The Myth of Starving Cells

On the heels of my last post discussing Tom Naughton's novel theory on obesity and blood glucose regulation, I'm reminded again of the whole "fatty acids are locked away in the fat cells" - what I'll call the Starving Cells  Myth - of obesity.  Dr. Eades is weighing in on his blog on Taubes' Why We Get Fat and reiterates once again the fallacy that is the locked away fat.  Here's how he puts it:

... A non-obese person eats, uses the energy from the food and stores the rest. During the time between meals and during sleep, the non-obese person draws on the stored fat to provide energy. When the fat cell mass decreases to a certain critical point, the body signals the brain that the fat cells need a refill, so the brain initiates the hunger response. The non-obese person eats, uses some energy for immediate needs, fills the fat cells with the rest, uses the stored energy as needed, and then the cycle repeats.
It doesn’t work that way in the obese. Obese people eat, use the energy required for immediate needs and store the rest. But–and this is the extremely important ‘but’– during the time between meals and during sleep, obese people can’t access their fat stores because their baseline insulin is too high. When they can’t get to their stored fat, the lack of access to energy sets in motion all the same biochemical signals in the obese person that get sent in the non-obese, who have depleted the energy storage in their fat cells. And these signals are converted by their brains into the drive to feed, i.e., intense hunger. They have to eat to provide for their immediate energy needs because, thanks to chronically elevated insulin levels, they can’t get into to their own stored fat, even though it’s there waiting in massive quantities.
Now this all sounds perfectly reasonable, which is probably why so many just accept this as truth coming from an expert and all.   

After all, just a few paragraphs earlier, Eades makes the following statements:
We now know why we get fat. Excess insulin drives fat into the fat cells increasing the fat cell mass, ultimately leading to the state we call obesity. If we keep walking this progression back, the next question has to be, Why do we make too much insulin?
We make too much insulin because we eat too many carbohydrates, especially sugar and other refined carbohydrates. With that statement, we’re starting to edge into controversial territory, but it’s only territory populated by the ignorant. The hard science is emphatic that carbs are a pure insulin play. Eat them and your insulin goes up....

... carbs increase insulin, excess insulin drives excess fat into the fat cells, the fat cell mass grows, and we become fat. This chain of cause and effect leads to the ineluctable conclusion that excess carbohydrate intake leads to obesity. And each and every link forged in this chain is scientifically unimpeachable.

So if you are fat and want this progression to reverse itself, wouldn’t it make sense to reduce your carbohydrate intake? All the science is valid.
This is an area where I'm going to acknowledge the absolute genius of Gary Taubes.  He's made quite the career citing valid science but then spinning it to convince people that the same science supports his theories.  Only he ignores a large (and growing) body of scientific research that directly contradicts his hypothesis.   See, the science is all there and indisputable on carbohydrates, insulin and fat cell metabolism.  But nobody denies any of the following scientific facts of what happens after a carby meal:
  • Carbohydrates stimulate an insulin response
  • Insulin favors storage of fats in the fat cells by suppressing lipolysis (HSL) and/or stimulating uptake and esterification.  
  • Insulin stimulates glycogen synthesis, de novo lipogenesis, glycolysis
  • Insulin suppresses glycogenolysis, gluconeogenesis, and fatty acid oxidation
But it's taking these essentially out of context -- extrapolating short term actions to metabolic behavior over the full 24 hours in a day -- that the problems lie.  So let's return to Dr. Eades' scenarios now.  Lean people apparently do all the things above, but he acknowledges that in between, insulin levels fall favoring release of fatty acids from fat cells, uptake by muscle and other tissues and subsequent "burning" for energy.  He claims that obese people do all of the above, but their insulin never drops low enough to allow for the release.  

Now ... the first question I always have when I hear such theories is how did the lean person's fat cells go rogue in the first place?   There are billions of lean humans on this planet for whom the 151st gram of carbohydrate didn't spark an adipocyte mutiny!   Eades and Taubes and so many others are stuck in the mindset of carbs causing insulin resistance.  They can only do this by ignoring a vast body of peer review research from scientists Taubes has interviewed for his books (though apparently not read much of their work).  I'm talking Keith Frayn and Guenther Boden here.  

