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  1. #1
    Techie's Avatar
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    Fat Cell (Adipocyte) Autophagy in Long Term Weight Loss

    Does anyone know of any studies that look at whether Adipocyte / Visceral Fat cells actually die (apoptosis) and not be replenished after sustained weight loss?

    I know the current studies / CW show that the lipids inside the fat cells shrink in size but that adults keep the same number of cells. (Which still keep producing hormones).

    We know that IMF can induce autophagy in inefficient cells and free amino acids, but is there anything similar on the fat cell front.

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    I would seriously doubt this exists.

    An empty fat cell is a fat cell that has given up its contents in the line of duty ... that is, during a period of energy scarcity, this valiant cell sacrificed it's contents for the good of tissues at large, and you expect to repay it by killing it?

    Apoptosis of empty fat cells is not an evolutionarily stable strategy. You need empty fat cells because you need excess storage capacity to act as a sink for excess energy when the environment is kind enough to serve it up to you. Without excess capacity, you would need the ability to grow new fat cells very quickly on demand, something which is rather more expensive metabolically than keeping empty fat cells around.

    Moreover, if prolonged weight loss induced fat cell apoptosis, then over a long enough time frame, you would wind up with zero fat cells which means that precisely at a point in time when you desperately needed the ability to store energy. Further, yo-yo diets would logically conclude with the hapless dieter in possession of a few grotesquely enlarged fat cells. Neither of these outcomes is observed in real life.

    As a final point, fat cells never get "empty" per se. Rather, they contain very little triglycerides relative to the "full" version of themselves.

    -PK
    My blog : cogitoergoedo.com

    Interested in Intermittent Fasting? This might help: part 1, part 2, part 3.

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    there's some recent research about freezing those cells off. if you search for it you'll no doubt find it. Fat cells apparently freeze and die at a higher temperature than the rest of the skin and tissue. It makes interesting reading but don't nip to the freezer and cover yourself in ice-cubes just yet!

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    I came here looking for some info on this. Here's what I found online, but I need help interpreting it.

    So first I found this blog post:
    Kindke's Scrap Notes: Too many fat cells

    Which simply talks about the link between Leptin and weight loss. An interesting point though is that as you're gaining weight you also gain new fat cells. When you lose weight, say by switching from the SAD to Primal, the same number of cells are still present, but each is smaller. The smaller size of each cell would mean that it would produce less Leptin, and when your overall Insulin production is balanced with the lower levels of Leptin, you'd stop losing weight. A plateau. This makes perfect sense to me, and is what I observed in my own weight loss journey. I believe this is also why "Cheat Days" work, simply due to the increased Leptin levels. But that's off-topic.

    According to this blog post, a more ideal situation would be to return to having less fat cells, but each one would be bigger in turn, which would cause much higher Leptin production, he suggests as much as 7 times more. The only way this can happen is with Adipocyte Apoptosis, but there's no suggestion as to how this can take place.

    Then I ran across this (although I don't have access to the actual paper):
    ScienceDirect.com - Biochemical Pharmacology - Effects of leptin on apoptosis and adipogenesis in 3T3-L1 adipocytes
    Which seems to suggest some kind of connection between Leptin and Apoptosis. But again, I have no idea as to the details.

    The next piece I found is this study:
    PLOS ONE: Inhibition of Adipogenesis and Induction of Apoptosis and Lipolysis by Stem Bromelain in 3T3-L1 Adipocytes
    Which finds a link between Bromelain, an extract from Pineapple, and Apoptosis. Mark mentioned Bromelain briefly in a couple of blog posts.

    The original blog that set me on this track suggests more extreme measures. From Leptin therapy/supplements all the way to reconstructive surgery. Obviously that's not primal to say the least. But the Bromelain study seems like it would have potential.

    I was wondering if anyone has any opinions on this subject?

  5. #5
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    Quote Originally Posted by BigJohn View Post
    I came here looking for some info on this. Here's what I found online, but I need help interpreting it.

    So first I found this blog post:
    Kindke's Scrap Notes: Too many fat cells

    Which simply talks about the link between Leptin and weight loss. An interesting point though is that as you're gaining weight you also gain new fat cells. When you lose weight, say by switching from the SAD to Primal, the same number of cells are still present, but each is smaller. The smaller size of each cell would mean that it would produce less Leptin, and when your overall Insulin production is balanced with the lower levels of Leptin, you'd stop losing weight. A plateau. This makes perfect sense to me, and is what I observed in my own weight loss journey. I believe this is also why "Cheat Days" work, simply due to the increased Leptin levels. But that's off-topic.

