With that apology, I think it's time to discuss this paper.
So now we have the FIRKO mouse. This mutant mouse has been cleverly engineered to fail to express insulin receptors on its adipocytes. Everything else is normal. Functionally the adipocytes are severely insulin resistant. It does not matter how much insulin the pancreas secretes, adipocytes will not, cannot, listen to it. You know the rules. The function of insulin is to store dietary fat in adipocytes. In the almost complete absence of any insulin receptors on any adipocytes, this just ain't gonna happen. So FIRKO mice stay slim, slightly slimmer than a control mouse, and live a bit longer. All on CIAB and without cutting calories of course.
They also fail to develop age related insulin resistance. Please note as a complete aside; those mice on F9, boring old low fat CIAB, do develop age related insulin resistance and glucose intolerance. Wanna stay as healthy as a mouse on F9 with age acquired insulin resistance? Go ahead and eat low fat, about 10% of your calories will do. Try not to get too bored.
I could stop here with this comment from the authors:
"Our data further show that insulin signalling in adipocytes is crucial for triglyceride storage and the development of obesity and its associated metabolic abnormalities"
It would be fun to just thumb your data at those fixated on the central effects of insulin but that would be leaving a whole can of worms unopened. You know how it ticks you off to get partial information on a given study. The selective information rationing typical an obesity researcher. The data are actually quite complex.
Let's get a tin opener.
Sooooooo, what if you take a FIRKO mouse and inject it with gold thioglucose? Obviously you will bust its VMH. You could equally use a electrical ice-pick or a big meal at a Chinese restaurant (jk).
To summarise the last post: This injury increases the ability of adipocytes to divert calories away from metabolism and in to storage, by an increase in their sensitivity to insulin. Fat should simply pour in to the adipocytes of a VMH injured rodent and they should start eating big time. You could be forgiven for thinking you had removed their brain satiety centre or upped their fat set-point.
But the FIRKO mouse has very few insulin receptors on its adipocytes. The brain can scream, shout and have a temper tantrum to demand fat storage. Adipocytes stay cool as a cucumber and don't even give the finger to the brain. Pure ignore-ance. The brain has lost its tool for fat storage. You know the one, the tool which stops you being hungry (snigger) and helps you lose weight (sigh). Insulin.
Now let's look at some of the graphs. We'll start with the supportive one:
We can ignore the middle two columns, they're from different knockout mice. FIRKO mice with a gold thioglucose brain injury (right hand column) weigh the same as, or even a non significant smidge less than, WT mice (or FIRKO mice) without a gold thioglucose injury. Now that's no surprise. Brain:Adipocyte:Insulin.
But there is a shock in store. Here's the next graph, the columns are the same:
FIRKO mice eat MORE if they are injured by gold thioglucose than if they aren't. They eat almost exactly the same extra food as a wild type gold thioglucose injured mouse. While staying slim, of course. But they do eat more.
Does this mean that the VMH really controls appetite rather than the ability to divert calories to fat storage?
FIRKO mice have markedly reduced insulin receptors on both white and brown adipose tissue. The consequence of this on white adipose tissue is simple, insulin causes fat storage, lack of receptors limits fat storage. BAT is more complex. We do have a BATIRKO mouse which has had the insulin receptors knocked out on its brown adipose tissue only. This leads to combined atrophy of BAT (the normal lipid droplets in BAT never form) with marked up regulation of UCP1 production. They stay slim compared to controls while being fed CIAB (aside: although slim they do eventually become diabetic, the reasons for which are utterly unclear to anyone, see the discussion). As the authors comment on "normal" BATIRKO mice:
"Interestingly, the lack of IR leads to the over expression of the UCP-1 and also UCP-2 in the remnant BAT from BATIRKO as compared with controls. These data could be interpreted as a form of compensatory mechanism for the brown fat lipid content and mass loss observed in BATIRKO and may result in a potential increase in the thermogenic capacity of the remnant BAT that may account for the lean phenotype of BATIRKO mice compared with controls"
A lack of insulin receptors on your BAT up regulates thermogenesis. This has nothing to do with the brain and everything to do with the periphery. Why should thermogenesis be increased by VMH injury? I don't know. The control of BAT is complex and I don't think the work has been done yet. There are hints that insulin reduces UCP1 production in mice, bringing us back to changes in insulin signalling and thermogenesis. You might expect a system which activates fat storage might turn off fat burning and vice versa.
At the moment, for FIRKO mice, it looks like an open question as to whether gold thioglucose VMH lesions really increase appetite directly or increases thermogenesis in BAT causing a calorie loss, with compensatory hyperphagia. You can imagine which option I think may be the case, but I do have certain biases.
It's frustrating that there is no information to follow through on this. The group's last publication on the FIRKO mouse was in 2007 and was interesting in its own right.
The FIRKO mouse has white adipose tissue which, with age, gets to have better and better mitochondria. Probably more of them too. The authors talk about increased whole body oxidative metabolism but don't seem to consider BAT seperately from WAT... But having your adipocytes live in [what to them is] an hypoinsulinaemic environment seems to be rather good for them. And the mouse
Anyway, summary:
Remember what is special about FIRKO mouse is that its adipocytes never see insulin, whatever the blood insulin level. Lacking IRs on all of your adipocytes keeps you slim, keeps your insulin levels low and extends your life expectancy by about 18%. It gives you shiny new mitochondria in your adipocytes as you age. If you are a mouse.
