I've been wanting to write about this paper for some time. But it annoys me. A lot.
I only realised yesterday that it is from Carpentier's group. Clearly Carpentier is asking questions about subjects which I am interested in. So it's time to say something.
First comes the title. From my point of view it absolutely concurs with what I would expect. If we accept that people have impaired glucose tolerance because they have accentuated lipid release from adipocytes (due to increased lipid droplet size necessitating elevated basal lipolysis), then storing lipid after a meal *should* increase FFA efflux from adipocytes. Make them big, they then "leak" (in a very controlled manner).
Carpentier used a very comprehensive tracer study to show that this effect is real and does occur (though they didn't look at, and clearly don't have, an hypothetical mechanism). The other finding they report is that this rise in efflux is not from chylomicrons spilling FFAs when they dock with extracellular lipoprotein lipase. The excess FFA efflux comes from adipocyte intracellular lipolysis.
This is consolidated in the first sentence of the abstract:
"The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis..."
Both of which confirm my biases. Which makes me want to like the paper.
Here's the fly in the ointment, also from the abstract:
"Plasma glycerol appearance was lower in IGT (P = 0.01), driven down by insulin resistance and increased insulin secretion."
So.
The group is saying that they have documented elevated postprandial FFA efflux from adipocyte lipolysis in subjects with IGT. But they have NOT detected a rise in glycerol from that lipolysis. Quite the opposite.
What's it to be? More lipolysis giving elevated FFA efflux, or less lipolysis giving less glycerol efflux?
You can't have both at the same time. In the abstract and the discussion they are claiming that hyperinsulinaemia secondary to insulin resistance is suppressing glycerol release. But not suppressing (accentuated) FFA release.
Go figure.
So I've sat on the paper, because it confirms most of my biases but doesn't make sense.
The paper is important because, if their FFA flux data are believable, what they are saying is that adipocytes of people with IGT are releasing FFAs in the post prandial period, but there is, at the same time, enhance uptake of FFAs in to adipocytes.
In my terms: accentuated basal lipolysis, which is protective of adipocytes from over distention, is being offset by FFA uptake by adipocytes as a consequence of enhance insulin and insulin signalling secondary to linoleic acid's inability to resist it.
It matters because there is a battle over adipocyte size. When excessive insulin signalling wins over basal lipolysis, people get hurt. Especially their adipocytes do.
The downstream effects are not pretty.
Peter
Peter: "The paper is important because, if their FFA flux data are believable, what they are saying is that adipocytes of people with IGT are releasing FFAs in the post prandial period, but there is, at the same time, enhance uptake of FFAs in to adipocytes."
ReplyDeleteThis almost seems delicate, and subtle, when you think about what must be happening the the fat cells in the cases we read of where very large humans (vlh) have to be lifted out of their houses by cranes or out of their cars by engine lifters. With these people it is all in, in, in and seems like very little out. ( 'Outputs' raises other less attractive questions to ponder)
However they acheive this stunning outcome, the regulatory mechanisms should just burn them up into ashes with the sheer magnitude of the energy flows, but instead they become human balloons:
1000lb sisters
"Amy and Tammy from Kentucky have a combined total weight of a little over 1000 pounds (453.5kg) and are now seeking professional help and turn their lives around.
The sisters ... were quizzed on what they eat, ....
Fairy floss – also known as cotton candy – baked chicken, pork chops, beef, mashed potatoes, tacos, sloppy joe mix, pasta, peanut butter, barbecue sauce, Chinese food, snack cakes, pizza rolls, steak, chips and baked spam all made the list."
Just shovelling it in - imagine how many litres of linoleic acid these girls contain in their afipocytes, or the humongous quantities of insulin sloshing around?
"In older mice, a loss of glycerol transport results in a dramatic accumulation of triacylglycerol in adipose tissue and metabolic alterations, including elevated FFA, hyperglycemia, and insulin resistance."
ReplyDeleteFigure 1. is nice, unfortunately I can't embed it here.
MacDougald, Ormond A., and Charles F. Burant. 2005. “Obesity and Metabolic Perturbations After Loss of Aquaporin 7, the Adipose Glycerol Transporter.” Proceedings of the National Academy of Sciences 102 (31): 10759–60. https://doi.org/10.1073/pnas.0504965102.