    According to this blog post, a more ideal situation would be to return to having less fat cells, but each one would be bigger in turn, which would cause much higher Leptin production, he suggests as much as 7 times more. The only way this can happen is with Adipocyte Apoptosis, but there's no suggestion as to how this can take place.

    Then I ran across this (although I don't have access to the actual paper):
    ScienceDirect.com - Biochemical Pharmacology - Effects of leptin on apoptosis and adipogenesis in 3T3-L1 adipocytes
    Which seems to suggest some kind of connection between Leptin and Apoptosis. But again, I have no idea as to the details.

    The next piece I found is this study:
    PLOS ONE: Inhibition of Adipogenesis and Induction of Apoptosis and Lipolysis by Stem Bromelain in 3T3-L1 Adipocytes
    Which finds a link between Bromelain, an extract from Pineapple, and Apoptosis. Mark mentioned Bromelain briefly in a couple of blog posts.

    The original blog that set me on this track suggests more extreme measures. From Leptin therapy/supplements all the way to reconstructive surgery. Obviously that's not primal to say the least. But the Bromelain study seems like it would have potential.

    I was wondering if anyone has any opinions on this subject?
    Howdy, BigJohn!

    Those are some interesting links, and I've only had a chance to look quickly at the first link, but it seems that the conclusions being drawn by those bloggers outstrip the data by far.

    The Kindke link references this to explain the "fundamentals of the problem" :

    Nasty Insights into the Yo-Yo-Effect: Lower Body Fat Sticks and From Fit2Fat There's no Easy Way Back! Plus: Why It's Easier to Get 6-Pack Abs Than Striated Glutes & Hams. - SuppVersity: Nutrition and Exercise Science for Everyone

    That post in turn makes quite a big deal about this paper where scientists had volunteers gain about 3.1 kg over eight weeks and then try to lose that over the same time frame. Weight gain was accomplished by overfeeding, loss, as you would expect, by underfeeding. It turns out that some of the fat the subjects gained was retained, and it tended to be located in the lower body, rather than the torso. This is interpreted by the blogger(s) at suppversity to mean that "the fat stuck."

    Now, I don't have access to that paper, I could only read the abstract, if anyone else does and would care to share, I'll gladly read it. But to get back to this notion that "the fat stuck!" and going with what suppversity had to say about the protocol:

    Quote Originally Posted by suppversity
    Prachi Singh and his colleagues from the Mayo Clinic in Rochester, UK, fed 23 volunteers (15 men and 8 women; BMI 23.6 6kg/mē, mean age 30y), who were sedentary, but normal-weight and free of chronic disease, standardized diets with a macronutrient composition of 20% protein, 40% carbs and 40% fat. In addition each of the participants, who were weighed at least 5x per week had to eat 1-3 of the following snacks

    • ice-cream shake (402 kcal),
    • chocolate bars (a king-size Snickers bar, 510 kcal), or
    • an energy drink (Boost Plus, 360 kcal/8 oz)

    in order to gain ~5% of body weight within the initial 8-week weight gain phase. By dropping the extra snacks, dietary counseling from and an increase in overall activity the participants had shed those extra pounds in a subsequent 8-week weight loss phase
    My immediate thinking on this is: was this a metabolic ward study, or were participants periodically examined in a lab? I don't know, but judging from the length of the study, 16 weeks, I would wager we are not talking about a metabolic ward study where you carefully control calories and activity levels with subjects domiciled within the lab for the duration of the study. These are very expensive to run. So instead, you send people on their merry way and have them come in for periodic checkups. Accordingly, compliance to the protocol is self-reported and subject to rather wide variances.

    Given all of that, maybe participants were more highly compliant with the more pleasurable weight gain part of the protocol as opposed to the weight loss phase. Maybe lower body fat loss occurs at a slower rate than fat gain? I fail to see any reason to assume that the rate of gain should be equal to the rate of loss. If participants were to have kept up with the protocol for a few more weeks, would we have observed a return to pre-intervention levels of lower body fat? We don't know, which is fine, but the implicit assumption by suppversity is no. I don't see any valid reason for that conclusion. So at best, we have equivocal data.