But assuming we're en masse participants in a Fat Cells Gone Wild reality show, let's look at what the science says compared to what Dr. Eades "teaches" us.  
Eades:  In most people, the fat cells develop insulin resistance later, which creates the problem. If insulin levels are high to control the liver’s sugar factory output, then these elevated insulin levels are sending a strong message to the non-insulin-resistant fat cells. The message is take this fat and store it. High insulin not only drives fat into the fat cells, it prevents it from getting out. Fat is packed into the fat cells and kept there.
Between meals when insulin levels would normally fall, allowing the liberation of fat to feed all the body’s tissues, insulin remains high in an effort to keep the liver in check. Fat can’t get out of the fat cells, and the tissues begin to starve. Even though there is plenty of stored fat, the body can’t get to it because elevated insulin is preventing its release.

Frayn:  NEFA release from adipose tissue is suppressed by insulin in both lean and obese individuals, but in obesity the process is ‘insulin resistant’ in that the dose–response curve is shifted to the right. NEFA release per unit fat mass is actually less in obese subjects than in lean subjects (effectively, it is down regulated by the fasting hyperinsulinaemia).  However, because of the increased fat mass, total NEFA delivery to the circulation is increased in obesity.  Furthermore, if ‘lean body mass’ (including skeletal muscle and liver) is used as the denominator for NEFA turnover, then NEFA delivery to the consuming tissues is clearly increased in obesity. The ‘insulin resistance’ of adipose tissue lipolysis may be particularly relevant in relation to the delivery of NEFA in the postprandial period.  Despite high plasma insulin concentrations in response to a standard mixed meal, obese subjects fail to suppress NEFA release from adipose tissue at a time when it is completely suppressed in lean subjects.
I've shared quite a bit of material by Keith Frayn and related research groups.  But there are other "research conglomerates" out there.  One of note is Guenther Boden's group at Temple.   Unfortunately most of Boden's body of work finds itself hidden behind pay walls, but I've been lucky to obtain full texts of several of his more comprehensive review articles.   Just one such example includes the following:
...Plasma free fatty acid (FFA) concentrations are commonly elevated in obese individuals [1], most likely due to increased FFA release associated with an expansion in fat mass [2,3]. Elevated plasma FFA are common in type 2 diabetes [4] and early changes may be predictive for the transition of patients from impaired glucose tolerance (IGT) to type 2 diabetes [5,6]. Furthermore, studies indicate that elevated circulating FFA may directly contribute to the underlying pathophysiology of type 2 diabetes, in particular, the development of insulin resistance both in the periphery and the liver [7,8]....
...Over 80% of people with type 2 diabetes are obese, while virtually all are insulin resistant [7]. The association between obesity and insulin resistance is likened to a cause and effect relationship since both human and animal studies indicate that weight loss/gain correlates closely with increasing/decreasing insulin sensitivity, respectively [20–23]. Several factors are proposed to link obesity and insulin resistance and promising candidates include FFA, tumour necrosis factor-α (TNF-α) and leptin. This review will focus on the potential role of FFA while TNF-α and leptin are reviewed elsewhere [24–26].
Adipose tissue has been proposed to be a site of insulin resistance [27]. As insulin resistance develops, there is a decrease in insulin-mediated suppression of lipolysis leading to increased circulating FFA and ultimately insulin resistance in skeletal muscle and liver [7,8]. A strong correlation is observed between increased plasma FFA, intramyocellular lipid accumulation and insulin resistance [28–31]. A number of hypotheses have been put forward to explain the role of FFA and intracellular lipid in the pathogenesis of type 2 diabetes, but, until recently, a more detailed biochemical explanation for FFA-induced insulin resistance has remained elusive.
Like Frayn, Boden seems to favor insulin resistance developing in the fat tissue FIRST, not last, as Eades instructs us.    When this happens, we get in trouble because our cells are not starved, but presented instead with an excess of nutrition.  While cells can refuse glucose to some extent, they seem less able to refuse fatty acids.  While there is a body of evidence that the transport of fatty acids is actively mediated to varying degrees, passive diffusion remains a driving force/factor.  Indeed in the obese, not only are the cells presented with dietary nutrients, but the fat cells are offering up MORE fuel still!  The buildup/backlog/whatever you want to call it in our muscles and organs wreaks havoc on hormonal signaling and metabolism.