It it possible to mimic this state in non-FIRKO mice?
Perhaps it's time to revisit ketogenic diets in mice. Oh, and cirrhosis too.
Peter
78 comments:
Peter -- always nice to hear what you have to say. Super interesting ... and sure makes me think that keeping my insulin levels low (low carb) is so a good idea, even if I am not a mouse.
Beth
Peter,
In the comments to your previous post, I've cited a study which shows that calorie loss to muscle mass or increased insulin sensitivity of muscle mass reduces appetite relative to control.
Cheers, Nige.
Nigel,
Just replied. Nice to see that we just need a little exercise.
Peter
I don't know how reasonable people can read things like this and still believe that obesity has nothing to do with insulin signalling in adipocytes and is entirely controlled by the brain.
What I find most fantastic is the fact that the VMH damaged mouse with adipocyte IR knockout still eats quite a lot.
In straightforward VMH damage, the mouse eats and then begins to eat less as the fat stores increase. More than in tact WT mouse but less as compared to the pre-obese stages of VMH injury.
This suggests some PRODUCT of fat cell size, number, plus insulin signalling, is combined and required to terminate / reduce appetite in VMH damage. I wonder what that might be. Fatty acids? Once fat tissue reaches a certain size, FA levels are increased and appetite is somewhat reduced/compensated for?
I would suspect, perhaps, VMH injured / adipocyte IR knockout mice have very low FFA and glucose. This is because their fat cells are small, so do not release much FFA, and their liver is suppressed by high insulin levels, and so does not make much glucose and FA. I am assuming they have high insulin levels (due to a lack of receptivity of fat tissue)... but they may not, if there is another option for shunting energy excess (which they are consuming)... such as UCP1. The upregulation of UCP1 may spare these hyperphagic rodents of hyperinsulinemia and obesity both.
If the VMH merely regulated appetite, then VMH rodents would never decline appetite in response to growing fat stores, but they do after insulin signalling grows their adipose to a certain size.
Perhaps the augmented appetite in VMH + IR knockout is related to some other effect, such as screaming UCP1 from BAT. If a significant portion of my dietary energy was flying off of my body into the atmosphere, I would probably eat a lot too. Inverse, but similar, to the pure VMH injury where dietary energy is flying INTO the adipocytes.
Oh, this effectively settles the debate:
Does the brain control adipose, or does adipose control the brain?
It's pretty obvious the fat tissue has the final say. No IR? No fat. End discussion.
Brain only causes fatness if you destroy centers which are CRUCIAL for adipocyte feed back; e.g. leptin receptor or the hypothalamus. Then the brain operates as if it had low/no fat tissue at all and exhibits a non-terminating starvation syndrome.
THE HIERARCHY:
The adipocyte controls the brain (leptin, mainly, but also FFA and glucose and insulin which are all elevated as the fat stores increase).
Brain controls behavior.
Behavior modulates insulin (food seeking/activity).
Insulin controls the adipocyte (size/fat content/number)
Return to point 1.
This is the only way it could be, and the only reason we are all here on the internet talking, instead of long extinct.
Anyone arguing for the hierarchical importance of the brain has spent too long with mutant strains of rodents that have very little relevance to real world common obesity.
Kindke,
donny, who comments here sometimes, has written about it on his blog [naivenutrition].
I believe he said it made him a bit manic, but Emma of Plant Poisons has said it did the opposite for her (by affecting glutamate). I don't know about other effects.
@Woo,
I'm pretty sure appetite control predates the brain by a few hundred million years.
Caenorhabditis elegans (a nematode) doesn't have a brain but it has an appetite.
Epic post Peter, thx for good laugh, especially for a BATIRKO mouse :D
I have to wonder now, is there any chemical that can make you more FIRKO like and what percentage of obese persons that failed any therapy have higher insulin sensitivity in adypocites. This would confirm this in more realistic scenarios then knock out.
I searched Schoolar and as interesting found that CLA(http://goo.gl/udI27) for which we have obesity related review (http://goo.gl/zThsH), Fish oil (http://goo.gl/3CPzM) which is known to be good for obesity, and even Nelfinavir(http://goo.gl/6UlSN) with known side effect of peripheral lipodystrophy.
This also showed up:
"Adipocyte insulin resistance: effects of aging, obesity, exercise, and food restriction"
where they say:
"Sedentary free-eating (SFE) rats were obese and their fat cells were extremely insulin resistant, showing minimal increases in glucose oxidation and 2-deoxy-D-glucose (2-DOG) uptake in response to high insulin concentrations. The runners' adipocytes were smaller and had a greater responsiveness to insulin (approximately 9-fold for 2-DOG uptake and approximately 30-fold for glucose oxidation) than those of the SFE rats. Sedentary rats that were food restricted to keep their body weights the same as those of the runners had fat cells that were intermediate both in size and insulin responsiveness relative to those of the SFE rats and runners."
and
The Role of Adipocyte Insulin Resistance in the Pathogenesis of Obesity-Related Elevations in Endocannabinoids
Our findings suggest that insulin-resistant adipocytes fail to regulate EC metabolism and decrease intracellular EC levels in response to insulin stimulation. These novel observations offer a mechanism whereby obese insulin-resistant individuals exhibit increased concentrations of ECs.
which is somewhat opposite to what we have with FIRKO mouse model. Can you comment on those ?