    I also don't see much in the way of an explanation for why kindke seems to think that the root of the problem is fat hyperplasia, that is, the multiplication of fat cells instead of simple hypertrophy, or enlargement / growth of the cell. I certainly agree that if there were a way to induce significant adipose cell hyperplasia this would be a problem, but I have yet to see any evidence to suggest that this actually happens.

    Again, this is a very quick burn through that first link, but I'd not get overly worried just yet.

    -PK
    My blog : cogitoergoedo.com

    Interested in Intermittent Fasting? This might help: part 1, part 2, part 3.

  6. #6
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    Quote Originally Posted by BigJohn View Post
    I came here looking for some info on this. Here's what I found online, but I need help interpreting it.

    . . .

    According to this blog post, a more ideal situation would be to return to having less fat cells, but each one would be bigger in turn, which would cause much higher Leptin production, he suggests as much as 7 times more. The only way this can happen is with Adipocyte Apoptosis, but there's no suggestion as to how this can take place.

    Then I ran across this (although I don't have access to the actual paper):
    ScienceDirect.com - Biochemical Pharmacology - Effects of leptin on apoptosis and adipogenesis in 3T3-L1 adipocytes
    Which seems to suggest some kind of connection between Leptin and Apoptosis. But again, I have no idea as to the details.

    . . .

    I was wondering if anyone has any opinions on this subject?
    I actually disagree with the fundamental premise, which is essentially that fat cells are bad and killing them is somehow beneficial. This very closely mirrors the insulin is bad thinking that we've seen, something that culminated in Peter Attia's moronically entitled waroninsulin.com, since renamed. Given that Attia is an M.D. he probably should have known better. We know how to chemically induce Type I diabetes ( knock out beta cells ) yet we don't do this, because insulin is fundamental in energy metabolism. Before the wide spread availability of artificial insulin, IDM was characterized as the disease that turns flesh into urine. Very nasty stuff, to have no insulin in your system.

    A very significant partner to insulin in the management of blood sugar is adipose tissue. If I could wave my magic wand and relieve you of all of your adipose tissue I would instantly grant you type ii diabetes, rendering you massively insulin insensitive. So we need to be careful what we ask for, we may just be granted our wishes!

    Of course, given our current problems with obesity, everybody is feverishly trying to medicalize the problem and come up with a pill to address it ... a product bigger than Viagra, since it applies to both sexes, with attendant profit visions.

    Let me step off my soapbox and get back to that study ...

    Leptin is a hormone secreted by adipose tissue in direct proportion to the amount of tissue ( here we're talking about tissue mass, not necessarily cell count, so many large cells means more leptin than the same number of smaller cells ). So, as you gain adipose tissue, your circulating leptin levels increase and as you lose fat mass, circulating leptin levels decrease. It makes sense, therefore, that leptin levels ought to have something to do with the tendency of the body to generate new adipose cells. That is, if you don't have much leptin, then you don't have much fat, so it might be worth-while to generate some additional ones in order to trap more of the incoming energy. Conversely, if you have lots and lots of leptin circulating in your system, then stored energy is certainly not a problem for you, so maybe we should hold off in generating any additional fat cells.

    Ambati et al attempted to answer two basic questions: 1) does peripheral leptin cause fat cell apoptosis (i.e. will it kill off existing fat cells? ), and 2) does it have any effects on proto-adipose cells, that is, essentially on adipose stem cells.

    Question 1 we could have probably answered ourselves without the use of cell cultures or any fancy biochemistry by simply observing that hyperleptinemia does not cause a decrease in fat cell counts. That is, the individuals in our society with the highest levels of circulating leptin are the most obese. These folks are not walking around in the possession of a single, grotesquely distended fat cell. Rather, they have a normal complement of adipose tissue, albeit with cells overstuffed with lipids. It would be very difficult to explain this observation in a world where leptin causes mature adipose cell apoptosis.

    Ambati et al. confirm this intuition:

    Quote Originally Posted by Ambati et al.
    These results indicate that leptin does not act directly to induce adipocyte apoptosis, but can act directly to inhibit maturation of preadipocytes.
    As for question two, it makes intuitive sense that if you have a lot of adipose tissue you aren't going to invest metabolic resources in making additional ones, which again is confirmed by the study.

    In general, one needs to be careful about studies such as this one for a number of reasons. First, this study is in vitro. Scientists take a cell culture in a petri dish and subject it to all manners of strange treatment that could never be reproduced in a living organism. It is a highly artificial environment, good for fleshing out ideas, but with very speculative applications in the real world.

