbani said...

Really good article Stephan. I've been doing a lot more research into how the different nervous, endocrine and other systems affect energy levels, motivation, and especially bodyfat.

The more I look, the more it becomes clear how a lot of metabolic dysfunctions are related to an imbalance between the sympathetic and para-sympathetic nervous systems - Glucogen vs Insulin etc. With obese populations being dominant in the para-sympathetic axis which is responsible for the rise of insulin resistance/diabetes. I think this also goes in parallel with a lot of what you say about dopamine/reward circuits in the brain and how that stimulates the sympathetic nervous system.

Having said that, what has the research shown that helps increase sympathetic NS function? I've written a general article about lifestyle changes to improve hormonal function but I'm very curious about what you think.

ProudDaddy said...

And let's not forget that only a teeny tiny measurement error by this complicated homeostasis mechanism can lead to obesity.

One qibble: the use of the term "feel full". I know you were just using it for us laymen, but it leads to advice such as drink lots of water (and don't pee it out?). Personally, my stomach can be so full it hurts, yet I will still be hungry. And vice versa.

Scott Russell said...

Well written article. I'm becoming increasingly interested in the way hypothalamic damage can alter our TEE and promote long-term energy imbalance.

Do you have some studies suggesting highly palatable foods directly damage or alter the hypothalamus in humans? And what about things that are all palatablility and no reward, such as artificial sweeteners and flavor additives like msg?

Could it be primarily a mismatch between palatability and the corresponding reward that leads the hypothalamus to inappropriately determine how much energy to exend?

(In my mind, palatability is the immediate taste response, whereas reward is the bodies physiological response to the nutrients. Apologies if this is off from your definitions.)

CarbSane said...

Nice post Stephan! I've been looking at the TAG/FA cycle a lot (too much) lately, and it's just bizarre to me how many will fall for the one hormone puts FA in and 8 take them out, but only insulin regulates fat mass nonsense.

I'm glad you opened the ASP can of worms. It flies under the radar too often. Its importance is pretty much solidified by the fact that if you knock out either the insulin receptor OR the ASP receptors in fat cells, you produce the same phenotype. I blogged on that here.

Anonymous said...


Do you believe that gut flora influence the factors you have outlined?

P2ZR said...

IcedCoffee: What do you mean by artificial sweeteners or MSG being 'all palatablility and no reward'? I would imagine it's the opposite--artificial sweeteners have a disgusting aftertaste and MSG produces an irritating feeling on the tongue (complains this supertaster), but they are highly rewarding, making us want more (of either the very food containing it, or other calorific foods).

(Very roughly palatability as 'like', and reward as 'want'.)

Scott Russell said...

Everyone is different. I love the taste of artificial sweeteners. And instead of MSG, how about table salt? My point was that they are entirely taste, with no caloric value.

Granted my definition of reward differs from Stephan's. To me, "palatability" = taste, whereas "reward" = the body's hormonal response to the nutrients of that food.

I imagine that in whole food, palatability and reward equate fairly well. For instance, a blueberry is highly palatable, and the nutrients in it are physiologically rewarding. Dirt is not palatable, and there is little nutrition to find rewarding. We eat our blueberries and ignore the dirt. Everyone is happy.

Contrast this with white sugar, which is highly palatable, like a blueberry, but lacks much of the nutrition of a blueberry, so it is less rewarding. How does our brain respond?

I have quibbles with Stephan's definition of reward, partly because the "acquired taste" part doesn't make sense with regard to anything non-nutritive. And I don't think people like hyper-processed junk food because its rewarding, I think they like it because it is palatable.

Mostly I am interested in how this applies to artificial sweeteners. What are they doing to the brain, and does it matter?

Craig said...

As ProudDaddy indicated, it is tricky when viewed as a control problem. With a small systematic positive error in food intake you get fat; with a small systematic negative error, you starve to death. I'm guessing that Nature's chief designer (evolution) was far more influenced by the latter outcome.

gunther gatherer said...

Hi Stephan, I'd like to add another factor to the bodyfat equation: circulating estrogen levels. The more you have, apparently the more bodyfat you accumulate, and vice versa.

Dietary fiber has been shown to lower estrogen in the body, and serves as a general transport mechanism to dump lots of other body toxins too.

As hunter gatherers, we got a lot of it, every day. It seems we evolved with so much dietary fiber on a daily basis that our modern-day estrogen levels are quite high even while eating to the ADA's recommendations. This implies our modern day eating regime is woefully inadequate in fiber compared to our ancestors. I'm talking 100-150g/day instead of the some 40g we're recommended now.

