The Complexity of Fat Cells

adipose-tissue
(PJ) #1

I don’t know that this study is all that useful in an application sense right now. But I find it interesting, in that the complexity of adipose tissue is very gradually getting better understood. I mean look at how much understanding of ‘cholesterol’ (different ‘types’ and that vs. the ‘carriers’ of it, etc.) has grown over time. I think adipose tissue is not much understood at all yet.

Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin

Jesper Bäckdahl 5 Lovisa Franzén 5 Lucas Massier Mikael Rydén 5 Patrik L. Ståhl 5 Niklas Mejhert 5, 6 Show all authors

Show footnotesOpen AccessPublished:August 10, 2021DOI:https://doi.org/10.1016/j.cmet.2021.07.018 PlumX Metrics

Highlights

• Spatial mapping of human subcutaneous white adipose tissue detects 18 cell types • Neighborhood analyses identify cell classes with distinct clustering propensities • We report three fat cell types with specific localization and mRNA/protein markers • Only one of the three adipocyte subtypes responds to insulin stimulation in vivo

Summary

The contribution of cellular heterogeneity and architecture to white adipose tissue (WAT) function is poorly understood. Herein, we combined spatially resolved transcriptional profiling with single-cell RNA sequencing and image analyses to map human WAT composition and structure. This identified 18 cell classes with unique propensities to form spatially organized homo- and heterotypic clusters. Of these, three constituted mature adipocytes that were similar in size, but distinct in their spatial arrangements and transcriptional profiles. Based on marker genes, we termed these AdipoLEP, AdipoPLIN, and AdipoSAA. We confirmed, in independent datasets, that their respective gene profiles associated differently with both adipocyte and whole-body insulin sensitivity. Corroborating our observations, insulin stimulation in vivo by hyperinsulinemic-euglycemic clamp showed that only AdipoPLIN displayed a transcriptional response to insulin. Altogether, by mining this multimodal resource we identify that human WAT is composed of three classes of mature adipocytes, only one of which is insulin responsive.

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00363-6

Can you be Keto and get really fat?
(Bob M) #2

This might be why the hypothesis that saturated fat causes insulin resistance does not seem to work for some of us (like me).

(Doug) #3

That’s wild, PJ. Things get complicated very fast with hormonal initiation and cellular response, but I’m wondering if the non-responsive cells just don’t have insulin receptors - as if those cells don’t have all the same purposes?

(Jane) #4

Interesting that the AdipoPLIN cells were the ones that responded to insulin and the obese participants had fewer AdipoPLIN cells than the non-obese.

(PJ) #5

In lipedema, the integrity of the cell membrane of the adipose cells is… messed up somehow. I’ve long theorized that the reason this is hips-down – and sometimes upper arms – but not in the torso/neck (weirdly!) – is because the body is pushing it away from the vital organs. Because they need access to energy, storage near them serves that purpose, but these fat cells are forked up somehow and they don’t release their fat as they should, except perhaps as a sort of leakage created an inflammatory swamp instead. I don’t think they always die when they should either. Either way, they are not healthy, so the body gets them as far from the vital organs as possible.

And it will not redistribute that fat constantly, as seems to happen to everything else… the body’s constantly opening fat cells and dumping the contents into the bloodstream – minerals, toxins, fat, whatever’s there – a constant river of variables, and the body them puts stuff back, or gets rid of it, or detoxes it, or uses it to build something, and so on.

So clearly… the body knows what’s up with those cells.

It seems likely that adipose tissue is probably designed for a variety of different things. And I suspect something related to inflammation is one of those things… and that this is the type that fat people are more likely to have.

(Jane) #6

It crossed my mind to wonder if our bodies make different types of fat cells from seed oils vs animal fats we ingest.

(PJ) #7

I think a super interesting experiment would be the evaluation of a boatload of adipose cells from all over to determine whether they had all the same kinds of fat in them or not. Like you know, does it store all the PUFA together so when it needs that it dumps that cell? If so then I’d wonder if it stored the most SFA stuff nearer the organs.

(Bob M) #8

This makes some sense. One idea is that saturated fat causes fat cells to be insulin resistant. If you eat saturated fat, you basically stop being hungry.

However, if you don’t have many fat cells that are affected by insulin, this could mean it’s easier to get obese. (Though I’m struggling to find a good argument why…, and this does not bode well for the theory that "high PUFAs = obesity).

And, of course, this doesn’t discuss causation (do you get fatter because you have fewer insulin-responding fat cells, or does getting fatter cause there to be fewer insulin-responding fat cells?).

(Bob M) #9

I wonder if distribution is somehow related to this, too? For instance, I basically have zero fat on my legs, minimal on my arms, all in my belly. All of it.

And when I ate The Croissant Diet and gained so much weight, where did I gain it? All in my belly. (Which mouse studies indicate shouldn’t happen.)