I personally believe that endocannabionids are involved , based on well known munchees related to high THC and low CBD content weed.
Here is another review (http://goo.gl/YNN7q) on CLA which says in conclusion:
In summary, CLA reduces weight gain and fat deposition in rodents, while produces less significant and inconsistent effects on body weight and composition in pigs and humans
which combined with FIRKO study makes sense but gives a doubt that mechanism might not be in effect for humans?
@blogblog This is actually a very good point, seems to escape guyenet and the majority of obesity researchers who believe the fat tissue is a reflection of the brain. Even in worms, propensity to future feeding is controlled by nutrient signals from a prior history of feeding such as insulin.
I imagine they would argue that in complex animals like human beings, we have evolved to where behavior and will prevails over food and fat tissue feedback. In which case, we arrive right back to the gluttony and sloth hypothesis, in spite of the protests that food reward is not this at all.
Acidophilus converts glutamate to GABA; so here we have another possible interaction between microbiota and appetite. Does the Chinese diet promote acidophilus (or other GABA-producing microbiota)? This would account for MSG tolerance.
In a beehive, most of the honey is consumed by a minority of the bees, which specialise in providing warmth by running at a higher metabolic rate than the others, fidgetting as it were.
This is essential for the development of larvae.
So fructose is good for something; driving bees, and spermatozoa, into hyperactivity.
Nice post. Thanks for keeping me on my toes. With all the discussion these days re: "insulin drives fat storage, etc." versus "no it does not, etc.," I can never get comfortable -- there's always another interesting point just around the corner.
I've upped my carb intake to accomodate my high level of activity (after crashing a bit from 9 months or so of vlc) -- but if it weren't for my fasting most of the day, I still don't know how comfortable I am with carbohydrate throughout the day, that is, in a sort of continuous stream (irrespective of the amount; as a matter of # of spikes a day). Anyway, still trying to figure it all out but there's plenty of food for thought.
Prader-Willi patients have an completely insatiable appetite due to congenital damage to the hypothalamus. However the appetite becomes manageable on a ketogenic diet.
Am. J. Clin. Nutr. 23: 667, 1970.
Ketogenic diet and Prader-Willi syndrome.
Nelson, R.A., Hayles, A.B., Novar, L.P. Margie, J.D., Vernet, J.M.
http://www.pwsdots.org/w/index.php?title=Nelson_1970_-_Ketogenic_diet_and_PWS
@George,
many western foods are very high in MSG including stock cubes, Bonox and many fermented foods. Vegemite (Marmite/Promite) is basically pure MSG. Yet somehow it doesn't seem to cause any of the problems that MSG allegedly does.
Unless you are baby who eats massive amounts of MSG strait from the packet there is no real problem.
I'm confused. How come BATIRKO mice (which have fully functional WAT) become diabetic, whereas FIRKO (i.e. BATIRKO and WATIRKO) mice don't. That doesn't make sense!
Nigel, no it doesn't make sense. Knocking out BAT with diptheria toxin linked in with the UCP1 gene does the same thing, but the mice become overweight as well as diabetic. That mouse has zero BAT, the BATIRKO mouse has minimal-but-hyperactive BAT. But both become diabetic. Confusion is an admirable approach.
blogblog, immense thanks for the P-W link, even of it is only an abstract of a pilot study. I suspect that full ketosis is needed to control appetite in these people, hence the child for whom ketosis didn't work (the one with the lowest ketone excretion?). I remember being seriously chastised for using a mean and SD to describe three data points!!!!! Just the numbers would have been great. Interesting the Down's syndrome child improved too. This approach should work for ob/ob mice too.
George, for most people the BBB carefully controls blood glutamate access to glutamate neurons, while ever it is fully functional. Neonatal rats are not so lucky and the dose rates they get by injection are astronomical.
majkinetor and Kindke, thanks for the links. We all tend to think of insulin resistance as bad but this is probably how ketogenic diets control appetite. I think these things certainly tie together.
Its, the FIRKO GTG injured mice are so frustrating. I also want to know if they have the acute phase hyperphagia which becomes more modest as adipocytes fill... They measured food intake daily (I think) but this is not what they were interested in.
Peter
Confusion, part 2.
If FIRKO mice have hyperactive BAT, why aren't saline FIRKO mice (who have the same food intake as saline normal mice) lighter than saline normal mice?
Also, why aren't GTG FIRKO mice (who eat much more than saline FIRKO mice) much heavier than saline FIRKO mice?
Was the energy expenditure of any of these mice measured?
Nigel,
It's full free text, you can give us the answers.
Peter
So it is. Expenditure isn't mentioned, so body weights mean nothing.
@bloblog
MSG intake will not ruin your hypothalamus, but the reserach pretty much demonstrates that MSG in food leads to insulin overproduction at meals.
I have been able to correlate the problems between a high amount of MSG in processed food with carb-like appetite shortly after. At times I will get overt hypoglycemic signs like trembling and confusion.
MSG is definitely a problem for people who are prone to oversecrete insulin, who are prone to obesity.
Nigel,
Did you pick up this section?
