Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

{shhhhhhhhh .... don't tell Gary Taubes, this might just upset his 21DaySugarDetox approved green apple cart!}

You know how the story goes by now, right? In more recent lectures, Taubes is fond of using the slide below.

These are two quotes that Taubes cites from Lehninger's Principles of Biochemistry and he juxtaposes them to convince you how misguided such textbooks are.  How can, on the one hand fat cells "fatten" according to the action of insulin, but human beings get fat due to positive energy balance?   The simple answer is that insulin is not some renegade hormone and your pancreas is not a master organ in the body placating your rebellious adipocyte's every whim.

Yes, tis true that insulin has a stimulatory role in the storage of fatty acids by acting on LPL on the intake side, and yes, tis true that insulin "traps" those fatty acids in the adipocytes by suppressing HSL mediated lipolysis and release of same.  Sounds like a slam dunk.  If there's too much insulin, ostensibly from chronic spiking due to chronic carbohydrate consumption, the fat cells get stuck in storage mode and the horizontal growth disorder is primed for obesity!

Not so fast.  How can the results of this study be then?  Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.   The abstract, bullet-pointed for ease of reading:
  • When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. 
  • FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. 
  • Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. 
  • In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. 
  • The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. 
  • In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. 
  • In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. 
  • In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. 
  • Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
Cliff Notes Version:  Decreased lipolysis from WAT increased skeletal muscle glucose uptake and DNL in the liver without resulting in increased WAT mass.  In the obese, suppressing WAT lipolysis induces DNL in the fat tissue.  This improves glucose metabolism.

All of the evil things you were told insulin did to you -- turning carbs to fat in your liver and fat tissue and suppressing lipolysis from fat tissue -- are actually good for you.  And the (temporary) trapping of fat in the adipose tissue improves insulin signaling and glucose handling in the skeletal muscle.  

Imagine that ...


Erik Arnesen said…
See also:

«For years, scientists thought that blocking lipid storage or inhibiting fat cell development might be an effective anti-obesity therapy. Common sense suggests that less fat mass would be healthier. Yet, we know from mouse and human studies that this is not necessarily true. When lipid cannot be stored in adipocytes, it accumulates in other tissues where it should not be stored. This condition, known as ectopic lipid, has been associated with insulin resistance and the development of T2DM [1]. All these functions support the critical role adipocytes play in whole body energy balance. Disrupting any of these functions can lead to a metabolic disease state.»
Myron Schwarzennecker said…
Do you know that sometimes people make comments under the old commenting system, and those comments are invisible when Disqus loads?

Here is one from this article:

1 comment:

Erik Arnesen

See also:

«For years, scientists thought that blocking lipid
storage or inhibiting fat cell development might be an effective
anti-obesity therapy. Common sense suggests that less fat mass would be
healthier. Yet, we know from mouse and human studies that this is not
necessarily true. When lipid cannot be stored in adipocytes, it
accumulates in other tissues where it should not be stored. This
condition, known as ectopic lipid, has been associated with insulin
resistance and the development of T2DM [1]. All these functions support
the critical role adipocytes play in whole body energy balance.
Disrupting any of these functions can lead to a metabolic disease
Myron Schwarzennecker said…
Taubes is the "science writer" for the stupid. If insulin-trapping-the-fat is what causes obesity, then you have to keep eating carbs all day long to keep trapping that fat. In other words, OVEREATING causes the weight gain, but his followers overlook that calorie consumption as if the insulin makes fat out of nothing.
Myron Schwarzennecker said…
View the source of this page and you'll see Erik's comment in there.
carbsane said…
Erik's post approved now. Posts with links go to moderation.
carbsane said…
This looks like an amazing article, thanks for posting!!
Sue Staltari said…
Great article. So ketosis would disrupt normal functioning of adipocytes and can lead to osteoporosis?
Sanjeev Sharma said…
> OVEREATING causes the weight gain

Gary beat you to the punch: this is the first approximation ; )
Sanjeev Sharma said…
Thanks for the update on GT's activities. I wonder how many more PhD equivalents he did in making that slide

Really though ... I'm not concerned about Taubes much anymore; those who still follow him have the contra information available.

