Monday, 30 May 2016

I passed my driving test ....... but im still obese!

Thanks to all the public transport links in london I havent needed to have a car or pass my driving test for quite a number of years, im now 34 and finally decided to get it done.

I took an intensive 6 day course for manual transmission and managed to pass my test on the 7th day with 6 minors. I have no prior driving experience, but my instructor was very good all credit to him.

The point being, I had to put in ALOT  of effort, skill, willpower, concentration to learn to drive and pass the test. Especially in such a short amount of time. And I managed it in 6 days.

Meanwhile, I have been trying to diet and get lean for alot longer than 6 days, infact you could say my whole life! I never been in the normal BMI category I was the fat kid at school too.

If I was too take a "dieting test" it would be fail fail fail fail x 1000000




So the question is, why is it I can do a complex willpower thing like learn to drive in such a short amount of time but keep failing miserably to get normal BMI?

The answer is because the former IS mostly under my control, and the latter is not. As much as the diet and exercise industry and guru's would like you to believe you can achieve and sustain weight loss with deliberate intervention, the reality is that you cannot, because weight is largely NOT under your control.

While operating the mechanics of a car ....is.


Sunday, 29 May 2016

adipose controls appetite

Compensatory growth of adipose tissue after partial lipectomy: involvement of serum factors.

Abstract
The regulation of body weight/fat was studied by investigating mechanisms for compensatory adipose tissue growth after removal of bilateral epididymal fat pads from male adult Wistar rats. Food intake during the first 4 weeks and energy expenditure on Days 8-10 postsurgery were not different between lipectomized and sham operated rats. During Days 29-31 post surgery, a small (2.4%) but significant (P < 0.05) increase in heat production per metabolic body size was detected in lipectomized as compared with sham operated rats. The carcass composition of lipectomized and sham operated rats was not significantly different 16 weeks after surgery. The compensatory growth was fat pad-specific: mesenteric, retroperitoneal, and inguinal fat pads, but not perirenal fat pads, were heavier in lipectomized rats than in sham operated rats as early as 4 weeks postsurgery. Examination of fat cell size distribution in the compensating pads indicated a shift toward larger cells in retroperitoneal fat, but not in inguinal fat of lipectomized as compared with sham operated rats. Serum from lipectomized rats, but not media conditioned by exposure to retroperitoneal fat pads from lipectomized rats, stimulated proliferation of preadipocytes in vitro more than that from sham operated rats. Thus, compensatory adipose tissue growth after lipectomy may be mediated, in part, by blood-borne factors that are derived from tissues other than adipose tissue.


Food intake and energy expenditure measurements
focused on the early period up to 4 weeks postsurgery
and did not detect measurable increases in food intake or
decreases in energy expenditure that could account for the
lipid deposition associated with compensatory growth.

lol CICO?


Relationship of adipocyte size to hyperphagia in developing male obese Zucker rats.


Abstract
In growing male obese Zucker rats, hyperphagia reaches a maximum or "breakpoint" and declines at an earlier age with high fat than with chow-type diets. A serial adipose tissue biopsy technique was used to correlate changes of retroperitoneal adipocyte size and feeding behavior in 5- to 7-wk-old male lean and obese rats fed laboratory chow or a 35% fat diet until 30 wk of age. Although chow-fed groups had significantly greater cumulative intake, fat-fed groups had significantly greater body weight gain, retroperitoneal depot weight, and adipocyte number. Mean adipocyte size increased continuously in chow-fed groups but decreased over weeks 20-30 in fat-fed groups, reflecting increased adipocyte number. In fat-fed obese rats, hyperphagia reached a breakpoint at 11 wk and disappeared by 13 wk. In chow-fed obese rats, hyperphagia reached a breakpoint at 15-16 wk and disappeared by 19 wk. Biopsy samples revealed that adipocyte size of fat-fed obese rats was already close to maximal at 10 wk (1.12 micrograms lipid), while that of chow-fed obese rats only approached maximal at 20 wk (0.81 microgram lipid). At these time points, lipoprotein lipase activity paralleled adipocyte size. These data indicate that the duration of the growing obese rat's hyperphagia coincides with adipocyte filling and suggest the existence of feeding stimulatory and inhibitory signals from adipose tissue.


So again more evidence adipose tissue is controlling appetite and since this is in zucker rats something other than leptin is involved.













