What is "Fat-mobilizing substance" ???

In reference to the mysterious hormone Kekwick and Pawan talked about in their 1960's era papers. Seriously, does anyone know what this is?

Best & Campbell in 1936 spoke of a substance isolated from the pituitary that would cause liver fat accumulation during fasting, while simultaneously decreasing fat contents of the fat depots ( i.e. bodyfat ).In 1947 Weil et al also confirmed the presence of a "fat mobilizing agent" isolated from the urine of a fasting rabbit, but not the normally fed rabbit.

They describe how injection of this substance caused an accumulation of liver fat at the expense of bodyfat,

A more detailed paper from Kekwick and Pawan 1960 actually goes on to describe a procedure of exactly how this substance can be isolated and extracted from the urine of fasted or carbohydrate restricted humans/animals. Upon injection of this substance, liver fat, blood lipids, and ketones all increase. Surprisingly this substance is also effective at lowering blood sugar. Furthermore, no changes in appetite or food intake accompanies this increased utilization of bodyfat from the injection of this substance.

So in essence, this substance either just straight up increases energy expenditure and/or reduces energy harvest from metabolic fuels.

Below are graphs of bodyweight of mice following injection of this substance, the substance produces a decrease in bodyweight without any significant changes in food intake.

Here is a graph when the injections are stopped after 10 days, NOTE the rapid return of bodyweight?

In the study they confirm the substance is not Corticotrophin, or Growth hormone, although it has similarities with these.

So the question is, what is this substance? Does anyone else know more about it? Has it since been proven to be a hoax?

I and others have commented on how extreme carbohydrate restriction in particular seems to produce rapid loss of bodyfat, and I cant help but wonder that in addition to reduced insulin, that this mysterious substance is also playing a role. The most shocking point is above in Fig 3, I.E. the rapid return of bodyweight after injections cease without changes in food intake. This sounds eerily like the rebound weight gain people experience after a period of lowcarbing when they try to re-introduce carbs into their diet. A re-introduction of carbs according to Kekwick and Pawan's research would shutdown production of this fat-mobilizing substance, and potentially make your regain weight, as in Fig3. with no changes in energy intake.

Thanks to Bill, I was able to get hold of the 1964 study  by Kekwick and Pawan that looked at high-fat diets in mice, at 50% calorie restriction, an 80% fat diet produced substantially more fat loss than a 80% carbohydrate diet, Kekwick and Pawan noted increased excretion of energetic metabolites on the 80% fat diet in the urine including Pyruvic acid, citric acid, and lactic acid. In general they report that urinary carbon increases in response to carbohydrate restriction, I.E. "wasting of energy".

Where fat supplies the major part of an energy deficient diet, there appears to be no attempt to utilize the diminished calorie intake more effectively in terms of supplying the organism with energy. It must therefore provide the whole of the deficiency from its own fat stores. \Vhen carbohydrate supplies the main part of a calorie deficient diet, the organism appears able to utilize the energy to better advantage and the deficiency required to be supplied from its own fat stores is less. On energy deficient diets of equal calorie value the animals are likely therefore to lose weight more rapidly when the calories are supplied in the form of fat than when they are supplied in the form of carbohydrates

One of their ideas for the increased fat loss on the high-fat diet is again the increase in this "fat-mobilizing substance" which is turn causes increased excretion of energetic metabolites in the urine.

So please, maybe someone can chime in here? Is this "fat mobilizing substance" bogus? IS there more to lowcarbing than simply a reduction in insulin?

Dont stop exercising, it makes you fat

Cessation of physical exercise changes metabolism and modifies the adipocyte cellularity of the periepididymal white adipose tissue in rats.

Im still waiting to get the full text of this study but thought id throw up the abstract. The message from this study seems to be that, if you stop exercising, you activate a lipogenic gene profile in adipocytes that seeks to fatten you up.

This lipogenic gene profile seems to go above and beyond what you would of had if you had just been sedentary and never exercised instead. So in this context it looks like, its better to not start an exercise regime at all, rather than start it then stop it later.

If you start an exercise regime, better keep it up forever!

