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“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Thursday, June 28, 2012

Review & Critique: The Skinny on Obesity ~ Part III Hormones

Previously I've shared my thoughts on Episode I and Episode II in this series.  This third installment in the series is essentially Lustig's version of Adiposity 101.  


The video opens with an adamant Lustig declaring that weight management can't be done by eating less and moving more.  It's not doable.  Sigh.  I think at least the vast majority of NWCR members will disagree.  But in any case ...

At least Lustig mentions that six letter word that almost never passes the lips of Gary Taubes -- leptin.  Indeed there's no more simple reason to dismiss Taubes than that his hypothesis completely ignores this hormone.  No matter the mechanisms, there can be no doubt that leptin plays a key role in energy homeostasis and regulating the amount of adipose tissue we accumulate.  But Lustig plays fast and loose with the facts about leptin.  First, early on, he shows the cartoon woman eating, and leptin going to her brain saying "enough".  

Now I could be wrong on this, and I'm sure I'll be told so in comments if I am, but leptin does not appear to be an acute acting postprandial satiety signal.  I had some fun with L. Ron Rosedale and his "leptin spiking" theories, and blogged on a random assortment of 24-hour leptin profiles from various studies.  The bottom line is that leptin is not a hormone that is responsive to intake like insulin.  Generally it seems to be suppressed by intake if anything, and to a slightly different degree by fat vs. carbohydrate intake.  So Lustig's cartoon portrayal of how leptin is supposed to work, is factually wrong.   (I also don't get the  "it let's you exercise" thing??).  Leptin does regulate intake in some manner, but it seems to be more of a direct communication between fat cells and the brain or how the brain senses the level in the "fat tank" energy stores -- a fuel gauge of sorts.

So Lustig goes on to describe how the obese make lots of leptin and the apparent paradox there, because if leptin were doing its job they wouldn't be eating so much and getting obese.  So it's leptin resistance that makes us fat.  And what causes leptin resistance?  That's the holy grail of obesity research says Lustig ... to answer the question of why leptin worked 30 years ago and it's not working now.   Lustig refers to "our research" and it's specific and significant findings.  To sum it up, he says he can use one word:  Insulin.    

Lustig perpetuates this myth that when your blood sugar is high, insulin works to put that glucose into your fat.      This is what he says happens to the diabetic who injects their "diabetes hormone" insulin.  
Insulin shunts sugar to fat. Period.
Insulin makes fat. Period.
More insulin, more fat. Period.
Insulin drives weight gain.  


Here's where I get the mental image of Taubes v. Lustig in a Rock'em Sock'em robot brawl, with Taubes  shouting "Give me back my schtick!"

I suppose I don't need to go into all the ways Lustig's absolutes are wrong ... so I won't.  But Lustig just swerved way off the road here.  One minute he's talking about why leptin stopped working and the next he's blaming insulin for it using an even more incorrect and simplistic description of how insulin is a fattening hormone.  

Now Lustig launches into his warped experiment where he's going to stick an IV in the interviewer's arm and follow her around and every time she reaches for food, Lustig will pump her full of extra insulin.  If this is the sort of "research" Lustig engages in ....   C'mon, this experiment is ridiculous.  Everyone knows that excessive exogenous insulin causes hypoglycemia which makes you hungry ... but does this have any relevance to how obesity develops?  In one of his papers, Lustig cited a study that found postprandial hyperinsulinemia occurs earlier in obesity in children than does fasting hyperinsulinemia.  But since that study did not follow individual children in this progression, or from the non-obese state, but rather compared groups of children at various stages/durations of obesity, no arrow of causality can be drawn.  That study only showed that compensatory hyperinsulinemia seems to occur first in the postprandial state and later in the fasted/basal state.  In any case, responses to artificially elevated insulin levels have little relevance to how your body works and responds to the insulin pumped out by your own pancreas.  

So Lustig is going to "overinsulinize" whomever he's talking to in the video "just like we do our diabetic patients".  Huh?  Do we overinsulinize diabetics?  What is he talking about??    But I digress ...  We now get a second cartoon version of the Fat Head hungry fat cells schtick.  That the excess insulin locks some of our calories away in our fat, so the rest of us is starving, so we eat more, which makes more insulin, and cue the Faberge shampoo commercial.   It's just another version of Taubes' contention that obesity is a horizontal growth disorder -- the Fat Cells Gone Wild schtick.  There's no evidence supporting this, and copious evidence countering this, but that doesn't stop Lustig from explaining this in the video as if it's established fact. It's a convincing scenario, however, so what's a few incorrect statements if Lustig can help just one pudgy child eschew the Coke ... right?   