Like with Taubes, I had never heard of Eades until after I had lost the bulk of my weight two years ago.  But when I first found his blog liberally cited on discussion forums, I read with interest various older posts that were truly helpful and informative.  Somewhere along the way he wandered off the Reality Reservation where he used to acknowledge the role of calories as in here and here.   I'll not speculate as to why ...


Margaret said…
Great post. Just a comment: there is some evidence that insulin resistance in the brain turns off satiety signals normally mediated by insulin, so that goes a long way to explain the appetite dysregulation in insulin resistant and/or obese people, rather than their fat cells "starving". Insulin resistance is also linked to leptin resistance. In other words, obesity is not really a starvation state, but an appetite dysregulated state.
Anonymous said…
I'm confused about your position on diet. I understand that you find that Taubes, Eades et al propose flawed models. The question for someone like me looking to follow eating habits that promote long-term health is, do the theoretical flaws about a low-carb diet, regardless of who's right, matter? I've been going for a carbs target of <100g/day. I'm 5'7". male, 55-y-o. Lost 25lb since mid-December (198lb -> 172lb), with every blood index improving. I seem to have stabilized at 172lb. The key question for me remains the effects of eating fat in all its types (except for trans-fats, whose undesirability is clear). Cardiologist proposes low-fat; I propose not. Back to my original question, what do you think about the macro questions of low-card and low-fat?
CarbSane said…
Welcome rkoffler: I agree with the majority of what the anti-LF contingency says about the demonization of fats, dietary cholesterol and sat fat in general. It's ill conceived. However I believe the demmonization of carbohydrates is equally ill conceived - and this includes the singling out of fructose per se.

I lost a lot of weight on my second stint of low carbing (basically Atkins induction) several years ago but had some troubling symptoms - I now believe to be hypoglycemia. This time I didn't have those symptoms. My weight loss has been significant, perhaps 100 lbs, and I'm of a normal size. However my weight is still too high. I try not to focus on that, but would like to shed the excess. Just LC doesn't do it for me anymore. I'm maintaining nicely, but not losing.

So around 2 years ago - when I weighed about 10 lbs more than I do now - I decided to research if what I was doing was indeed a healthy way to eat for the long haul.

This is just my opinion, but I think VLC diets are perfectly healthy and acceptable for weight loss, although I question a bit the whole super-high fat version.

For maintenance? I've come around to believe that VLC/HF is probably not the best bet. That's just my opinion. But insulin resistance is the pathology underpinning CVD etc. So I think a diet that improves if not maximizes insulin sensitivity is the goal and VLC/HF in maintenance (or gaining) is not it.

It's bothersome to many, I know, but there's too much actual data out there on longlived relatively modern human cultures who eat relatively high carb/low fat diets to ignore in favor of guestimates of how paleolithic humans ate over 10,000 years ago or a couple of remote cultures living in extreme environments.
CarbSane said…
@Margaret: Thanks! Yeah, it may be IR keeps the normal carb satiety signals from reaching the brain. In the throes of IR then, this may explain why so many are more satisfied by a diet that "works around" this system.
Sanjeev said…
my 2 pennies for rkoffler - long term minimization of any of the macronutrients seems like a bad idea.

Paul Jaminet's mucus based case ;) against very low carbohydrate is well argued. I'd love to read counter arguments though.

I've also read about long term low fat diets reducing testosterone levels in men and increasing hunger to extremes (anecdotally, although I grew up on a very low fat variation of the traditional Indian diet - boiled lean meats, zero fat potatoes & rice & lentils & yogurt, I never really felt the physical sensation of extreme hunger- my obesity came about just by not knowing when to stop eating)

and of course, protein's seemingly well established appetite suppression makes lowering protein a bad idea for the obese
kds said…
CS: There are obviously a ton of people out there who are (significantly) obese but not even a bit insulin resistant. What factors do you think are contributing to the pathology of the IR obese vs. the non-IR obese vis a vis NEFA suppression?
CarbSane said…
@kds: I think one factor may well be where one stores fat. Which is why we sometimes hear "the women get fat, the men get diabetic". Thigh fat cells proliferate more - e.g. more turnover of young insulin sensitive cells in which to keep fat. Visceral and perhaps even trunk subQ fat seems to be more metabolically active (higher lipolysis), but more likely to be due to larger fat cells than differentiation.