More interesting is the psycological study of his followers and their processes.

And second is the psychology of how people can claim to "get" Taubes's invalid framework/arguments/(methods of "proof") - reductionism, cherry picking and observational studies and IMMEDIATEY after their critique of Taubes they take his framework, elide insulin and carbohydrate (the subject matter Taubes applies the framework to) and drop their own hobby horse in the empty space.
Myron Schwarzennecker said…
I've thought about that psychology also. There is the saying about con artists that "you can't cheat an honest man". That applies here also for many of the true believers. Others were just tricked.
Sanjeev Sharma said…
> Taubes is the "science writer" for the stupid

I would amend that to :

"science writer" for the belligerently afflicted with Dunning-Kruger
Sanjeev Sharma said…
I always took that as a tiny bit of truth about the victims, but much more as a desperate attempt at self justification. IOW, If I only con the dishonest I'm not really the bad guy.
Lighthouse Keeper said…
Interestingly the Inuits are supposed to have the highest levels of osteoporosis, though one has seen this as being put down to a lack of vitamin D in paleo circles .
Sanjeev Sharma said…
> I've thought about that psychology also

thoughts on the 2nd population I mentioned?

The "it's evil when Taubes does it but OK when I do it".
carbsane said…
I really need to take some time to read this thoroughly, but Sue's comment had me thinking the same thing about the Inuit.

I have an article on Sarcobesity around here somewhere I'll try and put in the library.
Morgan Pfiffner said…
Hey Carbsane! For what it's worth, I'm surprised someone could read Lehninger's Principles of Biochemistry and think those quotes are conflicting. I thought it makes it pretty clear insulin is far from the only player at work in fat storage. There's a figure in the fifth addition (23-40) showing, for example, how activated AMPK blocks TAG synthesis and adipose tissue fatty acid synthesis and promotes fatty acid oxidation (and inhibits lipolysis by blocking HSL!).

How does one activate AMPK and accomplish such things? Well, just prior to this figure is an explanation that as ATP is broken down to ADP and this ADP is then broken down to AMP by adenylate kinase and this molecule activates AMPK (thus the acronym AMP-Activated Protein Kinase). Well yeah, I'm pretty sure you break down ATP by (*gasp*) eating less calories than you burn (thus making less ATP).

Another quote from this wonderful textbook is as follows; "insulin acts on insulin receptors in the hypothalamus to inhibit eating".

Anyway, this was probably a superfluous comment (and lots of information you already knew), but I just wanted to throw it out there that there's a lot information about the biochemistry of fat storage, mobilization, and burning in Lehninger. If Taubes' juxtaposition of that first quote under the header "What makes fat tissue fat" is meant to indicate that is all the textbook is saying makes fat tissue fat, he's being a straight up silly billy.
Myron Schwarzennecker said…
Using psychology, as any marketer does, you could build a nutrition following mainly irrespective of what the actual nutritional approach is. But you do need some essential cultural elements, like so: everything you were taught is wrong, we are rebelling against the conventional, we are the elite with the special knowledge, we are smarter than everybody else.

Then you have to do some food banning, whether of individual foods (with the supposedly evil components), or else banning entire evil classes like carbs or fats. Just pick something, because banning shows discretion.

However, it is required for mass appeal that you MUST ban sugar, even in tiny amounts; and the same goes for "processed crap". Those are the essential food-banning trends for now, but they will change over time.

If your main pitch is weight loss, then you have to somehow say "it's not your fault". If your main pitch is about health, then you have to use phrases like "optimal health" which is based on always getting more and more of the miracle molecules such as antioxidants. Pick any class of miracle molecules.

Once you've followed the template, then just plug in whatever actual nutritional approach you want. There are enough studies done so that you can support any claim that you make. Any conflicting evidence gets dismissed by followers, because the followers are emotionally driven, not rationally driven. The masses just want studies, references and MDs and testimonials to reinforce what they've already chosen to do. The people who primarily want to rebel against authority also demand their own authorities to blindly follow.