I don't know that there's any association between someone's energy expenditure and how good they feel.  He cites exercise and caffeine as upping EE and making you feel good, and hypothyroidism and starvation of lowering it and making you feel bad.  I dunno, most people's EE's go down with significant weight loss, yet most people also feel quite a lot better than before.  And sleeping makes me feel good!    But here we go with more absolutes from Lustig:

How many calories you burn and how good you feel are the same.

Okey dokey.  Ya know, if I never hear the words gluttony and sloth again, it will be too soon.  Can we please take those emotionally inflammatory terms out of the discussion?  I'm so tired of this nonsense idea that this obesity epidemic is some mystery and some metabolic mahem preceded and caused the overeating and not vice versa.  There's just no evidence for this, and billions of humans eating far higher carb diets than the SAD whose fat cells behave for their entire long healthy lives.  Lustig claims the global industrial diet has done the equivalent to his insulin injection scheme -- that we produced our own excess insulin in response to this GID.   Well, here's where TWICHOO at least makes sense -- that carbs stimulate insulin production.  Fructose doesn't stimulate insulin production, and he specifically fingers sugar repeatedly.  He's also blaming foods that are carb+fat ... but these tend to be lower glycemic foods that generally elicit a smaller insulin response.  

Concluding this episode, Lustig brings it back to leptin.  And he makes the claim that this is all tied together because insulin blocks the action of leptin in the brain.  I dunno.  Leptin follows a diurnal pattern and peaks sometime during the night.  I've read lots of studies that look at this and how sleep patterns, meal timing, dietary composition, etc. can alter the overnight leptin patterns.  But all of these tend to conflict, and until (if we ever can) we can  measure leptin levels in the hypothalamus or binding leptin, this will remain a very confusing topic.  In one study I bring up many times, where they held carbs constant, and exchanged protein for fat so that the diet contained 30% protein, twice the 15% control.  The subjects spontaneously reduced intake by around 450 cal/day and this reduction was sustained through 3 months.  Leptin levels overnight went down, however.  They hypothesize this is probably evidence that the protein improved leptin sensitivity.  And then we have circulating leptin receptors -- what's that all about ??  So leptin levels per se don't seem to tell us much.    That is, I suppose, part of Lustig's point.  But he ends the piece again pointing to his research which he claims shows insulin blocks the action of leptin in the brain.  When I first watched this episode, that statement prompted me to post the question:    Does insulin block leptin in the brain?   Now when I hear something like that, I'm envisioning a study that assesses leptin transport in the brain or insulin binding/blocking leptin receptors in the brain, or something of this nature.  This is the specific claim Lustig is making.  Not that leptin and insulin have opposing actions in the brain, but that hyperinsulinemia per se prevents the brain from "seeing" and responding to leptin.  

"The work we've done" probably relates to this study:  Obesity, leptin resistance, and the effects of insulin reduction.  They  took obese people with established hyperinsulinemia and presumed leptin resistance (hyperleptinemia), and gave them the insulin lowering drug octreotide.    Octreotide has been used in the past by Lustig  -- who treats pediatric hypothalamic obesity -- to bring about weight loss.  Hypothalamic obesity is quite rare, it's not inherent, but rather develops in a small portion of children treated for brain tumors where hypothalamic injury occurs.  This injury causes inappropriate oversecretion of insulin.  I'd heard him talk about this two years ago in a podcast with Jimmy Moore.  His starving cells model perhaps fits these kids (though I think it more likely it's hypoglycemia driven), and blunting that inappropriate and abnormal insulin secretion is an effective treatment.  So why not all obese?  This was a rather small study -- 17 subjects -- and it was not controlled -- all subjects received the treatment, there was no placebo control group to compare to.  One of these days this paper deserves a more in depth look as it is quite a good example of bad science.  

But for now a shorter summary.  So 17 obese subjects were treated for six months.   The entire group lost an average of 4.4 kg (9.7 lbs), of which an average of 2.5 kg (5.5 lbs) came from lean mass as determined by DEXA.   Restated:  Only 43% of weight lost came from fat tissue, 57% of the weight loss came from lean tissue.  They then break out the group into categories of "responders".  Only 6 subjects (35%) lost "significant weight", defined as more than 10% starting weight.  I don't know about you, but these results are hardly convincing that hyperinsulinemia caused obesity, and I would also not be too thrilled with "weight loss" where more than half of the loss was lean tissue.  On average, these subjects became fattier!  Calculated from Table 1 (averages for all 17) initial weight was 125 kg with 52 kg fat-free mass = 58.4% fat.  After six months on insulin lowering therapy, their weight was 120.6 kg with 49.5 kg fat-free mass = 59.0% fat.  OK, not significant, but we can add this study to the list of evidences for my Insulin Paradox post.  In any case, just over one-third were "high responders" who:
In comparison to the low and nonresponders, the group of six high responders exhibited decline in weight, BMI, leptin, and IAUC with octreotide-LAR therapy, but without significant change in REE.
What's that there?  Nonresponders?  Let's look at how this worked out:

