Tuesday, 2 September 2014

Fat cell size regulation

Thanks to Bill for sending me this paper....

The premise of the paper is this......

Since individual cells from freshly isolated white adipose tissue (WAT) exhibit variable levels of fat accumulation, we attempted to determine which factor(s) cause this variation.

If you look at those micro-scope pictures of adipocytes from adipose tissue, youll notice that they are not all exactly the same size.  ( see here for ex ). Below is a distribution count of rodent adipocytes isolated and exposed to growth  + adipogenic media....

Cells were divided into a "high" and "low" category according to their BODIPY staining which was closely related to their size and therefore how much fat they stored.

As you can see from the top graph, you get an approximate normal distribution. But the question is why? Why arent adipocytes all the same size?

In general adipocytes from the same localized region of the body are exposed to the same concentrations of nutrients in the blood ( or there abouts ) and therefore CICO should predict for them to be roughly the same size. But they arent.....   therefore this can only mean there is a property intrinsic to the adipocyte that determines its size......

Now... if you want the TL:DR point of this post... it is this......

The extent of fat accumulation is correlated with histone acetylation of the Ppar promoter that is heritable and maintained even in dedifferentiated adipocytes.

What this means in plain english is, that if you take a bunch of adipocytes and expose them to growth media and adipogenic media, leave them to incubate for a few weeks, then examine them under a microscope, they are NOT all exactly the same size, even though they were all exposed to the exact same conditions. 

If you snoop around a bit more, youll find the thing that determines how "fat" an adipocyte gets is correlated with the histone acetylation of the PPAR-gamma gene. "histone acetylation" is how biology does gene regulation, I.E. how strongly a gene is expressed. As the paper says....

Histone acetylation is generally correlated with transcriptional activation

So a gene with a high histone acetylation will have a high transcriptional activity and be expressed strongly within the cell. Overall this is just a fancy way of saying, a fat cell has a "set point" for the amount of fat it will store that is dependent on the genetics of that cell.

To understand how I can make that statement, you need to go back all the way to this post...in which we learned that PPAR-gamma plays a huge role in determining how much fat you store.  Now we can understand a bit better why there is *some* truth to the idea of a fat/weight "set point", .

Each individual fat cell in your body has a fat/weight set point, that is determined by the histone acetylation of the PPAR-gamma gene. And your total body fat mass is just the sum of the fat mass of all your individual adipocytes...... therefore YOUR fat mass has a "set point".....unless you grow new adipocytes, in which case your fat mass "set point" goes up

This helps explain why people with more fat cells are generally fatter.

The following graphs show some of the characteristics of the fat cells before and after exposure to growth media....

Interestingly, the insulin receptor expression was not different between fat cells that ended up being small or large.....

This would suggest that it is post-receptor signalling that is involved in the "insulin sensitivity" of a fat cell.  Indeed you could say that large fat cells achieve their inflated sizes by having elevated expression levels of PPAR/GLUT4/SREBP1c.

I was especially interested in the GLUT4 graph, because I have seen previous evidence that GLUT4 is very anabolic for fat tissue. GLUT4 over-expression on adipocytes results in gross adipocyte hyperplasia, and that hyperinsulinemia selectively increases GLUT4 on adipocytes and reduces it on muscles.

Anyway, im not sure what controls GLUT4 gene transcription in adipocytes, I think PPAR-gamma is involved since Thiazolidinediones, which are PPAR-gamma agonists, increase GLUT4 on adipocytes. 

This study demonstrates that subpopulations reside within WAT and 3T3-L1 cells that vary in their capability to accumulate fat and that these differences are heritable. We have shown that the extent of the cell’s ability to accumulate fat correlated positively with expression levels of Ppar , a master regulator of adipogenesis, and with other markers of differentiated adipocytes, including Lep, Tshr, InsR, Glut4, Fasn, Srebp1c, aP2, and Pref1; exogenous expression of Ppar in 3T3-L1 cells increased fat accumulation; and the levels of histone H3 acetylation of the Ppar promoter in preadipocytes was a predictor of the extent of fat accumulation upon induction of adipogenesis.  
We thus suggest that epigenetic modification of the Ppar promoter is, in part, the mediator of the heritability of adipocyte differentiation.