If your approach results in fewer calories, the masses will say that it is really because they took in the miracle molecules and avoided the evil molecules.
carbsane said…
I've included the parts about leptin and insulin (the latter of which you mention). Taubes is grasping but some are apparently still buying his schtick. Last year or was it summer before last when he lectured at CrossFit he used this argument and then related a discussion with Keith Frayn. Audience laughed. And he dismissed the man in his "there's no talking to him" style. Because Frayn was probably being polite saying "I never thought of it that way" when Taubes launched into his diatribe. But Gary told the audience this was no newbie, he had just retired. So, there you go, decades as a distinguished researcher of adipocyte/fat metabolism all for naught. *sigh*

Feel free to point me to any Lehninger quotes ;-) I have 5ed in PDF.
carbsane said…
Well done!
carbsane said…
BTW, I've seen the comments in Blogger before Disqus loads some times. A glitch. They are synced so that if I ever drop the Disqus platform, all comments are in Blogger. However with oh so much spam from Anonymous :(
MartinSoderholm said…
I don't believe that's what it's meant to indicate. I believe his point is that cals-in-cals-out doesn't take into account anything we know about fat storage on a cellular level. So adding complexity to his simplified explanation actually corroborates his point, ie obesity is a hormone imbalance, not an energy one.
carbsane said…
But there is no scientific evidence to support that Martin. Distribution of fat among tissues, yes. Total fat accumulation, yes. BUT this is by altering energy expenditure in an attempt to correct for huge imbalances, not at the level of fatty acid uptake or release from adipose tissue.
John Smith said…
Talking quantum biophysics here

Rarely look at any paleo buzz articles anymore but the word "quantum" always catches my attention. Because once you venture into the bosun-higgs singularity matrix at a cruspucular level, we are talking about a whole new level of science.
Myron Schwarzennecker said…
Yes, it seems like the moderation roadblock-checkpoint is in Disqus, but not in blogger.
MartinSoderholm said…
Wouldn't say there is "no evidence", but it needs further studying, no doubt. As for the rest of your reply, it seems I got a compact version of what you wanted to say, as though you're reiterating points made in a previous post. I'm new here, so couldn't quite follow that, sorry :)
carbsane said…
Sorry about that, let me elaborate. But first let me extend my welcome!

As I understand him these days, Taubes is saying the fat cells get fatter, e.g. fat accumulates, due to hormonal effects. In GCBC it is stated something like 'anything that works to put fat into the cells is fattening and anything that works to get it out is not'. Conveniently ignoring ASP, Taubes states only insulin regulates fat accumulation. This is patently false as FA release is highly influenced by glucocorticoids.

What governs whether or not there is fat to accumulate is the energy balance of the organism and not the minutia of fat in/fat out at any given moment. Indeed fat is ALWAYS hydrolyzed in great excess and most is re-esterified. So this cycling is not what controls fat mass. Hope that makes sense. You might want to check out the TAG/FA Cycle label here, it would be the best place to start for additional posts. Happy to discuss further!
MartinSoderholm said…
Thanks! :) .. I have read and listened to Taubes but have never seen or heard him say explicitly "only insulin". I'm quite sure he knows fat accumulation is a complicated process, and one can not expect him to elaborate on all pathways involved. Insulin may not be the only player, but it's the most important one. And I have to disagree about glucocorticoids, as "release" is the opposite of "accumulate" ;P

One of Taubes main messages is that the energy balance most hold, but that it isn't _relevant_. What you're saying sounds a lot like creationists conceding micro evolution, but not macro :) Surely the total balance of fat in your body is a result of every "minute" chemical reaction in it. How could it not be? That isn't to say that regulation happens on this level. Different hormones act on different levels, some only signal from cell to cell, some affect the rate of every metabolic process in your body.