  • 6 high responders lost more than 3 BMI points 
  • 7 low responders lost between 0 and 3 BMI points
  • 5 non responders gained BMI (amounts not given)

Ummm ... how is one a "responder" if their weight does not change?  How many of these so-called low responders didn't respond at all.  Also, if someone gained weight, would that not also constitute a response?  Just because the response wasn't as desired or predicted by these (biased?) researchers doesn't mean they didn't respond.  Indeed almost as many  responded to treatment with weight gain as with significant weight loss.  In any case, here's the statement from the article that at least passed the peer review scrutiny for Nature:
They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.
These results are consistent with the hypothesis, but they are also consistent with the opposite.  This study and its results provides rather weak support for this hypothesis.   Last I checked, "may" does not equate with does.  Lustig's definitive language in this video is inappropriate at best.  He states that his work shows that insulin blocks leptin in the brain, complete with little cartoon demo, and it makes you hungry.  And the GID prompts your pancreas to pump out extra insulin equivalent to having Lustig follow you around injecting you with it, and this drives fattening.  I don't know how a study where almost 30% of subjects gained weight on insulin lowering therapy, and who-knows-how many didn't respond either way (no gain or loss) tells us much of anything about what the GID does to manipulate insulin or leptin per se to cause obesity.    

23 comments:

ProudDaddy said...

When VLC(arb) devotees are asked about the insulinotropic effects of amino acids, they tend to first deny, then dance around, and finally (correctly) note that glucagon is also produced. Where they will never go is the question of glucagon's effect on adipose tissue. I've found references to in vivo studies, but I cannot find them via Google Scholar. These studies supposedly state that glucagon has little if any effect wrt lipolysis, which may contradict some in vitro studies.

Two questions: has anyone got studies, and what is Lustig's take on proteins and glucagon?

LeonRover said...

It's Insulin Resistance, then it's Leptin Resistance modulated by Insulin Resistance.

And the French Paradox??

It's the French Resistance - take to the maquis, mes amis et amies, let us be Outsiders and get thin together.

This is the Theatre of Absurd Endocrinology, starring Lustig in place of Camus. Tres amusante.

Slainte

Evelyn aka CarbSane said...

The Theatre of Absurd Endocrinology. LOL! Love that!!

Evelyn aka CarbSane said...

Forget glucagon. Lipolysis is not the rate limiting factor in fatty acid release from adipocytes. One cannot address fat accumulation in adipocytes without looking at hormonal control of both lipolysis & re-esterification in the adipocyte portion of the TAG/FA cycle.

But, I have seen lots of conflicting info on glucagon's action on adipocytes. I think it's major function is to stimulate glucose production in the liver when protein stimulates insulin in the absence of carbohydrate to prevent hypoglycemia.

Thomas said...

It seems to me leptin should be looked at more in accordance with what it does when levels are consistently low; how it helps the body survive when intake/glucose availability is reduced: reduced fertility, increased fat oxidation, reduced energy expenditure, increased hunger and drive to eat, increased cortisol, decreased insulin sensitivity, etc. Does this not look like a survival hormone, it's fat reducing/increasing properties being purely secondary? It appears to me that Leptin is about survival, not body composition (or else it WOULD have a stronger effect as fat mass increased).

It also seems that as researchers get more media popular and media savvy, they tend to make more absolute statements about research that is anything but. This seems to be a dumbing down process and a way to bet their biased opinions across for the good of the masses. Of course this just goes on to create confusion and fuel more dogma, but oh well.

Evelyn aka CarbSane said...

That's an interesting take and I tend to agree. At the very least, leptin seems to be far more effective in defending against excessive fat loss than protecting against excessive fat gain whether it's "intended to" as it's major purpose or not.

Media coverage of science is getting worse I think. The way Peretti described leptin that he got from Lustig reminds me of that game telephone. Where you would sit in a circle and say something to the person next to you who would then repeat it to the next person and round the circle it went. By the time it got back to you, it often didn't even resemble what you said.

Lustig is more dangerous than Taubes in my opinion, as he has that extra gravitas of letters after his name. He's clearly got an agenda and he seems willing to lie or make stuff up to advance it. Oh, but I suppose I forgot to praise him for raising awareness ...

ProudDaddy said...