With respect to the bolded sentence, "exogenous expression of Ppar in 3T3-L1 cells increased fat accumulation", do you remember how to increase Ppar in vivo?......... Insulin.

I do also wonder about the implications of the epigenetic modifcation of the histone acetylation of Ppar and the coincidence of fat mothers ( parents ) giving birth to fat babies.


  1. Does this mean us ex fatties are doomed to regain?

    1. maybe ........what this shows is that fat cells have a "baseline" level of fat storage that is determined by the cell's genetics.

      A fat cell that is forcefully inflated by aggressive insulin levels should return to its baseline when insulin levels drop. I would expect this is where most of the initial weight loss comes from on LC diets. ( yes and the obvious water loss zzzzzzzz )

      The study also mentions adipocytes are able to "de-differentiate" back into precursor cells, Im not sure how that fits in with the whole obesity/weight loss picture and I also dont know the (-)stimulus for this refraction.

      Speaking for myself, I wont regain weight unless I start on carbs again. Aslong as I remain strict LC the weight wont come back. I can have the odd carb binge days and get away with it. But persistent carb feeding causes dramatic rebound. ( By persistent I mean > 3 days )

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  3. This is interesting. It suggests -- if I am clear on the arrow of causality (not certain about that...) -- that histone deacetylation inhibitors (HDAC inhibitors) could be useful for weight management especially in the formerly obese. By that I mean stuff like butyric acid and valproic acid. The butyric is mostly a function of dietary fermentable fiber v/v microbiota (right?). More research needed.

    Sugar-binging (high glycemic whatever binging) may be having the opposite effect (acetylation and methylation being in yin/yang relationship if memory serves):
    Genes remember sugar hit: Australian research
    "short-lived sugar highs, which occur even in insulin-treated diabetics, trigger histone modifications -- an established effect of long-lasting sugar highs. Persistently high sugar levels are known to create reactive oxygen species that induce the generation of methylglyoxal -- an activator of the histone methylating enzyme Set7"

    Digression on valproic acid, just because I feel like it, and for the benefit of the occasional geeky onlooker who might be interested:

    Valproic acid is a simple supplement used mostly as a psych drug ("Depakote" and other names) in bipolar. It has already been shown that valproic opposes NAFL (non-alc fatty liver) and produces generally desirable metabolic changes in obese animals. On the other hand, and paradoxically, in humans it sometimes CAUSES liver damage and NAFL -- not typically, but in a few cases. Why is this? Can't say for sure, but several things spring to mind. First, valproic imposes a mild oxidative stress on the liver by disrupting sulfur metabolism; it has this in common with many other drugs. This is easy to prevent or correct with nutrients/supplements. Also, omega-3 fatty acids prevent valproic's potentially hepatoxic effects; both EPA and DHA are relevant. Also, valproic has been shown to deplete tissue carnitine. What all that adds up to is obvious: never take valproic without appropriate nutritional fortification to avert the possibility (modest, but it exists) of liver damage -- to get the bennies without side effects. The few people who suffer from liver damage from valproic are almost surely people who are, from the start, oxidatively stressed without compensation (i.e. lousy diet, no supplements, alcohol, etc.), and/or omega-3-depleted or marginal (SAD), and perhaps also mildly hypothyroid and thus potentially carnitine-depleted.

    Other than that, valproic acid is a cheap and reasonably safe fatty acid; probably under $30/kg in reasonable quantity; you only need a couple grams per day, hence therapy should not cost more than, let's just say, .25 USD/day, or .50 at the outside.

    Valproic has many other and interesting mostly-beneficial effects in the neuropsych sphere. For example, it promotes neurogenesis (neuroplasticity), enhances learning, enhances social cognition (anti-autism), synergizes with anti-depressants, and a lot more. It is a really interesting molecule. On the other hand, there is a subpopulation of users who find it to cause tiredness, sluggishness, brain-fog, etc. (Does this by chance correlate with uncompensated liver problems?) Well, everyone is different; sweeping generalizations based on a few studies are always unwise.

    More on neural effects of valproic, and on preventing liver injury when using it:

  4. Thanks for that link, indeed very interesting that temporary exposure can make long-lasting changes, something we all intuitively know from experience.

    Will read some more on it