Compared with T, the isolated adipose cells (D rats) showed a 48% increase in both basal and maximally insulin-stimulated lipogenesis

This is as I suspected previously, I.E. that the adipocyte phenotype can control its size independent of numbers calories going in the organisms mouth. ( when I say adipocyte phenotype I simply the mean particular gene expression of an individual adipocyte, and the different ratio's of receptors on its surface etc.)

Mcdonalds in London

Mcdonalds is still very popular here in the UK/london, despite the fact that the vast majority of their calories are highly processed carbohydrates.

I went to my local Mcdonalds near my work during the nightshift recently, just for a change and because I havent had it in years, and even at 9pm at night, there was a queue for the drive-thru aswell as a standing queue of people that spilled all the way out to the entrance.

Everyone "knows" Mcdonalds is unhealthy, but walk into any chain in london and youll see business is booming for them. Ironically, the majority of the people eating at Mcdonalds are slim or only slightly over-weight, and we dont judge them for eating there.. But if we spot a fat person at Mcdonalds, we are instantly like "eeh dafuq? He shouldnt be allowed to eat here!"

I think fast food in general is a booming business, fried chicken shops litter literally every street in london. There is no better business model than cheap, tasty food. The only reason these people running these shops are not making more money is because competition is fierce.

Is it complex, or not? Make up your mind.

Often when reading papers on obesity, authors will quite commonly refer to body weight regulation as "complex". They will say things like, "bodyweight is regulated by a complex system of redundant networks".  etc blah blah

Usually, they will use this type of terminology only when referring to the difficulty of producing meaningful and sustained reductions in bodyweight. Although its also used to explain why bodyweight usually returns to normal after overfeeding studies.

And yet, the very same authors will quite facilely state that obesity is "caused" by over-eating and/or sedentary behavior.

So here we are presented with something of a paradox and contradiction, because, on the one-hand, bodyweight is supposed to be complex regulated system, but, it is easily manipulated by simple CICO, by simply having a bit extra on your dinner plate, or by simply missing your morning workout, you can apparently very easily change your bodyweight.

Nothing is more simple than overeating and being lazy. But apparently  these simple actions can very easily produce large and sustained perturbations in a complex and regulated system. I.E. bodyweight.

Now, how can bodyweight be a regulated, complex  and redundant system if it can be perturbed by such simple stimuli? Doesnt that sound contradictory? Isnt the point of a complex system is that its not easily perturbed? And protected from simple stimuli producing significant changes.

The only way to solve this contradiction is that, one of the premises is wrong. Either.....

1) bodyweight is a NOT a complex regulated system, but is a simple matter of CICO

2) overeating and laziness are not CAUSES of bodyweight changes, I.E. these simple stimuli are not capable of producing significant perturbations in the complex regulated system.

So please, obesity researchers, which is it? Complex or not? Either bodyweight is a complex regulated system or its a simple CICO program.

Can you make up your mind please?











*********************

There is a possible 3rd

3) only reductions in bodyweight are part of the complex regulated system, meanwhile increases in bodyweight are a simple CICO system. If this is true, then beware, because every time you overrate a measly 5 calories, those 5 calories become a permanent addition to bodyfat!

SCFA's inhibit insulin signalling in fat cells

I havent seen this study reported anywhere else in the blogosphere!

The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43.

 Hence, this report also supports our results that suppression of adipose insulin signalling by GPR43 activation leads to prevention of obesity and improves systemic insulin sensitivity.

Look at how blasphemous this statement is, suppression of insulin signalling in adipose tissue prevents obesity.    lol  whha  ??!?!?!?!?!!!!?

Anyway, to cut a long story short, GPR43 is a receptor for short-chain fatty acids including acetate, and is expressed in various tissues including the adipocyte. There was some controversy surrounding the function of GPR43 in adipocytes because in vitro studies had shown that it promoted adipogenesis, but this research group claims to have shown that the in vitro observations of GPR43 do not match those of in vivo.

This study seems to support the nutrient partitioning idea, as GPR43 not only suppresses insulin signalling in adipocytes but improves systemic insulin signalling including in the muscle.