Thursday, 12 May 2016

Why do obese regain weight ?

http://www.nytimes.com/2016/05/02/health/biggest-loser-weight-loss.html?_r=0

I suppose this question has been done and answered to death, including here on this blog, but theres a very very simple reason why obese people regain weight, and its EXACTLY the same reason that they got to their obese state in the first place.

I recently watched this excellent video by  Brian  who describes his theory of the "sponge syndrome" which is basically just another way of phrasing what I have been trying to say here on this blog. I.E. obesity involves recruitment of stem cells in adipose tissue called "pre-adipocytes" which morph into fully mature adipocytes and accumulate fat. And diet/exercise DOES not cause them to un-morph back into fat-less stem cell preadipocytes.

The reason reduced obese regain weight is exactly the same reason they got fat in the first place, with induction of adipogenesis in pre-adipocytes, ( adipogenesis being the phrase meaning the pathway of a pre-adipocyte morphing into an adipocyte ) the activity and load of enzymes involved in triglyceride synthesis increase massively, its been described here

When cells of the established preadipose line 3T3-L1 enter a resting state, they accumulate triglyceride and convert to adipose cells. The adipose conversion is brought about by a large increase in the rate of triglyceride synthesis
and this 

Glycerophosphate acyltransferase activity rises sharply during the conversion and reaches a level of 80 times higher than that of another 3T3 subline in which practically no adipose conversion takes place

And I blogged here about this.

So... a pre-adipocyte stores no fat....  CICO is irrelevant

Suddenly adipogenesis pathway activated, lipogenesis gene's switched on, Glycerophosphate acyltransferase activity rises, and Triglycerides accumulate........ again CICO irrelevant.

Go on a diet and exercise heavily, empty most of your fat cells to a smaller volume, but guess what, the excess adipocytes are still there, and because the excess number of adipocytes are still there.... excess amount of Glycerophosphate acyltransferase activity IS STILL THERE.

So guess what happens with time as Glycerophosphate acyltransferase activity remains elevated? Triglycerides ( fat ) accumulates again, and you regain weight.

Its really not hard at all.

P.S. I know Glycerophosphate acyltransferase is not the only enzyme involved in trig synthesis etc. Im just picking it out as an easy to understand example.







Sunday, 1 May 2016

The truth about obesity - and my weight loss recommendations

Everyday I read more bullshit and stupidness from people who are suppose to be clever and well researched about obesity, including doctors and research authors themselves. Your all wrong. You dont know jack fuck shit.

Having said that, there are a handful of lab guys out there who kinda know what they are doing and it is from their studies that I have gained the most insight and formed my own conclusions.

- obesity has an extremely large genetic component, and the analogy I like to compare it to is tanning, the response to tanning is a graded scale due to genetics and MC1R polymorphism, likewise Im pretty sure the susceptibility of pre-adipocytes to differentiate into fully mature adipocytes probably also has a graded scale.

- overeating is not the "cause" of obesity, signal transduction in pre-adipocytes to differentiate and high insulin are the causes of obesity.

- obesity is basically a "growth" of the adipose tissue depot. exactly like a mole on the skin is a growth or the growth of breat tissue in males as gyno. the reason adipose depots are large and heavy and store fat is because thats what adipocytes do, their chromatin is unraveled to expose gene's that synthesize large amounts of triglyceride and package it in central lipid droplet. Uuder-eating may temporarily reduce the amount of triglyceride an adipocyte can hoard, but it wont last, the solution is to dedifferentiate or kill the adipocyte

- obesity is best thought of as a disease of excess fat retention. That last word being absolutely key.

- obesity is largely irreversible because it is a growth of the tissue, tissue growths are permanent in most cases i can think of.

- starving yourself or cutting calories is futile, neither of these mechanisms have been shown to cause adipocyte dedifferentiation or apoptosis. It will shrink adipocytes from their hypertrophic state, but that is all.

- fat people eat more because they have more adipose tissue to feed. This is back to Taubes logic and it is correct, people eat more because they are getting fat.

- fat people have higher energy expenditures because they have more tissue, and this is another reason they eat more, they are eating enough to satisfy their higher energy expenditures.

- obesity resistance is real, just like tanning resistance is real. There is no such thing as will power when  it comes to controlling eating, if you think otherwise, take a shot of GHRP6 and try to stop yourself eating.

- weight regain after dieting is the norm because the adipose tissue depot genetic profile remains intact, The size of an adipocyte is determined by the epigenetic configuration of its adipogenic gene's, such as PPARg,  glut4, caveolin-1,  SREBP1c ,   etc.  Adipocytes do not accumulate fat indefinitely, they accumulate as much as the adipogenic gene's dictate and then stop, this is why adipocytes incubated under identical cultures come out all different sizes.