"We find that aging FIRKO mice have reduced body fat mass (when expressed as either percentage of body weight or absolute mass) and that this occurs despite normal to increased food intake as compared to control mice. In fact, when caloric intake is expressed as per gram body weight (gbw), the difference between FIRKO mice (0.44 cal gbw–1) and controls (0.34 cal gbw–1) is quite striking (i.e. about 30%) and this difference in body weight is maintained throughout life. The current study indicates that this discrepancy between increased food intake and lower body weight in FIRKO mice can be explained by an increase in whole body metabolic rate. Thus, FIRKO mice have increased oxygen consumption (VO2) and RER, and this difference is greatest during the dark phase that corresponds to the feeding time for rodents."
and this graph:
FIRKO Fig2
Read the legend carefully.
Don't forget that even during the night period, where FIRKO mice are as active as control mice, they are not carrying round the blob-mass of a wild type mouse. They look as active but this is an illusion because they're skinny. A modestly porky control mouse is shifting more weight per movement than a skinny one. Just like obese people.
FIRKO mice avoid the gym.
Good luck with the confusion.
Peter
Peter,
I missed that bit. The interesting part is:-
"The current study indicates that this discrepancy between increased food intake and lower body weight in FIRKO mice can be explained by an increase in whole body metabolic rate. Thus, FIRKO mice have increased oxygen consumption (VO2) and RER, and this difference is greatest during the dark phase that corresponds to the feeding time for rodents."
So, despite eating a bit more and moving a bit less fat mass around, FIRKO mice still manage to expend more energy than normal mice, without having a significant difference in body temperature. It has to be magic.
Nigel
Nigel,
No. They cannot store calories as fat. They burn them. Vo2 increases when they eat. You need a decent, logically self consistent framework to understand weight control. No need for weird ideas about boredom limiting D12492 consumption by 7 days exposure.
Peter
BTW, they clearly have SOMETHING which sets how much they eat. Insulin determines what they do with what they have eaten. If we lose calories to fat we have to eat more to cover the loss. It's quite simple, unless you are in obesity research or have a personal hatred of Gary Taubes (not particularly thinking of yourself there).
Peter,
If they're burning more calories, why don't they have a significantly higher body temperature? How do rodents regulate body temperature?
Re boredom: Why is that a weird idea? The difference between D12492 and the CAF diet is that D12492 always tastes exactly the same, whereas the CAF diet has variety. Rodents never become habituated to the CAF diet so get really fat on it. If sex with the same partner can become boring to a rodent (the Coolidge Effect), why can't there be a similar effect with food?
You wrote "If we lose calories to fat we have to eat more to cover the loss. It's quite simple..."
But losing calories to muscle doesn't make us eat more. It's not simple. The VMH is affected by lots of hormones. That sets how much they eat. It's really late, so I'm off to bed.
Nigel.
@Nigel While admittedly i have not studied or heard of the "coolidge effect" Do I really need to point out that sexual partners and food choices are quite different, and serve different biological purposes?
It is in an organism's genetic best interest to diversify partners, particularly male animals (females/high investment partner will opt for quality, not quantity). It's that whole sperm vs egg, long term investment (pregnancy) vs a few minutes investment. R vs K selection, etc. http://en.wikipedia.org/wiki/R/K_selection_theory
Enjoyable, rewarding feelings don't exist for fun. They exist to motivate us to behave in biologically, genetically productive ways.
What is the purpose of growing bored of nourishing food? If food is nourishing (which, we presume, our appetite/brain reward circuitry is trying to detect) then we should continue to consume it at the same intensity.
On the other hand, if you are a male animal, genetic programing to seek many different partners makes a lot of sense and is a good reproductive strategy.
@Nigel
Actually it is quite simple unless one has an emotional investment in the gluttony/sloth hypothesis.
Calories lost to fat must be compensated for (eaten in excess) because fat calories are unavailable for metabolic processes; you know, like, keeping your brain and heart and intestines functional. Staying alive. Moving. If your fat cells are touched by a magic wand that says "be hyper sensitive to insulin and grow very, very large", this will result in an increase of food consumption so that one may both stay alive AND maintain the hypertrophic adipocytes.
Think of it like this; if you tell your job to automatically credit your savings account with 75% of your paycheck, meanwhile everyone else at your job is crediting 25%, you have about 1/3 of the available financial resources as your coworkers. You need to INCREASE your total pay in order to have the same quality of life as your coworkers. Remember, 75% of your takehome pay is being directly locked in savings - you can't access it. You've got to either make due with 1/3 the net pay (i.e. live like a pauper and starve and live under a bridge) or you have to increase your TOTAL pay so as to equal the same relaxation and luxury your coworkers enjoy, who are NOT bloating their bank accounts with inaccessible money.
If one is in a polar opposite condition - fat cells are abnormally insensitive to insulin, say, IR only 15% of normal - then far less of our consumption is lost to adipocytes, more of it is available for use. Brain/heart/kidneys/intestines and all that goodness. More energy available for work and heat.
This is like a coworker who takes his or her paycheck and rolls up to work with the latest car and does coke every weekend but has a dollar in the bank. Live hard and fast, buddie, I just hope you don't get fired - you're screwed. This is why metabolism only works at full speed if endocrine signals indicating prosperity and health are adequate (e.g. HPA axis not to crazy, leptin feedback sufficient to hypothalamus, dopamine signalling / low melatonin and so fourth)
This explains why BAT with less insulin signalling generate more heat/UCP1 activity - insulin makes BAT grow just like WAT, and signalling of insulin appears to be a switch which tells the bat to either grow in size, or alternatively, to generate more heat (from calories). If the insulin switch is OFF in BAT, UCP1 is upregulated and thermogenesis increases.