One observation I would like to make however, is that I have tried on numerous occasions high dose inulin for several days/weeks at a time but did not notice a reduction in fat mass.

sigh..............

More on Fat Cell dynamics, - in response to weight loss/calorie restriction

cba today so ima just copy/paste

Adaptation of human adipose tissue to hypocaloric diet

• In a study on type 2 diabetes patients submitted to 1-year dietary intervention combined with exercise, the authors stratified the adipocytes into four subfractions in respect to the cell size.16 At the end of intervention, the adipocyte size was reduced just in subfraction of ‘large’ adipocytes, while the other three remained unchanged.
• investigations suggest that individuals with hypertrophic obesity—who are at higher metabolic risk6, 18, 19, 20—are more responsive to the adipocyte size-reducing effect of hypocaloric diets in comparison with those with small adipocytes, that is, with hyperplasic obesity.
• In another study, using electron microscopy, the response was variable in a group of six patients submitted to 6 weeks’ LCD: in subjects with higher proportion of large adipocytes (hypertrophic obesity), the authors observed a shift from the fraction of large adipocytes towards the small ones, whereas in subjects with higher proportion of small adipocytes (hyperplasic obesity) no shift between the fractions occurred.
• no reduction of adipocyte size in abdominal (but not in gluteal) SCAT was found after 20 weeks’ LCD in one study.15

Lipogenesis

• insulin stimulation of de novo lipogenesis measured on isolated SCAT adipocytes was blunted after 4-weeks’ VLCD.10 However, in weight-maintenance phase, 1–3 years after initiation of the weight reducing program or after gastric banding, both, the basal- and insulin-stimulated, de novo lipogenesis measured on isolated adipocytes were increased when compared with the pre-diet condition.31

Prospective and controlled studies of the actions of insulin and catecholamine in fat cells of obese women following weight reduction.

• Many of the adipocyte abnormalities associated with obesity improve after weight loss [12–15]. Fat cell size decreases, as does basal lipolysis. Insulin and catecholamine actions are improved. However, it is not known if these actions completely return to normal. A full normalisation would suggest that the abnormalities are secondary to obesity. However, incomplete normalisation would suggest primary defects in adipocyte function that cannot be cured by weight loss
• A prominent finding in this study was a decrease in fat cell volume below the control level in weight-reduced obese subjects. Since BMI, fat distribution and body fat content were similar in obese subjects and their controls, the results imply that adipose hyperplasia (at least in abdominal subcutaneous adipose tissue) is a major feature of weight-reduced obese subjects
• This further strengthens the idea that insulin resistance is secondary to obesity, whereas adipose hypercellularity and low adipose lipolytic rates may be primary factors in obesity.
• In conclusion, adipose tissue hyperplasia (many small fat cells) is present in the weight-reduced state and probably explains the low rates of adipocyte lipolysis in this condition. However, adipocyte insulin resistance is a secondary and fully reversible phenomenon in obesity.

You cant select a random obese person from the population then tell him "fat mass is only about CICO", because you have no idea of the amount of fat cell hyperplasia they are suffering from. The more fat cells you have, the fatter youll be, BY DEFAULT.

Why am I posting this? Because I want it to be apparent that people suffering from significant hyperplasia will be unable to resolve their dysfunctional metabolism with diet and exercise alone, despite what you may hear from high standing medical doctors and bloggers. More likely we will need pharmaceutical intervention or in the worst case scenario, surgery.

How can you tell if your suffering from hyperplasia? Well, while I dont have references to back up these claims, I have several ideas. Firstly, the ease with which you rebound weight gain after weight loss will signify hyperplasia. Also the degree to which you are metabolically healthy despite significant increases in weight will signify significant hyperplasia. If you was very heavy but with no clear signs of diabetes = significant hyperplasia.

Also, just look at your fat tissue, is it very "lumpy" with lots of partitions? or is it very roundish and circular? The former = hyperplasia. See pictures in this post for example. The guy in the left most likely has significantly more hyperplasia than the right.

The dissonance of obesity

I was prompted to write this post after watching a guest video by David Pizzaro on the topic of "disgust".

He describes the emotion of disgust as a universal response, i.e. it is similarly present throughout many different culture's, and so this is good evidence that it is hardwired into our biology.

