Monday, July 10, 2023

Insulin sensitivity makes you fat. Insulin resistance makes you fat. Discuss. (03) Visceral vs subcutaneous

Visceral adipocytes are exquisitely insulin sensitive. Visceral adipocytes are insulin resistant. Let's go.

This is another of the anchor studies which has informed my world view over the last decade or so:

Insulin signaling in human visceral and subcutaneous adipose tissue in vivo

I like it because it used real live intact human beings, it used a physiological dose of insulin and it looked at the signalling pathways within cells. It then compared the effects within visceral adipocytes (omental in this case) with those in subcutaneous adipocytes. I'm not sure that I had much of an opinion about this before I read the study but it locked me in to my still current opinion that visceral adipocytes are particularly insulin sensitive.

This has been reinforced by the PET scan data from this next study. The mouse section is poor as it compares SC adipose tissue to epididymal adipose, the effect would be more marked if they had used omental/mesenteric as the visceral adipose source but hey, the PET data in real live humans are nice...

Increased glucose uptake in visceral versus subcutaneous adipose tissue revealed by PET imaging

This property of visceral adipocytes appears to be intrinsic to their stem cells. If you differentiate stem cells from SC and visceral tissues in to adipocytes those adipocytes, generated in-vitro, retain this exquisite insulin sensitivity.

Fat depot-related differences in gene expression, adiponectin secretion, and insulin action and signalling in human adipocytes differentiated in vitro from precursor stromal cells

So visceral adipocytes are the most insulin sensitive in the body and this is programmed in to their stem cells, which makes me accept that it is evolutionarily conserved and so essential their function. Which, surprisingly, is neither to kill us nor give us metabolic syndrome.

But we also have this:

All of the below quotes are taken from the same screenshot.

This was 2010. I doubt that there is any less confusion nowadays.

"Adipocytes from VAT are more insulin-resistant than SCAT adipocytes (39,40)."

"Visceral adipose tissue has higher rate of insulin-stimulated glucose uptake compared with SCAT adipocytes."

"Visceral adipocytes are more metabolically active and have a greater lipolytic activity than SCAT adipocytes (44,45)."

which gave me this image:

The lines represent paired adipose samples, a control sample labelled "Basal" (open circles) and a sample to which a fixed concentration of noradrenaline (NA) had been added at all insulin exposures.

The first red flag is that basal lipolysis can be suppressed by insulin. So what this paper means by basal lipolysis and what other papers mean by basal lipolysis appear to be quite different. The other really strange finding is that under noradrenaline induced lipolysis insulin is suppressive (as you would expect) up to 250μU/ml at which point insulin enhances lipolysis, markedly. Hmmmmmm. I would suggest insulin induced insulin resistance but that seems like a long shot. Ultimately the model doesn't seem to be a very good one.

The only difference I can see between this group's model and the rest of the world is that they use tiny cubes of adipose tissue rather than isolated adipocytes. If I had to guess I would suggest that there are the end terminals of noradrenergic neurons present in their adipose samples and these are modifying the response to insulin and noradrenalin. It could also be that having structure around adipocytes might alter their behaviour ie this might be a better model than isolated adipocytes. Hard to compare when almost all of the surrounding work is done with isolated adipocytes. Generally I would be very cautious about looking for understanding in such a model as the results are counterintuitive, but I could be wrong. That's a few days of my free time I'll never get back! Next I checked the other three refs.

Ref 45

Metabolic complications of visceral obesity: contribution to the etiology of life of type 2 diabetes and implications for prevention and treatment.

is a review and not available on Pubmed or Sci-Hub and I doubt it it's worth chasing.

Ref 39:

does not, as far as I can make out, in any way support the statement it is purported to. The study wasn't designed to do so and I can only hope it was a typo when it was cited.

Ref 40 is gold dust

because it says this:

"In one study in vivo , subjects were given isotopically labelled fatty acids, and biopsies of different depots were taken at abdominal surgery 24 h later (Marin et al. 1992); accumulation of label was most marked (per g TG) in the omental and retroperitoneal depots."

which used real live humans in a tracer study coupled with adipose tissue biopsies during abdominal surgery. My sort of study. Just from the abstract we have, in-vivo:

"Adipose tissue lipid uptake, measured after oral administration of labeled oleic acid in triglyceride, was approximately 50% higher in omental than in subcutaneous adipose tissues."

and in vitro

"Adipocytes from omental fat also showed a higher lipolytic sensitivity and responsiveness to catecholamines"

So, easy in via insulin, easy out via sympathetic nervous system stimulation.