The energy balance is as relevant to weight gain as it is to global warming. If you asked a climatologist what the cause of global warming is, and he said "More energy is coming in than going out.", would you be satisfied by that answer? What he's saying is true, but it is also completely redundant.
carbsane said…
You'll have to pardon me here, but this line of reasoning is quite old to me and I lose patience with it. Taubes says insulin fundamentally regulates fat tissue mass and he is wrong about that. We eat more, we are fatter. Insulin doesn't even begin to explain that.
Martin Söderholm said…
I know the feeling :) Maybe you can refer me to those previous discussions that made you lose patience instead. Just curious, if your approach to this is "eat more, get fatter", what's the point of discussing the details of a study on HSL haploinsufficient mice?
carbsane said…
I am interested in the link between obesity and metabolic health. That seems to originate with the fat cells dysfunctioning and it is exactly the opposite of what the LC "science" (including Taubes in GCBC) says. I came across this paper looking into glucose metabolism going awry in adipocytes. It is, however, yet another nail in the coffin of Taubes' alternate hypothesis.

Perhaps this post may help you out:
Sue Staltari said…
For how many years have you listened, read Taubes?
Martin Söderholm said…
First thing I read was maybe two years ago. Why?
Martin Söderholm said…
Fat cells dysfunctioning? Sounds interesting. I'm guessing overeating somehow causes this dysfunction, or what's the proposed mechanism?

Also read the paper, but didn't find the results so surprising. If you limit access to FA, tissue will have to burn glucose instead. Don't see how it's a nail in anything, they're testing HSL inhibited HFD-fed mice? The HSL null mice that were "paradoxically resistant to diet-induced obesity" was the most interesting part, I thought.

Thanks for the link, have read similar GCBC-bashings before, and of course most objections are valid. But being wrong on a couple of points doesn't mean there's no basis for any of it. If it did, we would have thrown out most of modern physics.
carbsane said…

Fat Head: In Why We Get Fat, you wrote that some people might have to give up dairy products and nuts to lose weight. Dr. Mike Eades has also mentioned that nuts and cheese seem to inhibit weight loss in some low-carb dieters. What is it about those foods that can stall weight loss? Is it just that they’re so calorically dense, or do they produce a higher insulin response than their low carbohydrate content would suggest?

Gary Taubes: I think the caloric density thing is nonsense. Remember, I’m trying to get every last one of us away from thinking in terms of calories as the variable of interest. What we want to know is whether these foods stimulate insulin secretion, or cause insulin resistance, or have some other effect on the storage of fat in the fat tissue or the oxidation of fatty acids by other tissues in the body. So nuts still have carbs in them, and for some people they might contain too many carbs. Same is true for nut butters.

Dairy products can stimulate insulin secretion beyond what you would expect from the carbohydrate content. I don’t know if this is true of cheese because I’ve never seen data on this, but it is possible. And some cheeses could be better than others — hard cheeses, for instance, may be better than soft cheeses.


When you use terms like bashing, I tend to think you're not here discussing in good faith. But ... the dysfunctional fat cell may just be from exceeding the normal storage capacity of the adipose tissue. There is also evidence that high fat diets act on the brain and increase WAT lipolysis inappropriately. Stick around.
Martin Söderholm said…
I wrote a long response to your Fat Head snippet, but after further reading I realized you already knew all of it, so I'll spare you. But now I'm like, – Hmm.. she knows all of this, and yet she thinks CICO is relevant, and for some reason obesity originates in dysfunctional adipocytes?

I was under the impression adipocytes were thriving in obese individuals, at the expense of other tissues? I don't believe there is any exceeding of "normal" capacity. If it wasn't dependent on the organism as a whole, adipose tissue could just keep on growing. Have you seen how big some people get? I mean the crazy morbidly obese. If adipocytes get dysfunctional past some limit, they would be proper dysfunc'ed 400 lbs ago, no? :)

You know about the thyroid system and adipose tissue being our largest endocrine organ, yet you believe the inhibition of increased metabolism in these individuals isn't an evolved survival mechanism?