Seeing as there are CLEAR cut links between insulin levels, food availability, season, and need for thermogenesis, this is clearly evolutionarily logical. Lower insulin states, lower food intake states, are a marker for cold weather and increased need for thermogenesis. Of course, this would only be true up to a point of hypoleptinemia/starvation, where in which just like VMH injury, fat tissue (including BAT) would switch function away from energy use / waste (e.g. BAT thermogenesis via UCP) and toward hypertrophy (via low-leptin, hypothalamic feedback leading to BAT/WAT insulin hypersensitivity.
Really there is nothing at all foggy about this, but if I was faithful to the idea that fat people are lazy and gluttonous and really really believed that I could see how all of these things seemed mysterious.
@Nigel,
rats are very small with a large surface area. They have have far more difficulty keeping warm than keeping cool.
The Coolidge effect doesn't apply to food. Most animals, including humans will only eat a very small small range of familiar foods based on eating habits established in infancy.
The idea that we eat a lot of of foods is purely an illusion. The thousands of foods in a supermarket are really just a few dozen basic ingredients recombined in a vast number of ways.
In reality most Westerners eat little more than a subset of:
- sugar
- cows milk,
- vegetable oil
- salt
- a few species of mammals and birds
- four closely related grains
- a few common fish species
- a dozen common fruits
- a dozen common vegetables
- some herbs and spices
- beverages (tea, coffee, cocoa)
- alcohol from grain or grapes.
I will explain the disconnect between deliciousness and reward. I will also explain how the Coolidge Effect does apply to food in humans.
Your favourite food is "X" cooked exactly the way you like it.
Example 1:- 2lb of "X". Each mouthful of "X" is as delicious as the previous. The first mouthful is rewarding. As you continue to take mouthfuls, the reward falls until you become full at which point there is zero reward. If you continue to take mouthfuls, it becomes uncomfortable, then painful and then you puke. All of these mouthfuls have negative reward, despite them being equally delicious.
Example 2:- "X" for every meal. By your last meal on day 7, will "X" be as rewarding as it was for the first meal on day 1? I don't think so.
The brain doesn't run on fats or fatty acids, so it isn't sensitive to how much there is/are in the blood. Parts of the brain run only on glucose, so the brain is very sensitive to how much glucose there is in the blood. Therefore hypoglycaemia or rapidly-falling blood glucose increase hunger. The heart & intestines get their energy from local fat stores & blood glucose.
I'm sorry, but "calories lost to fat must be compensated for by increased appetite" doesn't convince me at all, because calories lost to muscle aren't compensated for by increased appetite.
If BAT disposes of excess energy, why is no increase in body temperature?
Um, wut?
It seems to be that the problem is you are incapable of abstract conceptuatlization that muscle tissue is different from fat tissue.
Calories can only ever be lost to fat; they are stored in fat and unavailable otherwise, due to an imbalance in insulin sensitivity.
Calories are not LOST to muscle. Muscle, which does work, like lifting your hand to type on the keyboard, utilize CALORIC ENERGY to accomplish this task. Calories are USED by muscle to do work, which we all require of ourselves, regardless of what our fat tissue is doing. Your boss doesn't care that you have hypersensitive adipose - he expects the same level of performance as your metabolically healthy thin coworker. Better get to eating twice as much if you hope to have a similar energy level as a constitutionally lean coworker. I mean, you COULD attempt to starve yourself and resist the appetite: enjoy hypoglycemic trips and half assed energy levels. Unless, of course, you do something to change how your body fat is regulated. What oh what could that something be? ;)
Saying that calories are "lost" to muscle just as they are "lost" to fat tissue, is irrational. If calories are locked in fat tissue THEY ARE UNAVAILABLE for work. The point of calories is to create energy to fuel metabolic processes so we can use the muscles in our arms, move our arms and type stupid crap like "insulin does not cause obesity'. If our caloric energy is being shunted to our fat tissue instead, we need to eat MORE CALORIC ENERGY if we want to move our arms as fluidly and effortlessly as a person without this liability.
Two mothers have 10 pounds of food each.
One mother has 4 children, the other mother has 1.
A child requires 10 pounds of food.
The mother with the 4 kids needs to find herself 40 lbs of food or she's going to have very hungry malnourished poorly thriving children.
By your reasoning, you would deny the rule of 10 pounds of food per child is minimum, because the mother with 1 child does well and does not require more food. This would be terrible logic because it is as if you are trying to retroactively explain why the mother with fewer children does not scavange for more nutrition ("It must be because 10 pounds of food REALLY IS adequate, the rule is false, if it was true, the other mother would not gluttonously search for more food")
This is precisely the argument you make when you say that people who preferentially oxidize glucose in muscles do not increase feeding, therefore, people who preferentially store nutrition in body fat shouldn't eat more, either.
@Nigel
Regarding a lack of fever in mice with more UCP1 activity....
We are not computers, or car engines; our brain has a thermoregulatory center that keeps our temperature in a narrow range. THere really is a thermostat, homeostatic set point of temperature. Temperature only rises when physiology purposefully increases our temperature - e.g. cytokines that respond to infection like IL-6 will increase the body temperature, as well a pregnant woman with high progesterone. The utility of the higher body temperature in pregnancy and in illness is to inhibit growth of microrganisms. The body does not willy nilly go about making our temperature 100 degrees for no reason.