My understanding of the role of glucagon is the same as yours. But how does one answer the folks who insist insulin will make you fat only if it is caused by carbs (assuming they even admit that protein can be highly insulinotropic)?

Evelyn aka CarbSane said...

Do you want my real answer? He hee. That they are wrong, and idiots for insisting on defending a flawed hypothesis in the face of overwhelming evidence to the contrary.

Insulin regulates -- or tries to -- circulating substrate levels: NEFA, AA and glucose. It does this by suppressing and stimulating metabolic processes in virtually all cells, but most importantly in liver, muscle and fat cells. Your pancreas doesn't give a damn about your fat mass. My own pancreas sent me an email the other day confirming this.

Sorry ;) I'm in a mood! :D

Thomas said...

Obesity simply is not a real health concern from an evolutionary perspective. It was rare for most of human history, doesn't present a threat to survival in the short term, and is usually only a real problem in the later years (generally speaking). There is no physiologic need for a strong defense against obesity and the leptin system generally isn't "broken" in obese people.

Nigel Kinbrum said...

Maybe naturally-skinny people have CIAB Resistance! :-D

Evelyn aka CarbSane said...

I prefer MEFP = Molecularly Engineered Food Product.

Dunno if you have Cheese "Food" by you, but most American Cheese is not technically cheese. It's "cheese food".

Stephan Guyenet said...

Just chiming in to confirm that leptin is not a satiety hormone, i.e. it does not act on meal-to-meal timescales. It's a longer-term player. A couple of days of overfeeding will increase it.

ProudDaddy said...

I remember reading a study or review that fingered CRP as the cause of leptin resistance. It seemed a lot more convincing than the Lustig paper fingering insulin. OTOH, there's these nasty confounder thingies. CRP is accompanied by inflamation and numerous associated adipokines and often metabolic syndrome which could include hyperinsulinemia and obesity and chickens and eggs and I'm getting a headache just thinking about it.

justjuliebean said...

Here's my non-scientific anecdote, from a freak of nature judging by what I've been reading, who managed to ELMM, going from BMI = 34 to 26, and stable, still decreasing extremely slowly. I think CICO is not inaccurate, but with a caveat - hormones are what must be manipulated/obeyed, not will power. Though I dislike it, I've taken enough biochemistry to know that life is very complex, enzymes and hormones, etc., all do amazing and complicated stuff, counteract or enhance each other, gain/are outcompeted for their receptors, and so on, no part of our endocrine system works in a vacuum. Honestly, I think both Taubes and Lustig understand this, but Taubes is a salesman who wants to be a guru, and Lustig? Not sure why he is going this direction, unless he really is pushing an agenda that he's sure science will someday confirm, though it's not there now.

ProudDaddy said...

Thanks to Prof Dr Andro for finding the studies for me. Help me out just a little bit more. The 1991 Jensen study actually measured "palmitate flux" but used the term lipolysis in the conclusion. Does all this mean that glucagon has little or no effect on fat accumulation, or not?

(Just because Fred Hahn responds by implying that I'm an idiot doesn't mean that I would respond in kind. I prefer discussing studies or physiology texts. Besides, he has more muscle than I do and my address is in the phonebook.)

ProudDaddy said...

BTW, the 2001 Gravholt study measured plasma glycerol and FFA to reach the same conclusion.

Evelyn aka CarbSane said...

I noticed in the Frayn book, Figure 5.16 (http://bcs.wiley.com/he-bcs/Books?action=resource&bcsId=5402&itemId=1405183594&resourceId=20824) has a ? on glucagon stimulating lipolysis or mobilization.

qw said...

May insulin resistance affect the amount of carbohydrates that is converted to fat?

Evelyn aka CarbSane said...

Welcome QW! I don't think the evidence supports that -- as in increasing it. The increased liver triglyceride output in the IR is generally related to increasing fatty acid release from fat cells. I think I stumbled upon a huge bomb the other day when I learned that GLUT transporters are downregulated in adipose but not in muscle in the IR. Lastly, I fail to see how converting an equivalent amount of carb to fat vs. just already having that fat that must go somewhere makes us fat.

qw said...

May insulin resistance affect the RQ?

P2ZR said...

The Theatre of Absurd Endocrinology--
where pond'rous moobs southward migrate, so rapidly...

RRX said...

Thomas, that's been my view for a while too.

RRX said...

Ugh. This stuff has gotten so ridiculous and so far from the actual research. After looking at a lot of it myself and seeing the lies and throwing low/no carb out the window, I could not be more happy. Neither can my physique, my fiancé, my bloodwork, and my PCP. Thank you again and continuously, Sane.

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