- insulin causes adipocyte hypertrophy aswell as differentiation of pre-adipcoytes, this is why its the key hormone to control.

Weight loss Recommendations

Keeping in mind that weight loss is extremely difficult and maintaining that weight loss is next to impossible, but if you still want to have a go my recommendation is basically atkins with some intermittent fasting and weight lifting in the gym.

- minimize insulin secretion, low carbs but also watch the dairy, cheese , cream, butter is ok, milk and yogurt and even whey should be avoided.

- stick to whole foods with minimal processing.

- small amounts of fruit is ok, no bananas though.

- high protein, I dont recommend low protein at all even if its ketogenic, forget about ketones, the goal of fat loss is to minimize insulin signal transduction in adipocytes, this also allows higher beta-adrenergic signal transduction which is what causes the weight loss!

- protein is important for satiation, another reason to keep it high, Hungry dieters will be unsuccessful.

- intermittent fasting helps but low carbing gets your most of the way there. 8-16 is fine imo.

- try to go to the gym and lift weights, HIIT style exercise is also good.

If you stick to all these points and still find yourself fat or failing to get to your goal weight, its not your fault, you have just created so much fat tissue growth that its not reversible,  only liposuction will help.

-

Friday, 25 December 2015

Do these people need to go on a diet?



And if so, what diet should they go on? Should we fast them? starve them? low-carb them? haul them to the gym?

Also, what kind of increased fatness are they appearing to suffer from? adipocyte hypertrophy? hyperplasia? ( I suppose the one on the right is quite typical of what you would find in western women these days )

How did they get like that? Did they eat too much? Exercise too little?.......   Think about what kind of initial "intuitive"  judgement youd pass on these people.





The picture was pulled from this paper  where the subjects have a genetic condition referred to as "cohen syndrome".   But you didnt know that from just looking at the picture. I bet you just thought they ate too much , or maybe too many carbs?

What I find interesting is how they could just pass for normal random fatties by todays public standards, despite the fact the have an underlying genetic condition that makes their preadipocytes more sensitive to differentiation into mature adipocytes, they appear quite symbolic of the kind of increased fatness you can expect in "normal" people.

Even more interesting, I expect youd be less inclined to recommend "lifestyle" interventions to these people now you know they have a genetic condition, yet "lifestyle" interventions are recommended to normal obese people everyday despite the fact we are all suffering from the same condition, I.E. excess preadipcoyte recruitment. When it comes to obesity, it seems we are more inclined to prescribe treatment that is dependent on how we view the causality to have progressed.

Got fat by eating too much/exercising too little/ too much carbs? -> solution is to cut cals/carbs/exercise more! Trying fasting for a month maybe.

Got fat by having an underlying genetic condition ???? -> hmm probably need medical intervention.

Anyway I want to talk a bit more about what exactly is increased adiposity. Lately I have been reading more on adipocyte differentiation / adipogenesis, and I really feel this is primarily whats happening in all forms of obesity regardless if it is genetic or ,  :cough:,  "lifestyle" induced.

I wrote a another post on this idea here   I think theres probably a few people in the literature that also think hyperplasia is the primary thing in obesity.

Adipogenesis, the differentiation of precursor cells into mature, terminally-differentiated adipocytes, occurs throughout the human life cycle and is believed to be the primary cause of increases in body fat.*

If preadipocyte recruitment is the primary lesion in increased fatness , this ties together so many loose ends, It fits in with bauer's "lipophilia" hypothesis, and helps explain why obesity is persistent, ( dieting probably doesnt cause adipocyte de-differentiation )

Personally I think low-carbing only works to solve the adipocyte hypertrophy part of obesity, that part of your increased bodyweight that is due to insulin induced hypertrophy rapidly resolves upon low-carbing, but the part of your increased weight that comes from new pre-adipocyte differentiation is ""sticky" and doesnt resolve after lowering your insulin.**

I always make the analogy with MT2 and freakles/moles, with super levels of melanocortin receptor agonism I differentiated additional stem cells in my skin into melanocytes but they didnt go away when I stopped MT2. Similarly with super levels of insulin from carbs I differentiated additional preadipocytes into mature adipocytes that dont go away when I lowered insulin with low carb.

Is there any hope?