The fiber question also segues into Mark's question about gut flora above. The gut bugs need food to do their beneficial work and to outpopulate pathogenic bacteria (which, BTW, have also been implicated in obesity).

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Scott Russell said...


I was under the impression that ASP's role is primarily for the esterification of fatty acids in fat cells, and only has an indirect effect on bringing fatty acids into fat cells. While ASP is clearly important in promoting fat storage, it doesn't seem to compare with insulin in its ability to push fats into fat cells, so to speak.

I would like for someone to actually articulate how ASP promotes excess fat storage in the absence of insulin.

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Anonymous said...

It's ALL about MONEY. There are many powerful monetary agendas out there by the Internet gurus who sell fat loss books and try to discredit insulin's role in fat gain. Insulin is not the only thing involved in fat storage by any means, but it IS involved pretty strongly.

Theories in science MUST:

*contain an explanation

*make predictions

*have stood up to REPEATED testing

These Internet book sellers ofer NO theories of their own.

Google "Authentic Chinese Cuisine." There you will see how Chinese people really eat and it is MUCH more similar to Gary Taubes' way than his bashers.

The "tons of white rice" is an American MYTH based on misinformation, stereotypes, ignorance, and propaganda from uneducated people with agendas.

All the Asian marklets are FLOODED with seafood, animal food, insects.

A lowER carbohydrate lifestyle is good and we should AVOID all the white stuff.

Adam said...

As an Asian who has grown up in Asia, I do agree with the overestimation of our rice consumption by the authors of many articles who write about "oh look at how much rice the Japanese/Chinese/insert your preferred Asian eat.

The typical rice consumption is a small bowl of rice per meal. It's used as a "chaser" if you like, for the meat, fish, veggies and bone broth. A piece of chicken > a small mouthful of rice to balance out the saltiness.

ProudDaddy said...

On the other hand, my thin muscular Filipino brother-in-law eats a full plateful of rice with every meal and sometimes in between. We are all different.

Thomas said...

"The "tons of white rice" is an American MYTH based on misinformation, stereotypes, ignorance, and propaganda from uneducated people with agendas."

Razwell, you're killin me!

I lived with the Japanese for several years and white rice IS a staple food, not an American myth. They eat plenty of carbs. They generally eat less than Americans and move a heck of a lot more.

Does my experience count as ignorant propaganda from uneducated people with agendas?

Maybe the Japanese changed their eating style to fool me? All of them.

Thomas said...

"The typical rice consumption is a small bowl of rice per meal."

Yes, per meal, which ends up being quite a lot of rice consumption overall-FAR more than Americans. I'd venture to say the Japanese eat rice like American's eat bread.

Japanese traditionally DO NOT eat low carb, which is the idea (Asians) that is subtly trying to be promoted here.

nada said...

These are fishermen of kerala (south India)

AND this is the amount of rice they eat maybe two or three times a day.

Sanjeev said...

Hi Nada - I can't see anything that indicates the scale in this picture - but the glass at top left looks like the standard size stainless I used when I visited the south - around the size of a 300ml cola can

AND this is the amount of rice they eat maybe two or three times a day.

Puddleg said...

Thomas said
"the Japanese eat rice like Americans eat bread. "

In fact europeans ate a lot of white bread long before there was an obesity epidemic. In my childhood white bread was the only bread, lollies were cheap, degenerative diseases were common, yet obesity was rare.

The countries with the highest rates of obesity are tiny pacific island nations, Nauru, Cook Islands, Samoa, etc.

Small island populations that subsist by fishing are called sedentary hunter-gatherer populations.
So cultures with pre-existing sedentary lifestyles are hardest hit when western foods arrive.
Larger islands - Fiji, Tahiti, New Guinea - are further down the list.

The number of fast-food franchises, of the sort that are the usual suspects, doesn't seem to make the difference here.

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Anonymous said...

You're killing ME, Thomas.

More American propaganda and misconceptions.

A Google Image search of authentic Japanese and Chinese cuisines reveal a different story.

My brother lived in Japan. Most Americans incorrectly assume that rice is the staple dish there. In fact, it is FISH, FISH that is featured far more prominently on the Japnese plate. S mucvh so that the average Japense eprsonj eats about 154 pounds anualy ( 1/2 poun per day)

If you want to copy the Japnese diet better learn to like FISH and SEAFOOD.

Animals foods are enormous in Asian cuisine. GOOGLE IMAGE as well as my brother's extensive experience in Japan, THailand and China and their street markets reveals this.

The REAL authentic Thai, Japanese and Chinese diets are far more similar to Gary Taubes' way than his bashers , who are clueless uneducated ,Internet guru , shyster salesmen promoting an extreme opposite view. Many of whom were touting low carb just a few years back. Complete reversals are very common amoung frauds who follow the money and are opportunists. They realize the Internet health market is huge.