"people seem to have a natural aversion response to things that are gross, i.e. things that might contaminate us or give us diseases"

Obviously the emotion disgust has survival benefits, by making us avoid things which "disgust" us decreases our likelihood of infection. A key point here is "avoidance". Usually, "avoidance" is the primary action we take when our emotion of disgust is invoked. But there are ofcourse other actions we might take depending on how it directly affects us.

For example, imagine you wake up one morning and find a pile of dog shit right in the middle of your doorstep. What action will you take? Now ofcourse, upon first contact, your very likely to experience the emotion of disgust and your natural instinct will be to "avoid" the poop. But there is a problem, it affects you because its on YOUR doorstep. Avoiding it forever is not a viable option. So instead, you will most likely, reluctantly,  clean it up, using plastic gloves ( avoidance again ).

But now lets say one morning you wake up and find a pile of dog shit on your neighbor's doorstep. What action will you take here? It will ofcourse be complete avoidance, you certainly wouldn't clean it up for your neighbor would you? Since its not on your doorstep, it doesnt directly affect you, and so complete avoidance is likely to be the ONLY action you will take.

Anyway, cut to the chase, something which I have long noticed, and cant seem to shake, is that fat people, especially morbidly obese people, seem to invoke the disgust reflex. I cant speak for others, but when I see the severely obese people, I am revolted. This is despite every logical and rational thought telling me that these people are essentially, victims.

When I see a severely obese person in the street the first thought that comes to mind is "how could you let yourself get like that, its gross" But this is not me thinking, its not my conscious logical rational mind coming up with this, but rather this thought is coming deep from the hindbrain.

The question is, why ? WHY does obesity invoke the disgust reflex? Well, if we go back to the definition etc, we know the disgust emotion has been designed to make us avoid things that could contaminate us, infect us, or things that are likely to be diseased. In this light, it seems as if the body instinctively regards the state of obesity as one of disease. We all know that obesity reduces sexual attractiveness, being disgusted by obese people could be one way our biology protects us from mating with potentially poor gene's. 

As an example, physicians are less likely to 'Bond' with overweight patients. Why is that? Does the state of obesity in the patients subconsciously invoke the disgust reflex and subtly guide the physicians to action "avoidance" with them?

'Most' of us who has studied the subject of obesity intensely know all too well the truth. I.E. that obesity is a disease. Something about the adipose tissue has malfunctioned. The dissonance part is what I find interesting.  I.E. the dissonance between our bodies instinctively regarding obesity as a disease and the idea that "over-feeding" causes obesity.

The dissonance is that I believe that these 2 points ( i.e. obesity being a disease and simultaneously being caused by over-eating ) are evolutionary incompatible.

In an uncertain, unpredictable, and aggressive world, it should be advantageous to have access to a large of amount of calories. Having a consistent and bulky supply of nutritious food would surely be of benefit to those organisms who can access it. You might even expect this advantage to propagate and advertise itself through the organism by having the organism display a physically and sexually appealing phenotype. Afterall, we all know that emaciation is a massive sexual turn off.

And the more, the better, right? I.E. The greater the quantity of nutritious food we have access to, the more likely it is that we should survive in a harsh world. Right ? And we should advertise that increased chance of survival through consumption of that food which will gives us a physically pleasing phenotype.

But here's the paradox, because apparently, taking advantage of that large cache of food and consuming it leads ( allegedly ) to the state known as obesity, which accordingly, decreases our chance of reproduction through reduced sexual appeal, aswell as ( again, allegedly ) predisposing us to a whole host of other ailments that reduce our chance of survival.

If you believe that over-eating causes obesity, then essentially what your saying is that,  paradoxically, having access to and taking advantage of large caches of food which would normally increase an organisms survival, actually leads to a state that reduces survival and chance of gene propagation.

Having access to something which normally increases your survival, actually, decreases your survival if that something ( food ) is overindulged in.

Does that make sense?

Remember that our biology regards the state of obesity as a disease. So its almost like saying your body regards the state of having access to large quantities of food as a disease.

hhhhhhmmmmmmmm.