Tuesday, 14 April 2015

Obesity isnt "normal"

The more I learn about obesity the more depressingly obvious it becomes that it is an irreversible disease.

Thanks to libgen I got my hands on this paper which seeks to more closely examine the contribution of hyperplasia to obesity. ( basically hyperplasia is "recruitment of adipose progenitor cells" ) Normally adipose tissue is riddled with stem cells......( also referred to as fibroblasts etc ) .... think of them as building block cells.

These cells have most of their DNA coiled up tightly around the nucleosomes such that hardly any gene's are expressed, which means they essentially have no phenotype. Then, for whatever reason, at the on-set of obesity, these cells receive the message to differentiate into fully mature adipocytes, the DNA for the PPARg2 gene is uncoiled from the nucleosome, the activity of the triglyceride synthesizing enzymes increases many-fold, and the cell starts accumulating fat.

Here are some quotes from the paper.......

recent studies have found that adipocyte hyperplasia plays an important role in human obesity5,6. Specifically, obese individuals have significantly more adipocytes than lean individuals, and this trend is maintained throughout adult life5.


Even after obese individuals undergo severe weight loss, elevated adipocyte number is maintained5, indicating that increased adipocyte formation in obesity has lifelong effects on adipose tissue homeostasis and WAT mass.

In the study, they put mice on chow and HFD's and looked at when recruitment of pre-adipocytes occurs with respect to obesity development. Surprisingly, pre-adipocytes start to get activated within 1 day of HFD exposure, peak at 3 days,  and returns to baseline at 5 days. ( although it takes 7-8 weeks for them to fully differentiate into adipocytes and store fat, it seems you can get the "ball rolling" extremely quickly, i guess I need to think carefully next time before I indulge in a cheat meal...........)


Perhaps the most interesting part of the study is what they found when they tried to determine the pathway's involved in the activation of pre-adipocytes. They focused on the phosphoinositide 3-kinase (PI3K)-AKT pathway ( which is downstream of insulin ) . Specifically, they looked at AKT...

The AKT kinases regulate several processes, including cellular growth, survival and metabolism29. The most prominent mammalian isoforms are AKT1 and AKT2. Whereas AKT1 is widely expressed and promotes the growth of many tissues30,31, AKT2 regulates metabolic flux within liver, muscle and adipose tissue

They found that after several days of HFD exposure, AKT1 was unchanged while AKT2 was elevated, which led them to speculate it was AKT2 that got the pre-adipocytes ready for differentiation. Next they knocked out the AKT2 gene specifically in adipose tissue. The Akt2􀀀(-/-)  mice actually developed normally with normal body fat levels, and as expected, were resistant to weight gain and adipocyte hyperplasia when fed a HFD.

This actually has profound implications, it suggests that the "new bodyfat" you develop in obesity is different and distinct from your "normal" adipose tissue that you get from birth and when growing up. Obesity is like an addition of a "new" type of adipose tissue, it is not merely the expansion of your normal fat mass, but a completely new beast altogether....

Although the formation of adipose tissue in development,.... and the expansion of adipose tissue in obesity..... are often viewed as temporal variations on the same regulatory process, we show here that the formation of adipocytes in obesity and development are controlled by distinct molecular mechanisms. The existence of an aberrant mechanism of adipogenesis in obesity supports the American Medical Association's classification of obesity as a disease

What happens to an ob/ob ( leptin deleted ) mouse that is also akt2(-/-) ? ....Yes, they are also resistant to fat gain, further indicating the importance of hyerplasia in obesity development.


Our data suggest that even relatively short binges of altered eating behaviour may stimulate obesogenic adipogenesis, resulting in an intractable increase in adipocyte number5 that may make future weight loss more difficult.

The only caveat to mention is that almost all the hyperplasia was detected in the visceral depot with only small amounts in the subcutaneous depot. I would extrapolate this with caution to humans however, and im pretty sure the subcutaneous depot undergoes massive hyperplasia in human obesity, I mean you dont think a panniculus is due to hypertrophy do you? Or that all that excess skin is "just skin", and not billions of shrunken hyper-plastic fat cells......










10 comments:

  1. Wow, no wonder staying non-obese after weight loss is so hard. Thanks for the article.

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    1. A decrease in leptin and hyperplasia are indeed the reason maintaining weight loss is nigh impossible.

      everyone can lose wt by starving themselves but you cant starve yourself forever and calorie restriction simultaneously decreases leptin and increases AgRP which leaves a "fat debt collection program" in your adipocytes so that if you ever start to increase your food intake, calories are quickly shunted there.