Peter: you would find this study very interesting: no weight gain with a short chain fatty acid but the same rodents had weight gain when switched to MCTs: https://pubmed.ncbi.nlm.nih.gov/37997471/
ReplyDeleteThose SCTs produce even less ROS than MCTs but are not fattening at all (according to the study)
ReplyDeletePass, yes, they must be doing incredible adipose hyperplasia. Hypertrophy might be maximal but cannot account for that size.
ReplyDeleteHi Tucker, nice find. Going to the actual paper at https://www.pnas.org/doi/full/10.1073/pnas.0503291102 they found lots of interesting things. Sadly the one thing which they didn’t ask is whether DIO control mice had differing glycerokinase activity or glycerol blood levels cf controls. If, as looks likely, adipocyte glycerol efflux is under hormonal control then they have an explanation for Carpentier’s anomalous and ignored finding about glycerol efflux in IGT people. The Aqua7 deficient mice merely alter reaction kinetics by increasing G3P formation to push the balance towards esterification and triglyceride formation. This doesn’t seem to affect reverse process of basal lipolysis, presumably because its glycerol is converted to G3P and so doesn’t apply concentration effects to the lipolytic reaction. If basal lipolysis is high enough we can have elevated FFAs and appropriate insulin resistance. Of course they don’t look at crown like structure formation and the associated insulin resistance in their KO mice. Next two posts, part written.
Hi Mikey, will have a look. Gotta take the family to the bouldering wall now...
Peter
May I jump in with a completely unrelated question, Peter? I have contracted Lyme-borreliosis, likely contracted on my frist holiday trip to England in decades (never found the tick bite unless what I thought was a reaction to giant hogweed was the bite). I started taking doxycycline and likely will have to for at least 20 days (again, the first antibiotic for me in ages). Did a little search, and yes, as expected, it impacts mitochondriae. I found a few papers warning that it may skew the results lab experiments on cell cultures where it is used as a switch, but nothing on what it does in live humans, not even by any of those outside of the mainstream who write about metabolic health. Can any of you point me to something if it's out there? Is there anything I can do to minimise the impact, if there is anything to bother about at all? Thanks
ReplyDeleteWhen Trygly gets to an adipose cell - it has to be broken down into FFA - then it can enter - (I Don't remember what happens to the backbone.) On the way out, it is the reverse process - you need a backbone glycerol to put it back together again. So from the paper Tucker posted a link to - the export of glycerol might not happen. Seems to be regulated by AQP7 - but what exactly is happening there is not clear.
ReplyDeleteSo LPL and HSL control the construction of the trygly - both are either directly or indirectly controlled by insulin ( this sensitivity might not be the same as what controls insulin sensitivity). I would suspect that there is a similar insulin control to produce the glycerol back-bone - or to absorb the glycerol. My understanding is normally the FFA gets reassembled just outside of the cell.
I ended up looking at this when I looked at a paper that didn't make it clear what form they used for the FA in a diet - it sounded like they just added the FFA to the diet - not in the triglyceride form.
So breaking down the trygly to pass into the cell as FFA - then convert it back to trygly - later break it down to exit the cell and put it back together outside the cell I think is the normal state. This flux is supposed to continue in both directions at once - leaning to one direction or the other (but do we really know that?). There is a narrative that inflamed adipocytes is the cause of obesity and T2D - claiming that the tissue damaged that produces T2D is in the adipocytes - but the list of narratives is VERY long - and there are various experts that will reinforce whatever type of tissue is damaged that you want to believe.
Eating low-Carb can compensate for the damage - but that is a life-long intervention (the MDs tell me people fix BG - but never get cured via low-carb) - so exactly which tissue is damaged producing T2D - I don't think we know for sure. (I think the narrative that says that the carbs are the cause is probably wrong - some population live quite well on high carb diets). But even being able to know which tissue is damaged is not yet clear. I've been adding a new narrative of the cause of T2D about every other week for quite some time now to a list I've made. All the experts are certain their theory is the right one.