When we see changes in basal body temp as pertaining to food intake and diet, we only observe DECREASES in temp (to conserve energy), but that does not mean that generous use of energy results in an INCREASED temp. If you are a fatty with hyperinsulinemia who is trying to eat a 1000 calorie diet of rice cakes, your basal temp may drop to 97 degrees because every energy generating process in your body is laughing in your face. However, if a healthy person eats a boatload of food they don't run a 99 degree fever. The thermoregulatory centers in the brain prevent this.
So, if more heat is generated from UCP-1, as temperature began to rise abnormally, I would assume that there would merely be an increase in dopamine signalling in thermoregulatory centers of the brain, which then would act to suppress temperature. No fuss, no muss ;D. FYI central dopamine signalling is a crucial component of normal metabolic health. Dopamine and melatonin are major seasonal indicators and control metabolism and physiology, starvation responses as well as hibernation. Much of leptins effects are exhibited by pulling the plug on dopamine.
I can tell you that changes in glucose oxidation capacity in muscle tissue will PROFOUNDLY affect subjective feelings of energy. You can literally operate your whole body easier, all the time, 24 hrs a day. I experienced this when I took an extremely low dose basal leptin to correct weight loss induced hypoleptinemia. AS a result I was able to eat calories and keep losing weight, and more weight, adn more weight... and I could eat 100 carbs per day and still burn gasoline all day long.
Truly a remarkable thing.
This change is caused by leptin normalizing physiology allowing for liberal use of energy from glucose, orienting physiology away from gaining body fat (terminating adipocyte hypotrophy). Perhaps a similar condition is achieved when we obliterate fat tissue IR but spare muscle tissue IR. Kind of like a bandaid, glue and tape repair job to fix what destroying the hypothalamus (leptin sensitive neurones) breaks....
With low-intensity exercise, muscles burn mostly fatty acids, not glucose. The study I cited showed that low-intensity exercise reduces appetite more than high-intensity exercise.
Sucking fatty acids from the blood, whether by fat cells or muscle cells makes them unavailable to other tissues i.e. they are lost.
Increasing the uncoupling of ATP always results in an increase in body temperature. Look-up 2,4-dinitrophenol.
@Nigel
I'm beginning to feel as if this is a waste of time, but I just can't help myself.
Exercise ("calories lost to muscle") only suppresses appetite in the short-term. In the long-term, we compensate by increasing caloric intake. This is as well-established and uncontroversial as anything in exercise physiology.
More importantly, you seem to be unaware of the logical inconsistency in your argument. If you believe that the food reward/set-point theory is correct, then it has to be true that, without changing one's diet, the "set-point" will cause us to increase appetite in response to exercise.
So, which is it? Set-point or appetite suppression through exercise? You can't have both.
This is a waste of time.
"In the long-term, we compensate by increasing caloric intake. This is as well-established and uncontroversial as anything in exercise physiology."
I've already explained the psychological reason why humans do that and it's got nothing to do with appetite. If you can't be bothered to read what I wrote...
"If you believe that the food reward/set-point theory is correct..."
You're combining food reward theory with set-point theory. They're not the same thing!
Therefore, there's no choice for me to have to make.
@Nigel
There's no evidence, other than anecdotal, that increasing food intake for "psychological" reasons is associated with exercise, and even if there was such evidence, it wouldn't prove that increasing food intake is caused by those "psychological" reasons.
In the study I cited, you were correct in saying that the goal was not fat-loss. That means that there were no incentives for the participants to "reward" themselves with extra food since they were not depriving themselves in the first place. Psychology was clearly not in play, and yet both the men and the women matched intake to expenditure with great precision, resulting in either trivial or no fat-loss.
Set-point is an inherent part of Stephan Guyenet's version of food reward theory. He mentions it several times in his attempts to explain it.
You are obviously a "last word" kind of guy. You think that if you can come up with some response, no matter how irrational or off-topic, then you haven't been shown to be incorrect, so this will be my last response to you.
If you are incapable of understanding even the most basic rules of logic or evidence, there's really nothing that I, or anyone else, can do to help.
Nigel, On day 1 the D12492 injured mice ate 70kcal more than controls. They gained, from graph F, about 5 grams of fat. The CIAB fed rats probably gained about 1g. So we can say that the D12492 injured mice lost 40kcal out of the 140kcal of their dietary calories in to their adipocytes.
How much fully aerobic, FFA fueled exercise by muscles would it need in a human to give an equivalent fat loss through muscles? We can't say because the metabolic rate and heat loss from a rat are massive compared to humans. But if we do reductio ad absurdum we will then have a human on maintenance of 2100kcal having to burn 630kcal in walking to lose the equivalent FFAs to muscle, ie to mimic the loss of calories in to adipocytes these D12492 injured mice experienced.
That would be 2 hours at a brisk 4mph or 3 hours at 3mph. Of course, this forced march might just leave you fully satiated and never wanting to eat again, or maybe not.
For animals or people on dinitrophenol, they have a whole body, uncontrolled mitochondrial uncoupling. This is not remotely the same as a localised and highly controlled thermogenesis in brown adipose tissue, which can easily be dissipated between the BAT and the rectal lining, where you have stuck your thermometer. Until you have anaesthetised as many rats as I have you have no idea quite how rapidly a rat or mouse can dissipate heat.
Peter
Sam: Amen
Peter
"There's no evidence, other than anecdotal, that increasing food intake for "psychological" reasons is associated with exercise, and even if there was such evidence, it wouldn't prove that increasing food intake is caused by those "psychological" reasons."