But also:

"Furthermore, these adipocytes were less sensitive to the antilipolytic effects of insulin."

which is illustrated like this

Here we have visceral adipocytes as black circles and SC adipocytes as open circles. It's true that visceral adipocytes exposed to noradrenalin at 10⁻⁴ mmol/l can suppress this lipolysis less effectively than SC adipocytes do but the difference is relatively small compared to the very marked extra lipolysis under noradrenalin exposure in visceral adipocytes. Visceral adipocytes *should* stay small by balancing insulin signalling against sympathetic lipolysis.

So let's summarise:

Visceral/omental adipocytes are exquisitely insulin sensitive.

They perform markedly augmented lipolysis under sympathetic stimulation.

They have mildly impaired insulin suppression of sympathetic lipolysis.

I think that sets us up to think in sensible terms about what visceral fat does and why it is associated with metabolic syndrome.



raphi said...

1) Visceral/omental fat takes up energy (via inuslin action) more easily

2) Visceral/omental fat releases energy (via sympathetic stimulation) more easily

3) Visceral/omental has a harder time stopping fat release (under sympathetic stimulation)

Are (2) and (3) different sides of the same coin?

Eric said...

Oh good, waiting for a quiet moment to read your two new pieces on fructose.

Meanwhile, where have these folks been living:

Eric said...

At least, the nyt article had a few good links, among these:

Fortunately, those fat eating cancers seem to be the exception.

mct4health said...

Maybe a stupid question, but I wonder if there is already an officially known mechanism by which ethanol suppresses the oxidation of glucose and fats practically immediately after administration and quite perfectly. I would probably have a hypothesis, but is it described somewhere? It could be key to understanding insulin resistance.

Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance.


Eric said...

Jaromir, right in the abstract: We conclude that ethanol was a preferred fuel preventing fat, and to lesser degrees, CHO and protein, from being oxidized.

Haven't read more than the abstract, but 22 g of ethanol does not appear to be sufficient fuel burn for 4 h, so that it would suppress all other sources of energy.

Peter said...

raphi, The only qualifier which has occurred to me is that 1) appears to be fundamental, 2) is probably so but 3) looks to be a more artificial construct. Does the body maintain active stimulation of adipocyte beta receptors in the face of hyperinsulinaemia? So yes, in this model, but IRL this may not be the case. I see a parallel for the toxicity of pure palmitic acid administered at fasting levels to any cell in culture under glucose at 25mmol. In vivo the combination cannot occur.

No time for more, I'll try to get a look at your links Eric and for Jaromir I'd start with "ethanol" and "ROS" in Pubmed, usually the best bet...


mct4health said...

Yes, simple explanation, but why? I can also do a simple explanation, the liver is saying, "Don't disturb me, I'm processing poisons!". So metabolic problems probably mean "Too many poisons in the system, I can't process normal fuel".

But how is it arranged? There are five interesting moments in the glucose test of young adults with/without alcohol, aldehydes are immeasurably low, acetate is constant, as if controlled. the glucose curve is exactly the same from the first moment, the insulin level is adequately higher from the first moment. I think it is only controlled via substrate/product, no changes in gene expression. Why is insulin higher?

At the heart of the action is acetate/acetyl-CoA. It stop glucose processing, but does it also cause increased insulin to stop lipolysis?

The conversion to aldehyde is apparently limiting, two pathways, one needs NAD+, the other needs NADPH. They are converted to NADH and NADP+, that is the substrate for NNT and heat generation. Thus I think, increased ROS production is not due to more ROS, but due to the elimination of GSH recycling in exactly the same way as in the processing of fats with even-numbered unsaturated bonds (DECR). That's why alcohol seems like a good model I think.


karl said...

The NYT misses the elephant - sugar helps the EARLY cancer out grow the immune system. We all get caners on a regular basis - our immune system deals with them. Fructose in particular helps cancer cultures grow fast.

The other bit not considered is the daily-fast-time. Getting into the catabolic state - low insulin - helps the body with apoptosis - where the body gets rid of sick cells. People that are obese will have high insulin 24/7 - shutting down apoptosis for years at a time.

The mainstream take is so incompetent theses days - just got done talking to a friend who's MD is putting him on drugs to deal with arrhythmia - I asked him if they talked to him about coffee/tea/chocolate nope! Life long drug that might not be needed.

mct4health said...

Fatty acid oxidation – linking all illness (especially cancer) with stress and diet (fasting / low-carb)
It can be challenging for this community :-)

And my point. Sugar helps cells to survive hypoxic conditions by turning on HIF and that allows glucose fermentation, but also allows strange anaerobic fat metabolism, it's on the same switch.


karl said...


There are two issues
1 - what causes the initial mutation ( PUFAs could well be an issue) the production of proto-cancers - pre cancerous cells etc.
2 - what prevents the body from dealing with proto-cancers - (lack of fasting time, high glucose - high fructose - immune suppression by profitable pharma interventions).