I would also add that as IR is measured by glucose disposal, there does appear to be a defect in some genetically predisposed individuals - impaired non-ox disposal, aka glycogen synthesis. Perhaps we're seeing more IR only because more are getting to that degree of adiposity that overwhelms this defect that would otherwise go unnoticed?
Anonymous said…
Thanks for the comments. They the end I'm not sure how actionable these data are.

For good or for bad, Taubes et al explain a model that I understand and can follow without a checklist of meals and recipes. This is unlike typical diets that provide a formulaic approach instead of a model.

CarbSane, you propose, "So I think a diet that improves if not maximizes insulin sensitivity is the goal and VLC/HF in maintenance (or gaining) is not it." I am in agreement (after digesting Taubes' model.) So the question for me is, what is _it_ if VLC/HF is not _it_? (Question isn't intended to make fun of Bill Clinton.)
Melchior Meijer said…
Let us assume that in the end it's all about calories. If you consistently eat more than you expend, you become overweight and/or diseased. The conclusion should then be: eat less, move more. I think we can safely conclude that the majority of patients don't manage to get their energy intake sufficiently low to prevent or reverse disease on a standard western diet. We could quarrel about the reasons until we see blue in our faces, but there is a ton of anecdotal and some scientific evidence that excluding grains, legumes, dairy and added sugar (glucose/fructose) leads to both a spontaneous decrease in energy intake and the expected improved insulin sensitivity. The little hard evidence out there (Lindeberg et al), suggests that eliminating 'neolithic agents of disease' (you are welcome to punch me in the face from over the Atlantic) corrects almost any metabolic derangement, including out of wack lipolysis ---> lipotoxicity. 'Despite' a relatively high energy percentage fat.

It is very likely that the decreased energy intake is the culprit. Calory restriction studies produce similar favorable results (although we cannot ignore the possibility that removing some nasty xenobiotics like glutenend WGA offers significant or even crucial benefits). The difference is that folks following a 'paleo' approach spontaneously eat less (while getting enough micronutrients at the same time). So what do you have against this approach? Do you prefer people to follow weight watchers and fail?

Elsewhere you compare striving for low insulin with striving for a type 1 diabetic state. I think you cannot compare the two states. Low fasting and postprandial insulin is a well established hallmark of health and longevity. Usually it reflects excellent signaling. I agree that the low insulin achieved in Lindeberg's trials (not really low carb) is probably something else than the low insulin achieved on a super low carb diet. In the latter case signaling might be impaired (as suggested by the 'physiological' insulin resistance) and what we should find out is if this leads to lipotoxicity.
Alan said…
I would like to see Jaminet's mucus-base case in favor of not VLC/ZC'ing...... but not at the cost of penetrating a paywall.

Can anyone summarize it?

Was he the originator of the theory?
CarbSane said…
@rkoffler: I like LC to lose weight for the very same reason. I tend to think, however, that with the super high fat version some are eating the weight loss may be more lean mass. I lost weight doing good old fashioned Atkins induction style eating w/o shakes/bars/product except for the occasional LC wrap.

I think the Perfect Health Diet, Cordain-style paleo, Sisson's actual diet or Mediterranean diet are better frameworks to work from in maintenance. There's just not enough information on humans eating like 75-85% fat as some do. I'm still trying to get my mind in the game to drop a few more lbs. I'm hopeful that after a bit of a hiatus from VLC (I eat around 125g total carbs these days - not counting veggies 75g starch) that it will work its magic for a while ;)
CarbSane said…
@Alan: This is Part IV but links to other parts are at the end of the post.

@Melchior: At this point I remain concerned about beta-cell and organ lipotoxicity.