Then there is the whole thing about uncoupling "psychology" and physiology to begin with.
I suspect that mistake might even be the original sin that led us to our current rather dire state of knowledge.
Peter,
Thank you. THANK YOU. THANK YOU. I had a mental blockage and your post unblocked it.
Tiny animals like mice have a much higher surface area to mass ratio than we do, so lose much more heat per unit mass than we do.
Tiny animals like mice have tiny masses, so expend very little energy moving that mass around.
Therefore, virtually all food eaten is used for running organs and generating heat and virtually none is used for moving around.
Therefore:-
FIRKO mice eat more food than normal mice without gaining weight because FIRKO mice lose more heat than normal mice because FIRKO mice have less subcutaneous WAT than normal mice. It's that simple (I think!).
Nigel.
Sam Knox,
I just can't win with people like you.
If I don't reply to a post, I lose (as it means that I don't have evidence to refute your argument).
If I do reply to a post, I lose (as it makes me a "last word" kinda guy).
So, my "last words" to you are as follows:-
You seem to know nothing about human psychology, otherwise you would have known about the exerciser's paradox (the delusion that exercise burns far more calories than it actually does) which, by the way, has nothing to do with incentive. It's similar to The Dieter's Paradox, which is the delusion that "healthy foods" have negative calories.
I can't believe that you used the "Appeal to Authority" fallacy, especially when the authority is someone you don't even agree with (Stephan Guyenet)! I don't agree with everything that Stephan writes, and set point theory is one thing that I don't believe in.
So, good-bye to you.
EDIT: If you think that I'm making up the exerciser's paradox, see Normal Weight Men and Women Overestimate Energy Expenditure – Research Review
Ronnie: So it's good night from me.
Ronnie: And it's good night from him.
http://www.youtube.com/watch?v=-eZpHphhgpo
dat poor lil buggers.. thank good im not a FIRKO mice! Now excuse me gents, time to eat some awesome dulce de leche! (made with 1k SUGAR! + 3L raw milk)mmm... fat + fructose... soooo good.
@Nigel;
FIRKO mice eat more food than normal mice without gaining weight because FIRKO mice lose more heat than normal mice because FIRKO mice have less subcutaneous WAT than normal mice. It's that simple (I think!).
Mice have only about 1% body fat (less than 1mm subcutaneous fat) and rely almost entirely on their fur for insulation. Even in FIRKO mice the insulating role of fat is trivial.
Wild mice and rats keep warm by constantly running (they very rarely walk) and snuggling together when they sleep.
@Nigel,
every exercise physiologist knows that exercise is completely useless for weight loss.
If exercise was effective for weight loss there would be no humans because our ancestors would have starved to death a couple of million years ago.
We lose 80% of our energy intake as heat. So wearing fewer clothes is a vastly more effective way to lose weight than exercise.
"Wild mice and rats keep warm by constantly running (they very rarely walk)...."
Why would they need to do that when they've got all that BAT to keep them warm? I would have thought that mice run a lot as they are are near the bottom of the food chain.
"every exercise physiologist knows that exercise is completely useless for weight loss."
Exercise is for:-
a) Shifting nutrient partitioning away from fat towards muscle, so that you don't become "skinny-fat".
b) Maintaining fitness & muscle mass into old age.
c) Improving whole body insulin sensitivity and also leptin sensitivity in the brain.
"If exercise was effective for weight loss there would be no humans because our ancestors would have starved to death a couple of million years ago."
Why do you keep banging on about exercise & weight loss? Do you not read anything that I write?
"We lose 80% of our energy intake as heat. So wearing fewer clothes is a vastly more effective way to lose weight than exercise."
Wrong. REE for someone of my weight is ~1,440kcals/day. TEE for someone of my weight is ~2,500kcals/day. ~1,440/~2,500 = ~58%.
Wrong. Wearing fewer clothes makes us feel cold, which increases our appetites (due to all of the regulatory systems in our bodies) which makes us eat more.
You can have the last word if you like (unless it's uninformed nonsense that needs to be refuted).
"Mice have only about 1% body fat..."
From Validation and calibration of DEXA body composition in mice
"Male mice weighing 26-60 g and having body fat percentages ranging from 3 to 49%..."
"These mice ranged from 35 to 83 wk of age and were selected from a larger cohort of mice to have either low or high body fat contents. Two lean mice from this second group were fasted for 2 days to obtain very low values of body fat."
The lowest BF% they could get by selection & fasting was 3%.
@ Blogblog,
I just noticed your early comment on MSG. Nietzche said that the aristocracy's natural scepticism in regard to the reality of suffering was the cause of the French Revolution. If someone tells you MSG makes them ill, why not believe them?
The minute traces of MSG that occur naturally in vegemite, tomato, fish sauce, or soy sauce (which products are not PURE
MSG - why do I even bother disputing with a purveyor of such hyperbole?) do not compare with the tsp quantities used in Oriental junk food. We are not talking about an allergy here, more likely a dose-response relationship.
Blogblog
The Duchess, she say
"Speak roughly to your little boy
and beat him when he sneezes
he only does it to annoy
because he knows it teases."
@ Nigel,
exercise can improve (or indeed lessen) fitness, but how do we define fitness?
I define fitness as the body's adaptation to the future tasks that will be required of it.