I remain highly pessimistic but anyway, another paper caught my eye recently.. Now I didnt know this but apparently most in vitro work on adipose study is done with newly differentiated preadipocytes, and the reason being because mature adipocytes harvested from living organisms rapidly undergo de-differentiation in cell culture.

That is, they turn back into preadipocytes and relinquish their lipid hoard ( I.E. you lose wt )  and regain their ability to differentiate into other cell types.

Since adipocytes are terminally differentiated, they can be used immediately for test purposes.6 
Several studies have been performed to establish the isolation and characterization of mature adipocytes in between the 1960s and 1990s.7–10 Since then, mature adipocytes were only rarely used, probably because of their mainly cited drawbacks such as vulnerability and dedifferentiation under in vitro conditions. 
It is well known that these cells start to dedifferentiate after 1 or 2 weeks,7,11,12 at which point, the cells reach a multivacuolar morphology while they are diminishing their cell volume.9,13 Elongated, nonlipid filled dedifferentiated fat cells (DFAT) are further able to proliferate and exhibit multilineage potential.14,15 These cells are known to express stem cell markers, such as CD73.

My earlier work on adipocyte apoptosis was probably a bit pointless now as I realize its probably not necessary to kill excess fat cells with apoptosis but rather just make them de-differentiate back into their preadipocyte non-lipid filled state.

Easier said than done though I suppose ! So the big question is if we can get fat cells to de-differentiate so easily in cell culture how can we do it in vivo and lose weight?

I dont know the answer and neither do the authors, although they mention that agents/hormones that promote lipolysis seem to be facilitating de- differentiation this is just speculation, and I'd be quite surprised if the reason adipocytes de-differentiate just because they lose lipid from increased lipolysis, and more likely the agents/hormones are causing epigenetic chromatin changes to the adipocyte gene's, re-coiling up those parts of the DNA and silencing those adipocyte markers.

adipocyte dedifferentiation in pubmed yields 141 search results. its not a well studied area, and perhaps thats why we still have an obesity epidemic.

* I need to check his references to make sure they actually support that statement

**I think its possible that some adipocytes may de-differentiate while dieting, I cant rule things out without experimental data, I think we have to assume though that most people dont experience this as when dieting they reach a plateau.






Saturday, 3 October 2015

Does adipose tissue determine appetite?

Ive long held this belief that it does.

That, somehow the adipocytes drive to keep itself "filled" will not only alter systemic hormones and calorie partitioning to accomplish this but also drive the host to eat more.

I think this goes much beyond leptin, which is not an "anti-obesity" hormone that many people still think it is ( leptin resistance is a hoax lol, get over it ) but rather it is an anti-starvation hormone. Leptin becomes important when your deficient, and that is all.

A quick shout-out to Bauer's 1940 paper OBESITY , ITS PATHOGENESIS, ETIOLOGY AND TREATMENT,

I know, you might be thinking, "lol this paper is from 1940! we are much smarter "now" and have advanced much in the research and knowledge "now" ". ..... HAHAHA

Well youd be damn wrong. Read the damn paper. If you think your "smarter" than people that were around in the 1940's or earlier just because its "ancient history" , seriously, think again.

Anyway, I want to do a more formal post on bauers paper but I think it would be alot of work also it is not easy chasing his old references. Suffice to say he brings up alot of interesting points regarding obesity and dismisses the CICO idea, he puts forward the lipophilia hypothesis ( which is what I actually believe is the cause of obesity* ) This lipophilia idea is basically that it is the adipose tissue itself, factors intrinsic to the adipocyte, that determine its "drive" to store fat and that is the reason people become (maintain ) obese. Due to intrinsic factors, the adipose tissue not only is more willing to suck up and store fat, but it is simultaneously less willing to release that stored fat.

Infact this idea is a good fit with the observed fact that the vast majority of obese people who attempt to lose weight end up rebounding back to their starting weight and this even occurs in bariatric surgery though to a lesser extent. If we accept the idea that the adipose tissue has its own drive and blueprint for the size and shape its suppose to be ( determined by intrinsic factors like cell number, genetics, histone/methylation status etc ) then it makes complete sense why virtually everyone rebounds.

Theres plenty of evidence for the "lipophilia" hypothesis, adipocyte hyperplasia, cathecholamine resistance, I.E. adipocytes resist release of stored triglyceride, this study was another example where the average half-life age of triglycerides is increased in obese suggesting their fat cells like to "retain" fat. A 2008 study also found increased cavolin-1 in adipose tissue of  obese, this is something that is much less known about in the diet and fitness industry. Cavolin-1 helps make caveolae in adipocytes which are basically little docking harbors for nutrients to enter the cell, although I prefer to think of them as calorie uptake suckers.