Perhaps my wording of the T1 analogy is poor. What I'm trying to get across is that insulin itself does not have deleterious effects on the body so the focus on the levels is misplaced. The way some talk, it would seem that we want the lowest insulin level possible. But when we're sensitive to insulin, the levels mostly take care of themselves. If following a diet means one can no longer properly process a potato their pancreas is no longer producing insulin in a proper fashion. We don't know what that does to vascular endothelium, etc.

I see no downside to restricting/eliminating NAD's but I don't believe they are responsible for diabesity per se either.

With respect to Lindeberg,
The Paleo diet consumed for 12 weeks averaged 1344 cal/day 28% protein/27% fat/40% carb (4% alcohol) e.g. A high protein, low fat, moderate carbohydrate diet.
Anonymous said…
I do assume it's all about calories. With that in mind, Weight Watchers (which lowers calories) works. So does Paleo, so does the cabbage soup diet. So does Jenny Craig, so does Atkins. So does Fletcherism (chewing each bite 20 times before you swallow), so does any diet followed by Oprah in the last 10 years.

Whatever you can live with for the rest of your life (you do the diet, remember - the diet doesn't do you) is the best. The rest of your life is a long time, let's hope.
CarbSane said…
Amen eulerandothers! My big secret this time was to find a way to do whatever it is I'm doing for the long haul. I'm coming up on 4 years. I just want to make sure I'm counting for a long long time.

This was part of the impetus for my research and this blog. At the time Paleo was quite a bit more obscure than it is now so I was mostly just looking at low carbers. What I discovered was a group of formerly obese folks who were now mostly less obese but few truely lean, struggling to maintain, still cycling weight - some by falling off the wagon, some by remaining faithful, etc. Especially the women my age or a little older. That's just reality. I'm not picking on these folks, just looking for inspiration and confirmation and finding less than expected in that vein.
mamaelvis said…
I don't get how you are an expert on this topic.

You look fat to me. If you solved the issue at hand how come you haven't applied it yet?

Your face looks like a balloon ready to pop.

I am not trying to be insulting, but it is a

credibility issue whether people should accept

the advice of a fat person on how to eat properly.
CarbSane said…
Well I guess I need to find a better picture because I'm not fat. I can't help that I've always had a round face though. I guess I should use a posed professional shot in more flattering light, with my hand under my chin, not smiling fully, and carefully applied makeup.

Don't see how that's relavent to the science though.
Anonymous said…
Ewwwww! I hate those pompous photos. I love your pic, CS, because it's darling, and your personality shines through. You're someone I would seek out at a party.

Back to the science - you say that you see women particularly who can't succeed long term on VLC - why do you think that is? Is it just not ratcheting down the calories, particularly when building carbs back in? Or is it true, as Matt Stone says, that low carb lowers metabolism? Would this be for women, particularly? Or something else?
CarbSane said…
Thanks Steph!

My anecdotal evidence on low carb is that it does lower metabolism independent of calories. My body sure seems to get super efficient the longer I eat low carb. Perhaps this is more pronounced in women than men because on average we start out with lower metabolisms to begin with? It makes sense b/c carb restriction mimics starvation and we see that starvation and CR are compensated for with reductions in basal metabolic rate and such. Most studies I've seen just look at a weight loss phase or aren't looking at true VLC for a long enough period to see this in hard data, but having the body in perpetual gluco/glyceroneogenesis mode has got to be perceived as stressful to the body.

It seems that Dana Carpender has been struggling for a while now to keep her weight down and she sure has gone up and down over the years. She's not that much older than I am, and she's probably about my age or a little younger I think in this old publicity photo:

The pictures of the low carb women were what alarmed ... nah, darned near scared the bejeebers out of me ... back in 2009. I'm still not sure there's a formally obese paleo/primal female out there. I was hoping to find pics of a lot of slimmed down women and I didn't. I think this speaks to the sustainability of this WOE for long term maintenance.

I see having to go lower and lower carb as a terrible corner to trap oneself in for the rest of one's life. JMO.

I'm really not sure picking on my appearance is going to get "mama" very far ... :D
Mirrorball said…
CS: "I'm still not sure there's a formally obese paleo/primal female out there."