Lastly sciecne shows us so far that WHITE STUFF is NOT good for us.

Get your carbs from vegetables and whole grains NOT white stuff, regardl;ess of the obscure odds and ends cultures around the world who eat it. Italy still probably consumes white bread a lot etc. It doe snot mean it is good.

GOOGLE IMAGE will reveal the truth.

Deirdre said...

Seriously? White rice? Stephan writes a brilliant blog, and it gets hijacked by an inconsequential debate on Asian portion control?

Richard said...

Is it possible to increase neural signalling to fat tissue then? And would that potentially help regulate fat mass more effectively? Would some form of exercise or body awareness movements help with this process?

Richard said...

Is it possible to increase neural signalling to fat tissue then? And would that potentially help regulate fat mass more effectively? Would some form of exercise or body awareness movements help with this process?

Sanjeev said...

> possible to increase neural signalling to fat tissue then?

Whenever people reduce calories by any means whatsoever, low carb, low fat, conscious counting, low reward, whatever technique they use they lose weight

the more adiposity they have the higher the fraction of the lost weight is adipose tissue

so why would you think that neural control is any kind of limiting factor?

And in the absence of an overall caloric deficit (leaving disease states out for the moment), WHY would the brain tell adipose tissue to get lost?

As to "body awareness" ... Alexander and Feldenkrais teach one to support one's weight passively through the skeleton and RID the body of extraneous (Feldenkrais calls this "parasitic effort" or "co-contraction") muscular efforts. This would probably RAISE one's adiposity as fewer calories are burned by the now-relaxed muscles.

Anonymous said...

Stephen, it is clear to me that body weight and fat regulation are indeed controlled by the brain. Looking back on 45 years of battling weight issues and depression, I realized that only for one 5 year period in my 30's did my body behave like a naturally thin person who could eat what ever I wanted including carbs and sweets without gaining weight.

I lost the same 40 pounds three times in my life (twice by dieting and once due to depression). I regained all the weight lost by dieting rapidly when I quit the diet but the one time the weight loss was due to being severely depressed and I finally found an effective antidepressant (phenelzine) I effortlessly maintained the weight loss for the 5 years I took the medication.
I never dieted nor did I avoid sweets or starchy foods that I still craved.

I now believe that phenelzine accounted for this miracle -- which is amazing since the drug is usually considered to cause weight gain. Perhaps the fact that I started taking it after the weight loss made a difference? It is obviously a drug with very complicated neuro-endocrine effects including on the HPA system, neurotransmitters, GABA, leptin, sleep and circadian cycles and fat metabolism and undoubtably many as yet unknown factors.

What my experience tells me is that we are far from understanding obesity but possibly there is hope that there may be some effective medical/drug approach that can correct whatever goes wrong metabolically and neurologically at least to help with the all but impossible task of maintaining weight loss.

Docww said...

I completely agree that we are a long way from understanding what causes excessive fat storage. We do know that people with excessive body fat seem to also have some degree of brain dysfunction. They have brain dysfunction symptoms suggesting low levels of monoamine neurotransmitters.

How might obesity and brain dysfunction be connected? That's an interesting question. Fifteen years ago Hudson and Pope from Harvard proposed that a diverse group of brain disorders are somehow connected through a shared pathology. They called this condition Affective Spectrum Disorder. Because they never determined the pathology or triggers of the condition, their concept never made it out of academic medicine.

We now believe that we have identified the triggers of this condition--excessive fructose mainly from sugar and HFCS and high glycemic carbohydrates mainly from grains. We now call this condition Carbohydrate Associated Reversible Brain syndrome or CARB syndrome. Learn more about this food-induced brain dysfunction at

donheff said...

Good post Stephen. I read all of your stuff because I am interested in the science behind the obesity/diabetes epidemics. I agree that the factors appear very complex and a focus on a single factor (e.g. insulin) is misleading. On the other hand, most of us are also interested in the practical implications of theory concerning how to eat in a fashion that enables us to effortlessly maintain an ideal weight without counting calories, weighing portions, and other tortuous efforts. For the last year and one half I have successfully done that by initially adopting a LCHF approach for quick weight loss and then (after reading you and some others) slowly adding in some so called safe starches (rice and potatoes). So far so good, but, I feel like I am engaging in a fairly random course of self experimentation. I for one welcome more info from you and others in the research community about everyday practical dietary recommendations that flow from your research. The LCHF and Paleo camps offer that but as you base their dietary recommendations to flawed theory. I would like to see such prescriptions tied to more complete theories as well although I realize that may be too much to offer at this point.