      Despite what ppl think "starvation mode" is actually real and is mediated by the neuropeptide AgRP.

      Actually the main job of leptin is purely to counter-act AgRP, because if you delete AgRP in ob/ob they suddenly become normal and regain fertility. It seems the body is set up to naturally assume you are always starving and will only think otherwise when it sees leptin.

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  2. The general consensus at the moment seems to be that hyperplasia happens when an individual has reached obesity. Why then, is it so difficult to keep off 10-15kgs even? I suspect it may be gradual, not all at once when you reach obesity. What do you think?

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    1. "The general consensus at the moment seems to be that hyperplasia happens when an individual has reached obesity"

      actually this study disproves that as you can see pre-adipocytes already have the signal to differentiate within 1-3 days of HFD exposure, long before the rodents are "obese". but it may take them 7-8 weeks to complete differentiation and store fat, so I guess that is where the confusion may lie. A few days of binging on processed carbs might take 7-8 weeks before it shows up on your wasitline. I doubt many people would be able to remember what they ate 2 months ago, So if you wake up one day and find yourself a bit fatter, this can explain it, even if youve been eating clean lately.

      Also the authors state the idea that hyperplasia occurs when exsisting fat cells are "full" also turns out to be false

      ""It has been hypothesized that once adipocytes reach their maximal size they stimulate the production of new adipocytes Our data show, however, that at the onset of diet-induced obesity, adipogenesis is initiated long before existing adipocytes reach their maximum lipid-filling capacity.""

      I agree that obesity progresses gradually, I dont think you recruit all your pre-adipocytes at once. Mature adipocytes cannot undergo mitosis and once mature they live out thier lives they die, which is approx 10 yrs. However I think before they die they flag another pre-adipocyte to differentiate to take its place.

      Also I suspect pre-adipocytes undergo mitosis before they differentiate into adipocytes otherwise youd run out of pre-cursor cells.


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  3. Kindke this is all so depressing! Makes me even more determined to keep this weight off. What do you think of Lyle McDonald's work? He has added a patch to his stubborn fat solution http://www.bodyrecomposition.com/the-stubborn-fat-solution-patch-1-1/. Its only a booklet and I assume it's going to be a hack using some kind of med that either I can't get in my country or will cause interactions with other meds, eg yohimbine, The alternative is - "Rauwolscine HCL: targets visceral fat (fat that is stored in the ‘stubborn areas’ ex- buttocks, stomach and waist). It also acts as a central nervous system stimulant with out the side effects normally associated with strong stimulants (ex- no crash or jitters).*" but impossible to get on it's own, it's always mixed with other thermo ingredients.

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    1. yohimbine is useless ive tried it.

      temporarily using a drug to lower the amount of fat in a fat cell will not work longterm because as soon as you stop the drug the fat will come back. fat cells have a "set-point" for the amount of fat it will store that is atleast in part determined by the histone acetylation of the PPARg gene.

      there are no effective weight loss drugs on the market at the moment. even DNP does not produce weight loss in everyone.

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  4. Kindke, I too believe that fat cells have a set point for fat but how does this explain individuals have starved themselves to a normal weight? (Im not talking about 500-1500 cal diets, like total starvation for weeks). Mind you, it is not common at all (well documented anyway). Are there fat cells somehow reset? Or do they leave the body? Im not suggesting its healthy at all, far from it, but humans didnt always have abundant food supplies and obesity wasnt a problem. I have found an article based on AB Scotsman and there was an AMA done a while ago http://www.reddit.com/r/IAmA/comments/1o5ndh/iama_guy_who_went_from_430_pounds_to_170_pounds. Something Ive been pondering and would like your opinion

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    1. I wrote a post on this few years ago after I found that extremely low insulin levels can cause apoptosis in fat cells. I speculated that people going on pure fasts might get their insulin levels low enough to cause apoptosis in fat cells.

      Although Sidereal later informed me she found several other accounts of people attempting pure fasts and it didnt work out so well for them, and some of them died.

      If theres one thing thats clear its that males do substantially with fasting than females. Add to that genetics and it gets complicated. We must careful not to use statistical outliers as our basis for analyzing why the general population can or cant do something.

      As an example, its well documented that after weight loss, some people need surgery, while others dont because their fat and skin "snaps" back into place very well.

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    2. From my experience, fasts make liver very efficient in a glyconeogenesis. May be some fat sells in especially wrong places should be killed permanently with something like laser cavitation, liposuction or cryolipolysis ...

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