Saturday 13 October 2012

Is Starvation the cure to obesity?

Im sure there are many people who would like you to believe this. Something to do with "negative energy balance" im sure they would say, displaying complete ignorance for the fact that biology employees countless homoeostatic feedback loops to keep certain parameters within a tight range.

Myself, I hate calorie restriction, it is nothing but misery and torture. Infact, I would rather straight up fast than subject myself to the inhuman suffering of eating less than what I feel like I want to.

When I eat, I want to continue eating until I get complete satisfaction, until my body naturally tells me ive had enough. I cant just eat a small meal for lunch, eating in this way just makes me MORE hungry. Im pretty sure now, I know why that is....... ( i.e. inhibition of hepatic fatty acid oxidation without the corresponding incretin secretion to offset the hunger ).

Do not under-estimate the contribution of hepatic fatty acid oxidation to whole body energy expenditure, even if organ mass makes up only 5–6% of body mass, it accounts for almost 80% of resting energy expenditure ( 1 ), Contrast this to muscle, which most people says keeps you lean, but according to Mark Sisson, a pound of muscle, at rest, burns about six calories per day. ( 2 )

Instead I expect the way that muscle helps keep you lean is because it helps improve nutrient partitioning towards there and away from adipose tissue by increasing insulin sensitivity and allowing more glucose/GLUT4 disposal in muscle, probably in the same sense that skeletal muscle LPL protects you from fat gain ( 3 )

Anyway,

I want to make a somewhat outrageous speculation that starvation "might" atleast in part be the cure to obesity.

First note, that obesity tends to involve more adipocyte multiplication/differentiation, rather than just an increase in adipocyte volume. ( 4 ) I.e. Fat tissue growth. This is what Thiazolidinediones do, and how they make you fat, new fat cells are born and because the are small, they are exquisitely insulin sensitive. I hope I dont need to convince anyone that adipocyte insulin sensitivity is a determinant of how big it can get......

OK

Something we also know is that weight loss typically only involves reductions in adipocyte volume, not number, a drop in volume makes the adipocytes more insulin sensitive, and thus make you prone to weight gain. Despite all the complications in trying to find out why dieted down people regain weight so easily, I expect the answer to be as simple as this. i.e. a failure to reduce adipocyte number.

Consider the example...

Bob = 15% body fat,  500 adipocytes
Joe = 15% body fat, 1000 adipocytes

In this scenario, both joe and bob are just as fat as each other, by definition their adipose tissue is 15% of mass. Since bob has less adipocytes, it must follow that bob stores MORE TOTAL fat in each of his adipocytes. ( we have to also accept the pre-condition that in general, fat mass is dividend evenly between adipocytes, I.E. We dont store all our 15% fat in our belly and thighs. But the 15% is distributed over the entire body. )

Adipocytes that store more total fat are larger in circumference and so are less insulin sensitive.

Meanwhile joe will store less total fat mass in each of his adipocytes, meaning their circumference will be smaller and therefore meaning they will be more insulin sensitive. Joe will thus be more vulnerable to weight gain.

So a person who has lost weight, in the typical fashion of calorie restriction, can be just as thin as a lean person, but will probably have more total adipocytes, because as we just agreed, weight loss usually only involves reductions in adipocyte volume, not number. A tell tail sign of this is leptin. If your just as thin as someone else, but have less leptin, its most likely because you have more fat cells. Thats why  Thiazolidinediones are reported to either leave leptin unchanged or DECREASE leptin, because  Thiazolidinediones increase fat cell number.

Reversing obesity is all about reducing your adipocyte number, in addition to their size.

Short of surgical intervention to remove the excess fat cells, is there anything else that can be done? What about adipocyte apoptosis?

OK this is where my speculation gets outrageous, I wouldnt want to get anyone's hope up falsely! zomg!

A curious case of the man who fasted for 1 year ( 5 ), but what is most impressive, is that he only gained back 16 lbs after he stopped dieting. I dont know if he had any kind of surgery, or if he had just hulk like willpower, but I was intrigued after reading also this study ( 6 ).  It talks about a protein called CIDEA.

Apparently, CIDEA is involved in adipocyte apoptosis, and is negatively regulated by insulin. Starving fat cells and exposing them to very ( VERY ) low levels of insulin seems to induce, or rather, "allow" apoptosis. To quote....

After starvation for 72 h, numbers of adipocytes were decreased by 18.0 ± 7.7% and 6.6 ± 0.6% of adipocytes were TUNEL-positive

The adipocytes were incubated with or without insulin, and without insulin they started to self-destruct, this is because without insulin, adipocyte CIDEA starts to increase.

So my question is this, did the complete starvation in the 1-year man allow significant adipocyte apoptosis and thus inhibit his potential weight regain? Now, im not suggesting that you need to completely fast from food until you reach your goal weight.

Instead, what im thinking is that short bursts of fasting, perhaps 48-72 hours, could possibly enhance adipocyte apoptosis. And adipocyte apoptosis is absolutely necessary for "curing" obesity. Ofcourse at this moment in time, I dont have any in vivo evidence of this. Extrapolating from cell culture to in vivo has many flaws, not least of which is that nobody has zero insulin, even when fasting. But complete fasting is one of the few ways to get insulin to its lowest.

At this point, its worth remembering that Peter thinks that obesity can result from a failure to generate superoxide in adipose tissue, I.E. from a failure to make adipocytes insulin resistant. Mice that are deficient in NADPH oxidase 4 ( NOX4 ) in adipose tissue display increased susceptibility to obesity. What does NOX4 do? It is involved in the generation of superoxide. NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro.

Obesity in NOX4 deficient mice results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency.

Bingo!

So reduced superoxide in adipocytes leads to them multiplying and growing faster. But why am I talking about this? Is there a connection with CIDEA?

Besides the point that genetic Polymorphism in CIDEA is associated with obesity, Another team of researchers had a very interesting hypothesis, that CIDEA regulates fatty acid oxidation in adipocytes.  And we know that fatty acid oxidation in adipocytes produces superoxide, making adipocytes insulin resistant and protecting us from obesity. Further the researchers speculate that it is calorie restriction per se, that increases CIDEA.

The last link in the chain is if there is a connection between superoxide production and apoptosis. And I think the answer to this question could be yes, anti-HIV drugs are associated with lipodystrophy, and there are also associated with oxidative stress and ROS. This study reports that anti-HIV drugs increase oxidative stress and subsequently overwhelm antioxidant capacity and that this can lead to apoptosis.

Summary :-

For the TL:DR newbs, here is my theory..( its just a theory, I welcome criticism/feedback )

1) Fasting ( or SEVERE calorie restriction ) leads to increased CIDEA in adipocytes.
2) Increased lipolysis occurs along with increased fatty acid oxidation actually inside the adipocyte
3) Generation of oxidative stress and superoxide, leading to insulin resistance in adipocyte
4) Adipocyte insulin resistance along with low insulin from fasting leads to complete insulin insufficiency in adipocytes
5) Blindless to insulin removes protection of insulin mediated anti-apoptosis. ( i.e. insulin protects adipocytes from apoptosis )
6) Superoxide production overwhelms antioxidant capacity, eventually leading to apoptosis.












1 comment:

  1. I think you are right here kindke. Many have seen benefits from water fasting, so I have heard. There was also this case http://www.reddit.com/r/IAmA/comments/1o5ndh/iama_guy_who_went_from_430_pounds_to_170_pounds.

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