I know, too many questions...
carbsane said…
Martin, the notion of adipocytes ruling the roost is a fallacy. The notion of lipophilia was lost with WWII for a reason ... it did not stand up to the evidence. Now Taubes is clever in convincing folks there was some anti-German scientist thing involved, but the truth would have come out.

Instead, scientists like Keith Frayn and Guenther Boden and others have spent long hours studying adipocytes and hormonal regulation. The adipocytes do not rule the roost. It is not all about insulin. However, the adipocyte is where the metabolic derangement begins -- in 80% of type 2 diabetics, this is as a result of obesity, it is NOT the cause. Everything you have been told about muscles becoming IR first and the adipocytes sucking up glucose till the bitter end? Sorry, the scientific evidence does not support that.

How anyone can say CICO is irrelevant escapes me. It is the only relevant thing in the establishment of obesity. Even the genetically obese animal models (for which there are no human equivalents) can all be explained by this. I do not understand this desperate attempt to maintain otherwise, but for the fact that some several millions with more promised are promised to NuSI to find the answer.

I'm out the door but don't want to lose this response ... will return to finish later.
Martin Söderholm said…
I'm not saying adipose tissue acts independently as if it "ruled the roost". Just that it could, grow, larger and larger without any internal dysfunction, as long as it was instructed to do so.

As I understand it, insulin resistance is not a dysfunction per se, cells are doing what they're supposed to as a result of their own internal situation. The dysfunction arises when too many cells are doing it. And the actual problem isn't the IR but the hyperinsulinemia and hyperglycemia that follows.

What scientific evidence? The purpose of adipocytes is to store energy, as opposed to myocytes that can only store a relatively small amount. And adipocytes have bidirectional transmembrane energy flux, as opposed to myocytes that only have influx. The fatty acid flux in adipocytes does not rely solely on insulin, like you said. Transport of FAs within the AT is likely facilitated by other signals. So the option of decreasing insulin sensitivity is only really necessary if the surrounding adipocytes are equally "full" and doesn't want the excess FAs. Normally this situation would trigger cell division, increasing fat storage making room for more FAs. The point? Both in terms of storage capacity and functionality, adipocytes should be much less likely to go IR. What you're saying doesn't make any sense.

Explained how? What does CICO explain when it comes to genetically obese animals? Does CICO explain why the HSL null mice were resistant to diet-induced obesity?
carbsane said…
CICO explains every genetically obese animal because they all exhibit hyperphasia and/or suppressed metabolic rate.

I will always go back to this because it is the proverbial black swan: Why is the LIRKO (liver insulin receptor knock out) mouse hyperinsulinemic and hyperglycemic but not diabetic (its beta cell function keeps on going) or obese?

I contend that what I'm saying doesn't make any sense because you are working from a faulty hypothesis. We are eating more, perhaps moving less (though this is more difficult to assess), and getting fatter. Why are we eating more? The most obvious reason that likely applies to the most individuals is that Americans have an obsession with drinking calories and for whatever reason, our bodies don't sense liquid calories as well. There was a study where the intent was to replace 25% of intake with sugar sweetened beverages, but what happened is that the subjects ended up consuming 10% more calories overall. They gained weight.

The scientific evidence for obesity-related metabolic disorders very strongly points to glucose uptake and metabolism in the adipocyte and faulty restriction of FA release from same. Very strongly.
Sanjeev Sharma said…
>adipocytes were thriving in obese individuals, at the expense of other tissues?

AFAIK this happens in non physiological scenarios (genetic leptin disorders, drug injection), and even in these cases the adipocytes are downstream from the initiating cause.

Look for populations whose adipocytes may be the originating or central site of disfunction - Do you get "Biggest Loser" where you are?

medical case studies describe year-long fasts of the hyper obese; they lose fat crazy-fast in large calorie deficit scenarios.
Blogger said…
New Diet Taps into Pioneering Plan to Help Dieters Lose 20 Pounds within Just 21 Days!