A dramatic increase in the cell surface expression of caveolae is what happens when a pre-adipocytes morphs into a mature adipocyte and almost certainly is what facilitates the massive increase in lipid storage that occurs in the transformation. This is probably what they were observing in this 1983 paper when they state      ... quote...
 a ninefold increase in small invaginations as the cell differentiates from the fibroblast to the adipocyte phenotype;

ok enough of that , just read bauers paper.



Back to the topic of this post, which relates to this paper  they didnt know about leptin in 1977 but they had strong reason to believe that body weight and fat mass was "regulated" around a certain point. The reason for this paper was the continuing investigations into compensatory adipose growth that sometimes occurred in rodents with surgical removal of their adipose depots. In some cases, surgical removal of some adipose depots caused enlargement of the remaining ones so that total body wt stayed close to that of intact controls. Hence giving rise to the notion that wt is "regulated" to a certain value.

In this study, they cut out a large portion of the epididymal fat depot aswell as some of the subcutaneous inguinal fat depot, ..... THEN ...... they split the rats into 2 groups, chow diet and high fat diet.

On the chow diet, as expected, there was compensatory growth in the un-touched fat depots of the lipectomized rats such that their fat mass got to a level similar to intact controls.

However on the high-fat diet something unexpected happened, the lipectomized rats ate less than the normal rats on high-fat and ofcourse ended up with less total fat mass.



The cause/effect direction of the results of this study are open to "debate" but the crux is this, why did the lipectomized rats on the high-fat diet eat less and gain less fat than the high-fat controls?

If you assume that they gained less fat BECAUSE they ate less, your still left with the corollary that removing adipose tissue reduces appetite. I dont see any way around this conclusion.

Alternatively, you could take the taubsian stance and postulate that they ate less BECAUSE their adipose storage capacity was reduced. ( or rather their potential for adipose growth was reduced. )

Either way, your stuck with the inescapable suggestion that adipose tissue controls appetite.




* - about the asterisk above, I wouldnt say that the lipophilia is *the cause* , but rather , it is what is responsible for the maintenance and persistence of the obese state. I still believe that the cause and triggering event is high glucose and insulin concentrations.







Monday, 27 July 2015

Cryolipolysis gone wrong

Cryolipolysis is relatively new method of getting rid of excess subcutaneous fat. It works by freezing the localized area to 0C for about 1 hour.

The way this works is that lipids in the adipocytes freeze a bit sooner than water, basically you can trigger an apoptosis pathway in the adipocyte before the freezing causes significant local damage to all the other tissues.

"Crystallization of cytoplasmic lipids within the adipocytes initiates a cascade of events, characterized by adipocyte apoptosis, panniculitis, and eventual loss of adipocytes. Clinically, this translates into an effective decrease in fat layer thickness"

The fat gradually "melts" away 2-3 months post treatment as the adipocytes undergo apoptosis, however, there are some rare case reports of the opposite happening, where the treatment site initiates an increase of fat mass via hyperplasia,. The main article is here..

Whats interesting is that the fat growth hyperplasia is restricted to the treatment area. If the patient had gained weight in a more evenly distributed pattern over his body, the doctors would accuse him of eating too much and exercising too little. Its things like this where hopefully intelligent people will start to wake up and realize that the CICO model of fat mass has to be wrong.

If we couldnt apply the CICO model here, why can we apply it in more generalized obesity?

The caveat is ofcourse that we cant apply the model of systemic hormonal control of fat in this situation either.



The only possible way to explain the localized growth of the fat is to look at localized factors, I.E. the tissue and cells there. The treatment had obviously caused some kind of change in the gene expression patterns of the cells in that area and/or initiated an adipogenesis program to the pre-adipocytes in that region.

Recall from my previous posts, that once a pre-adipocyte morphs into a mature adipocyte its guaranteed to store fat, regardless of food intake, exercise, insulin, leptin, etc  once the activity of lipogenic enzymes increases and the cell surface gains significant caveolae, the jig is up.

The how and why of why the cryolipolysis causes this is a mystery at this point in time. The only clue seems to be that its more common in male patients, but the sample size might still be too small.

As an aside, it seems the incidence with which this happens may also be under-reported, the first paper estimated the cases to be  0.0051%. while a revision put the number closer to 0.47% or 2 in 422.