(PJ) #10

I thought the reason SFA keeps you satiated is because the IR of the adipose cells means the SFA keep circulating in the bloodstream for longer. IOW I didn’t think it had to do with the fat stored but simply the real-time-presence of it.

#11

It has been hypothesised that PUFAs may allow fat cells to be become more insulin sensitive, i.e. to grow! This may explain the findings of a study that saw improved cholesterol markers when subjects on a KD changed their fat ratios from SFA to PUFA. See below:

Differential Metabolic Effects of Saturated Versus Polyunsaturated Fats in Ketogenic Diets. The Journal of Clinical Endocrinology & Metabolism , Volume 89, Issue 4, 1 April 2004

Abstract

‘Ketogenic diets (KDs) are used for treatment of refractory epilepsy and metabolic disorders. The classic saturated fatty acid-enriched (SAT) KD has a fat:carbohydrate plus protein ratio of 4:1, in which the predominant fats are saturated. We hypothesized that a polyunsaturated fat-enriched (POLY) KD would induce a similar degree of ketosis with less detrimental effects on carbohydrate and lipid metabolism. Twenty healthy adults were randomized to two different weight-maintaining KDs for 5 d. Diets were 70% fat, 15% carbohydrate, and 15% protein. The fat contents were 60 or 15% saturated, 15 or 60% polyunsaturated, and 25% monounsaturated for SAT and POLY, respectively. Changes in serum β-hydroxybutyrate, insulin sensitivity (SI), and lipid profiles were measured. Mean circulating β-hydroxybutyrate levels increased 8.4 mg/dl in the POLY group ( P = 0.0004), compared with 3.1 mg/dl in the SAT group ( P = 0.07). SI increased significantly in the POLY group ( P = 0.02), whereas total and low-density lipoprotein cholesterol increased significantly in the SAT group (both P = 0.002). These data demonstrate that a short-term POLY KD induces a greater level of ketosis and improves SI, without adversely affecting total and low-density lipoprotein cholesterol, compared with a traditional SAT KD. Thus, a POLY KD may be superior to a classical SAT KD for chronic administration.’

EDIT: I have added the study graph, which I found useful:
image
Of course, if PUFAs are as deleterious as they are believed to be then these results should be short-lived. A longer duration study would be required to validate this.

(Bob M) #12

I’m not sure I’ve seen a graph of saturated fat in blood, even on Hyperlipid. I think the saturated fat has to get to the fat cell, otherwise, there’s no way for a fat cell to become insulin resistant via saturated fat.

(Bob M) #13

[quote=“Jamesbrawn007, post:11, topic:110991”]
It has been hypothesised that PUFAs may allow fat cells to be become more insulin sensitive, i.e. to grow! [/quote]

This is my understanding.

I hypothesize this may be one reason different people have different effects on The Croissant Diet: maybe those of us (like me) who gained weight have a different “fat profile” than those who lost weight. That is, perhaps I have many fewer insulin-responding fat cells than someone who was affected by saturated fat?

(Bacon is a many-splendoured thing) #15

The cholesterol-lowering effects of polyunsaturated fatty acids have been known for at least sixty years that I am aware of.

Beware of comparing the ketogenic diet for epilepsy with the type of well-formulated ketogenic diet recommended by Phinney, Volek, Westman, and others, which contains a great deal more protein than the epileptic diet. The epileptic diet is so low in protein that the growth of a number of children was stunted from it. A well-formulated ketogenic diet contains a fat:protein ratio much closer to 1:1 by weight, and the fats are more evenly distributed between saturated and monounsaturated.

#16

Yes, good old Ancel Keys.

I don’t think the macros ratio is the headline from this study. Besides, it was 15% CHO and 15% PRO, which is not a classic KD for epilepsy. As it was a weight-maintaining diet, that would equate to something like 94g PRO for an average adult male.

(Michael - When reality fails to meet expectations, the problem is not reality.) #17

I’m going with my standard fallback re PUFAs: human evolution. Our (pre &) Pleistocene ancestors ate almost exclusively meat and animal fats for 3 1/2 million plus years. Animal fats (including fish) contain the essential PUFAs in small amounts and I presume we evolved to consume them in those amounts and porportions. Anyone who didn’t has been selected out and is no longer with us. And probably has not been for a very long time.

We’ve only had access to PUFAs extracted from seed oils under pressure, heat and often solvents for 150 years - since the advent of cottonseed oil.

(PJ) #18

So… I don’t know a lot about this topic, just have interest. But…

  1. What are the assumptions about cholesterol and are they actually correct? Because you know, first it was omg it’s all horrible, then it was well only the small type is horrible, then it was well the lower the better, then it was oh yeah turns out low chol signals much higher death rates and is worse than high, then… well you see what I mean. When I read something that refers to how lipid/cholesterol biomarkers are “better” I think: by what standard?