BTW: I would agree that MCT(MUFA) are probably better for you than PUFA - but I don't think better than SFA. I would not add large amounts of MUFA to my diet.

The complexity of diet issues - the poor quality of what gets published these days, gets us into a situation where we lack anything close to perfect knowledge. This is why I use the heuristics(rule-of-thumb) of the Great-grandmother rule - I try to not eat anything she didn't - and she didn't have MCT in a bottle.

The heuristics leave us with other exposures we can not easily prevent - PCBs Atrazine, lead(Pb) etc etc.

When I worked on electronics for water systems, I saw how the sausage was made and installed an RO system. People (like me) that grew up where there was massive PCB pollution, have a higher rate of thyroid problems(like me). Which exposures are most critical is very hard to filter out.

So the problem is today the regulatory systems/medical systems are captured by this emerging fascism across the west. We are left to look after our own health. I think avoiding exposure (nothing that comes in a bag or box) is more important than adding some supplement.

It would be nice if our captured universities were busy identifying which food additives are doing harm - but the money for that work has mostly been diverted to pharmacology - no money for research that might be a bother to big-ag.

We are left in a world where the leading distal-cause-of-death is T2D - A world where it has become obvious that there is now wide spread sexual-endocrine disruption (if this was just a social phenomena we would see regression to the mean) and the greater public is left mostly in the dark - MDs that studied text books written by Big Pharma and who don't instruct patients how to avoid exposures (not a billable procedure).

mct4health said...

Yes, I agree, limit exposure to toxins. But it cannot be completely avoided. Therefore, I am not against remedies (antidotes) that can improve the excretion or burning of poisons. Are we perhaps focusing too much on food, what about the air? Lately, I have included as a possible cause of metabolic problems the connection to too much breathing volume at rest, at night, during sedentary work, 24/7. The content of dissolved CO2 in the blood is probably increasingly replaced by lactate and this causes less oxygen availability for some tissues. This forces us to breathe more, but this further worsens the situation and lowers the concentration of CO2 in the blood. By consciously reducing the volume of air we breathe, we can probably do interesting things. I like the universality of it, because almost all toxins cause increased lactate. And BOLT score measurement is really easy.

karl said...


Antidotes are for specific toxins - we don't even know which ones are the biggest problem.

Many antidotes have their own toxicity.

Elevated lactate is likely from high fructose exposure form sugar consumption:

Refined sugar did not make up many of the calories my great grandmother ate.

mct4health said...

Your great grandmother could definitely drink goat's milk (high in MCT), eat fruit (with fructose) and not inject fructose into her veins. The speed of administration is essential, the same things have very different effects. It would be interesting to observe the breathing parameters after administration of the fructose infusion. That lactate is from glucose, lactate blocks the oxidation of glucose, fructose is just such a switch. This concentrated fructose makes glucose poisonous and other poisons like PUFA make the switch more sensible. Lactate displaces CO2 (they report a decrease in bicarbonate in the paper), so those changes in breath volume and oxygen availability in tissue or brain should be very noticeable.

karl said...

I think the central part of the insanity of the medical community is they think our bodies are engineered - rather than evolved. They think insulin exists to control blood-sugar - when they are clueless to all the other effects.

Genetic engineering is quite different - everything effects everything. A maze of nested feedback loops that exist not because it is good engineering, but because it works. Complex systems are not going to improve via drugs or supplements - the best we can do is provide a diet similar to the one we evolved to eat. ( The replacement of best medicine with pharmacology is a failure of our time - medicine ≠ pharmacy).

Back to insulin - it has MANY effects - ignore the others and you have a false narrative:
Insulin also has MANY other effects::

Decreased autophagy - decreased level of degradation of damaged organelles. (Postprandial levels inhibit autophagy completely.)
Controls the storage of fat - Decreased lipolysis
as a growth factor.
glycogen synthesis
Increased cellular potassium uptake
decreases production of glucose from noncarbohydrate substrates
Increased lipid synthesis
Increased production of trygly from fatty acids
decreased breakdown of proteins
forces cells to absorb circulating amino acids
forces arterial wall muscle to relax
Increase in the secretion of hydrochloric acid in the stomach (improves sales of PPIs)
Decreased renal sodium excretion (Sells BP meds)
enhances learning and memory
increased fertility

cavenewt said...

@karl—"A maze of nested feedback loops that exist not because it is good engineering, but because it works. Complex systems are not going to improve via drugs or supplements - the best we can do is provide a diet similar to the one we evolved to eat."

Got it in one. Is Brett Weinstein and Heather Heying substack constantly saying, we ignore complex systems at our peril.

karl said...