    Second, the cell culture under consideration here, 3T3-L1 adiopcytes, are not adipocytes as in the stuff on your abdomen, but rather, they are proto-adipocytes, cells that have yet to mature and become fully functional adipose tissue. It is a stretch to apply any finding pertaining to this cell strain to fully mature cells that form the bulk ( yeah, punny ) of an adults adipose tissue.

    -PK
    My blog : cogitoergoedo.com

    Interested in Intermittent Fasting? This might help: part 1, part 2, part 3.

  7. #7
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    Quote Originally Posted by Techie View Post
    Does anyone know of any studies that look at whether Adipocyte / Visceral Fat cells actually die (apoptosis) and not be replenished after sustained weight loss?

    I know the current studies / CW show that the lipids inside the fat cells shrink in size but that adults keep the same number of cells. (Which still keep producing hormones).

    We know that IMF can induce autophagy in inefficient cells and free amino acids, but is there anything similar on the fat cell front.
    my n=1

    fat cells take 4-6 months to be decommissioned after they are emptied and not refilled. they hold water until that time and are easily reopened for business.

    Cold does have an autophagic effect if one is willing to endure the low temps required. anything above 40F for less than 30 minutes is useless for provoking autophagy.

    any substance that will mediate estrogen production or storage can also assist in reducing the time the body takes to signal cell death.

    there is a huge metabolic effect to adipose tissue. my success came from both HCG ( which flushes the LHS receptors of the cell) and Ketosis. once my fasting insulin dropped below 9 i started seeign real results.

    however your mileage may vary
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  8. #8
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    Quote Originally Posted by pklopp View Post
    Question 1 we could have probably answered ourselves without the use of cell cultures or any fancy biochemistry by simply observing that hyperleptinemia does not cause a decrease in fat cell counts. That is, the individuals in our society with the highest levels of circulating leptin are the most obese. These folks are not walking around in the possession of a single, grotesquely distended fat cell. Rather, they have a normal complement of adipose tissue, albeit with cells overstuffed with lipids. It would be very difficult to explain this observation in a world where leptin causes mature adipose cell apoptosis.
    Ok, so this is the part that confuses me. That's definitely the correct observation from my experience. And yet it also doesn't make sense to me that obese individuals would have the same amount of fat cells as they did when they weren't obese. Otherwise we're basically saying that the same number of cells contain that much weight? That can't be right. I would assume that past a certain point the body would add on more fat cells as necessary. Or am I wrong in that assumption?

    If that assumption is correct, as the blog post suggests, and if Leptin is secreted in relation to how "full" a fat cell is, then that would neatly explain weight-loss plateaus. You have an expanded number of fat cells which are all somewhat empty, instead of having your pre-obesity number of fat cells which, given that same amount of fat, would have otherwise been much fuller, and therefore secrete a lot more Leptin. This is where Apoptosis would come in handy.

    So I find this confusing. It seems that I can observe that both of these things are true, but they can't both be true together. What am I missing?

  9. #9
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    Quote Originally Posted by BigJohn View Post
    Ok, so this is the part that confuses me. That's definitely the correct observation from my experience. And yet it also doesn't make sense to me that obese individuals would have the same amount of fat cells as they did when they weren't obese. Otherwise we're basically saying that the same number of cells contain that much weight? That can't be right. I would assume that past a certain point the body would add on more fat cells as necessary. Or am I wrong in that assumption?
    If your assumption were correct, then there would be no such thing as type II diabetes (T2D).

    T2D is a failure of your system to respond to insulin signalling, that is, nutrients do not get assimilated by your tissues in general, and in particular, your adipocytes do not take up excess glucose because they have reached capacity. It is at this point that your assumption would kick in, additional adipocytes would be produced via hyperplasia, and we would be on our merry way, getting progressively larger and larger, but at least without any diabetic complications.

    Now, given that we do have T2D in droves, what looks to be happening is that depending on the individual, fat cells reach their capacity, and further, no hyperplasia occurs, that is, we do not produce additional fat cells to mop up excess nutrients. Individual differences in adipocyte count and distribution explain why some people can get very large, and yet not express T2D, whereas others while not obese in the clinical sense, do.

    -PK
    My blog : cogitoergoedo.com

    Interested in Intermittent Fasting? This might help: part 1, part 2, part 3.

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