There is me. I'm 5'4", used to weigh 200 lb (BMI 34.6, on the brink of type II obesity), now 124 lb (BMI 21.4). But I'm not low carb, not by any stretch of the imagination. I eat plenty of fruits and starchy vegetables. I mean plenty, because starchy vegetables make me feel good and I've a sweet tooth. When I'm near that time of month, I would make the 30-bananas-a-day guy proud. I go easy on the fats as well.
CarbSane said…
Thanks for sharing MB. What would you estimate your macro ratios to be?

I've got a post in the thoughts about the LC/paleo disconnect and just "paleo" confusion in general. I think I may send out a search party for Don Matesz over at Primal Wisdom. Seems his Venus posts have caused a bit of unrest and he hasn't published a comment since May 6th. Hope he hasn't been banished to internet Siberia!
Mirrorball said…
No idea, but if I had to guess, it would be close to Zone ratios (40/30/30), maybe higher in fat.
Anonymous said…
Mirrorball, that's really impressive, good for you.

CS if VLC lowers metabolism, I can't see it as heathy. I suspect VLC is what screwed up my thyroid, though I can't prove it. But in the LC world I hear little discussion of metabolism and thyroid...

I think I'm slowly building up my metabolism, and my diet is shaking out to look like yours, Mirrorball, now that I've made starches legal.

CS I think a paleo confusion post would be great!
CarbSane said…
Re-instating lost comment for:
Mirrorball, that's really impressive, good for you.

CS if VLC lowers metabolism, I can't see it as heathy. I suspect VLC is what screwed up my thyroid, though I can't prove it. But in the LC world I hear little discussion of metabolism and thyroid...

I think I'm slowly building up my metabolism, and my diet is shaking out to look like yours, Mirrorball, now that I've made starches legal.

CS I think a paleo confusion post would be great!
Unknown said…
Nice post!

Protein Power was the book that got me on a low carb diet last year, and I lost about 18kg in three months. The book was written in the 1990s and I would still recommend it - I agree that at some point after writing that book the Eadeses got a bit quirky. As you know, it's gotten to the point where they claim that you can't get fat by eating fat - and that's also the point where it becomes really dangerous advice.

But as I said, Protein Power is still a good book IMO - and the common denominator for efficient (and healthy) fat-loss still seems to be to eat adequate protein.
JSMLMSuccess said…
Great posts everyone. I think it's critically important to first determine what body type you have along with some basic body chemistry testing. It's possible that the body of our dreams may simply not be attainable based on our eating habits, genetic makeup, etc. But remember, there are many plans out there based on body types and, unless other uncontrollable issues exist, it is possible to change how the body metabolizes food for fuel vs. food for long term periods of starvation. Unfortunately, there is not a "one size fits all" solution. What has worked for me could make another person gain undesirable weight.
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Victor Venema said…
Could be that the mechanism described by Eades is wrong. (That would
not proof that the main idea is wrong: that hunger and not eating is
driving weight gain.) However, I am not that convinced by the text you
provide as evidence.

"However, because of the increased fat mass,
total NEFA delivery to the circulation is increased in obesity.
Furthermore, if ‘lean body mass’ (including skeletal muscle and liver)
is used as the denominator for NEFA turnover, then NEFA delivery to the
consuming tissues is clearly increased in obesity."

Isn't is
normal that NEFA delivered to the muscles of obese people is larger?
They have a larger body to support and movement takes more energy.
Normalising by lean body mass does not seem to be the right way to make a
fair comparison.

"...Plasma free fatty acid (FFA) concentrations are commonly elevated in
obese individuals [1], most likely due to increased FFA release... "

Sounds logical, but only a first sight for someone not thinking in terms of systems. The latter is typical for the Eat Less Move More Movement.

reason for increased FFA release will be increased demand (the amount
of FFA in the blood cannot growing continually, the body naturally has
feedbacks to match supply and demand). With an equilibrium in release
and demand, I see no a-priori logical reason for a specific
concentration in the blood; it will depend on how the FFA are transport
to and from the blood and the FFA concentrations in the lean body mass.

running a marathon will also have an increased FFA release. Would this
also "logically" lead to higher FFA concentrations in the blood?