I mean mainstream thinks saturated fat is bad and recommends canola oil, these are not people I trust to evaluate what’s actually healthy regardless of how many degrees they have. There are other ‘experts’ also with degrees who have very different opinions.

  1. I consider PUFA kind of the lipid equivalent of trace minerals. We absolutely need some of it – of course. Not even counting Omega 3s. We absolutely would suffer without any of it. The fact that nearly every source of fat in our world has a blend of several if not all of them is a good clue to how critical having a variety within us, for the body to use as needed, likely is – that’s what we developed with.

When you look at how common PUFA is in what people likely had to eat in ancient times – well, it’s not very. Maybe if you lived on fish… ish. As Michael noted it’s only the modern world that’s given us the disaster of massive quantities of it.

To digress a tiny bit, my theory about fructose is that it actually does legit harm in terms of storing fat around the liver and storing more in fat cells – but that it’s supposed to. That this ‘harm’ actually helped people survive often enough that just like how a Reactive Oxygen Species molecule can function as a Signalling Molecule – a negative thing used in a positive way because it’s expected to be there – that this is simply how it works. Yes it’s harmful but yes that was actually for the good – in small, seasonal doses mind you.

Well I suspect it might be similar with the PUFA fats. They might actually make fat cells store fat more/better/whatever. That might in today’s world be a form of harm. (And there may be other things of course.) But maybe that’s a harm that the body adapted for and is actually a good thing under normal, highly seasonal, limited food conditions. Maybe the fact there was so little of it, and it is so needed like for winter, is good reason for the body to store it more efficiently and allow more storage of it.

Just musing.

(Bacon is a many-splendoured thing) #19

The original assumption was that cholesterol deposits in arterial plaque were the cause of coronary heart disease. Ancel Keys showed, apparently correctly, that cholesterol in the diet has no effect on the level of cholesterol in the blood stream. But he also showed, apparently fraudulently (according to re-analyses of his original data), that saturated fat in the diet caused serum cholesterol to rise, and the assumption was that elevated serum cholesterol caused cholesterol deposits in arterial plaque. We now know that these cholesterol deposits are part of the repair process and are not the cause of cardiovascular disease.

Given that well over half the people presenting in the emergency room with a heart attack have normal or low cholesterol, you’d think that the notion of cholesterol as a the cause of cardiovascular disease would never have gained currency in the first place. Moreover, a study of people with familial hypercholesterolaemia done in the 1960’s showed that the people with this condition who have clotting abnormalities—about 50%—are the ones who have heart attacks and other cardiovascular problems, while the other 50%, who have equally high cholesterol levels, live perfectly normal lives and die at perfectly normal ages of perfectly normal non-cardiovascular causes. The authors of this study concluded that the diet-heart hypothesis (as it was then known), therefore could not possibly be valid. But Dr. Keys was just gearing up to take control of the American Heart Association and get his friends placed in responsible government positions, so the study was ignored.

As several large, well-funded studies, intended to prove Keys’s diet-heart hypothesis, instead showed a negative correlation with either cardiovascular disease or with all-cause mortality (Keys’s own Minnesota Coronary Study being one of them), the artery-clogging-saturated-fat argument became untenable, so the focus shifted to LDL. Now it seems to be moving to lipoproteins.

Members of the International Network of Cholesterol Sceptics have proposed other mechanisms as the real cause of cardiovascular disease. It is likely, as David Diamond points out, that arterial damage is constant and ongoing, and that the arteries only become clogged when the rate of damage outstrips the rate of repair. The study of FH I mentioned suggested blood clotting as an issue, and we know that excessive carbohydrate intake glycates the haemoglobin more than normal, thus exacerbating any other clotting problems the patient may have. Ravnskov and Diamond have suggested, given where the cholesterol ends up in the coronary arteries, that perhaps it gets in from tears in the vasa vasorum, the network of smaller blood vessels that supply oxygen to the coronary arteries.

(Bacon is a many-splendoured thing) #20

It is worth noting, however, that we evolved eating only a very few specific polyunsaturated fatty acids. Unfortunately for us, the various industrial seed oils contain a large number of PUFA’s to which the human body is not accustomed; these are the ones that cause the problems. And, of course, it is PUFA’s that are the most vulnerable to oxidation when these oils are heated.

I recently realised, when reading something about the Mediterranean diet, that even olive oil, with its much lower PUFA content, was never used as a foodstuff until very recently in human history. The ancient Greeks and Romans used it exclusively as a cosmetic and a lamp fuel; their dietary fats were butter, lard, and tallow, all of which are largely monounsaturated and saturated fats, with a minimal PUFA content.

(Bob M) #21

That’s possibly true, that PUFAs we’re used to fatten us, as it seems to be true in animals. I think it would depend on where you lived, though, as your access to nuts and the like could vary. And they probably had to do something to these, as a lot of them have antinutrients that have to be addressed.