I would go a bit beyond Weinstein - there is this notion, this theme, that one if one is smart and clever enough to employ all these 'life-style-hacks' that we will get a no-down-side benefit. Just isn't true.

I think an example of engineered vs evolved might help.

What might not be obvious from the wikipedia article is the end product looks NOTHING like traditionally engineered antenna (try googling antenna images).

Yet in biology, there is this assumption that it is engineered - effects are linear, non oscillatory, isolated.

Most drugs are poisons - monkey wrenches we throw into evolved machinery. They can save your life by killing bacteria, but always with a risk cost.

A lot of this is about short-term vs long-term. Humans are pretty good at avoiding short-term harm - but mostly blind to harms that are slow or long-term. You can eat CIAB - short term, not likely to see harm - but long term - this harm may dominate life. (T2D appears to be the number one distal-cause-of-death.)

Today there is an excess death signal (amazing how well this signal has been suppressed from the public's ears) - might be due to a poorly tested pharma product, but might also be due to the T2D pandemic, or some other LSHGW(Life-Style-Hack-Gone-Wrong). What ever the cause, the number of deaths dwarfs the mortality of COVID. Compare the response - the reaction. In one case - no end of money flowed - the other - tip toeing backwards - nothing to see here:

Humans are pretty plastic, we can adapt our behavior to changes in the world better than any other animal. But there is a limit. Change is accelerating, The public is defenseless against psych-ops based on Bayesian or hyper-log-log technologies (and they ARE deployed).

They have been using psych-op technology to sell the public on all sorts of life-style-hacks - to the point of trans-humanism. What could possibly go wrong?

cavenewt said...

Hi karl—that's pretty much exactly how I feel. I even use "monkey wrench" to describe drugs. I think the current fad for lifestyle "hacks" is just that, a fad, pushed along by the usual opportunist suspects.

Basti said...

Me being me, im looking again at practical take aways...
So when trying to get rid of visceral fat, should you:
1. engage in cold plunges and high intensity exercise to take advantage of the augmented lipolysis from SNS activation?
2. Eat the least insulin sensitizing diet possible like try carbosis aka kempner rice and sugar diet?

Whats your opinion on these strategies Peter?

Peter said...

Hi Basti,

Sorry for the hiatus in posting and comments.

My own approach is LCL6.

I think Brad is the person looking to normalise insulin signalling on a mixed macro diet.

I don't really like the idea of "hacks" as such and really LC is a hack as much as the Kempner diet, but you have to do something if your adipose tissue is high in LA and it might take years to get rid of it.

Now I stay because of the low insulin effects on healthspan (and on longevity would be a bonus).


cavenewt said...

'I don't really like the idea of "hacks" as such and really LC is a hack as much as the Kempner diet'

I don't like hacks either, because they smack of hubris in the face of complex systems.

But would you call trying to eat in an evolutionarily appropriate manner a 'hack', or more of a return to normalcy?

Basti said...

Thanks, i appreciate your comments a lot :)
For me personally LCL6 didnt work (have done it for at least 3 years now) which is why i try the opposite carby approach now).

Which so far works amazing.

Peter said...

Ah, cave, normalcy on an evolutionary context is a good start. But I still recall Miki Ben-Dor's concept of adaptation. Over the last 10,0000 years a reasonable proportion of the population, say those in the upper 3% section of a normal distribution, *have* adapted to a carbohydrate based metabolism, so might do better on a Kempner diet, even if it rots their teeth... There again we might just be missing an agent which continuously generated ROS at insulin mimetic levels primarily in adipocytes. I have an infinite supply of things I don't understand!

Interesting Basti, and obviously there are precedents to this. As you (may) realise I've kicked this concept around on occasions and what I *think* I understand now will turn out to need/develop further modifications in the years to come. Glad it's going well for you.


cavenewt said...

"Fatty acid oxidation – linking all illness (especially cancer) with stress and diet (fasting / low-carb)
It can be challenging for this community :-)"

Challenging is right. I read the whole thing up until the study link and the series of quotes. There was one sentence I heartily approved of, "PUFA seem to have a unique role as not only a universally-consumed metabolic inhibitor, but also as the preferred fuel of cancer."

Note, I have read an entire book about Otto Warburg and his work.

But the rest made me feel like I had fallen into a pit of vegan vipers. Challenging!

Peter said...

Quote from "Haidut" on page 2366

"[taking vitamin E] may not be a bad idea considering how ubiquitous PUFA is. Not only in foods, but also cosmetics, household products, varnishes/dyes, etc."

Hard medical advice from myself: "Don't drink household products, varnish/dyes, etc."

Hahahaha bonk.

More seriously, how can someone come to correct conclusions (avoid PUFA) with such appalling logic? I've observed Peatians in the past do similar things.