If you are not fit enough to lift your shopping out of the car, you may a) go hungry, or b) pull a muscle, or incur some similar injury (or exhaustion) that you could have avoided by working out more.
In this model, fitness is being fitted for the life and activities we choose.
If we must sit for long periods, drive, or stare at computer screens or books, then fitness for that counts too.
Fitness = adaptation allowing chosen or necessary activity (or inactivity) to be accomplished without harm.
(i.e., "Not fit to carry guts to a bear")
What do you think?
And of course improvements in insulin sensitivity increase our fitness to metabolise and derive energy from the food we will eat...
the definition may be a truism, but an occasional dose of truism is protective against absurdity.
Hi George,
I would define fitness as the ability to perform activities without difficulty e.g. walking, running, climbing stairs, carrying things.
Adaptation to inactivity (e.g. muscle loss) adversely affects fitness.
Nigel
@Nigel
Okay, I changed my mind about not responding.
Although I'm not yet ready to take back the "incapable of understanding" bit, I apologize for the "last word" comment. I'm embarassed that I engaged in behavior that I would normally condemn, i.e., personal attacks or any other ad hominem remarks.
I mentioned Stephan Guyenet not as an appeal to authority but because, as I said, setpoint is part of his food reward theory. If you don't believe that there is such a thing as "setpoint", then good for you.
Good point Nigel. I was thinking that the fitness of our eyes, or our resistance to RSI, or our ability to be inactive without loosing muscle mass or getting backache or embedded sloth syndrome (ESS), might be forms of fitness too.
If (for the sake of argument) one became stronger, but deafer, as a result of a noisy exercise, the deafness would be considered a form of unfitness.
I don't know how much further I can usefully take this concept.
"They also serve who only stand and wait".
@Sam Knox: O.K. No hard feelings.
What is it that I am incapable of understanding?
Let me just flog this deceased equine creature a little further along the track;
fitness in my conception is like fitness in Darwin's "survival of the fittest" (but individual rather than collective).
Fitness of vision, intellect, etc. is also important if unfitness in these areas will increase the risk of injury or mortality.
(perhaps this is more akin to a martial arts conception of fitness).
Bearing in mind the importance of evolutionary theory in low-carb discourse.
A little n=1 might help to clear this up.
When eating high-fat low-carb I find exercise less stressful, but I also find that enforced inactivity becomes noticably less stressful too.
It feels as if these are two complementary aspects of fitness.
Nigel,
I shouldn't have wasted all those years studying food science, biotechnology and exercise physiology. Thanks to your wisdom I have discovered that all the textbooks were completely wrong and all those PhD academics who taught me were complete idiots.
I can only imagine how upset Peter is to discover that his mentor Professor Patrick Wall was a charlatan who definitely didn't deserve the Nobel prize for physiology. Maybe they will posthumously rescind it an award it to Stephan Guyenet instead.[Sarcasm off].
I really can't understand why you persist with this blog. You obviously don't have even the most basic understanding of any life science topic including biochemistry or physiology (or even the scientific method). Yet you constantly accuse people who are far more knowledgeable than you of ignorance.You randomly quote papers that you obviously don't understand and that generally have no relevance to the topic under discussion.
You have a amazing ability to combine total arrogance with complete ignorance.
Here's some news for you being a retired electrical engineer doesn't make you either a) a scientist or b) an expert in nutrition.
As for me being ignorant:
Predation isn't a major cause of death in mice or any other other mammal species. The vast majority of mice and other mammals die from starvation, injury and disease not predation.
Mice run constantly because they are active at night when it is cold. They would very qickly die from hypothermia if the didn't maintain high activity levels (running). Peter mentioned in an earlier post that rats suffer an extremely rapid heat loss under anaestehetic (due to a lack of muscle activity) . During the day resting mice always huddle together to conserve heat.
The Basal Metabolic Rate of mice is around 8W/kg. This is around 12x as high as in humans. The reason for this high metabolic rate is to maintain the 37C temperature necessary for life.
The lecturers at the School of Human Movement at the University of Queensland (one of the leading sports science faculties in the world) must be total idiots. This is because they constantly reminded us students that exercise is an ineffective means of losing weight (because exercise causes caloric intake to exceed that expended in activity).
You are obviously completely unaware that virtually all elite athletes are placed on calorie controlled diets. This is because on an ad lib diet vigorous exercise typically increases body fat levels and overall weight.
THAT'S RIGHT. EXERCISE WITHOUT CALORIE RESTRICTION CAN MAKE YOU FATTER.
Human metabolism is only 20% efficient. The other 80% of calories are converted to heat. Maybe you should open any physiology or biochemistry textbook and discover this amazing fact.
George Hendersen,
of course I dispute the argument that MSG causes all these mystery ailments. Why?
Dozens of controlled clinical trials have never been able convincingly reproduce the MSG symptoms. (In at least one trial some of the subjects reacted to the placebo but not the MSG).
1.5 billion Asians don't suffer these mysterious MSG ailments.
Many foods have naturally high levels of glutamate but don't cause these symptoms.
Here's a free basic chemistry lesson:
sodium (table salt) + glutamate = MSG
That's right. The natural MSG in Vegemite and soy sauce is EXACTLY the same as the artificial MSG that comes in a jar.
@blogblog
Putting aside claims of allergy/intolerance to MSG, do you agree that MSG is insulinogenic and may result in hyperinsulinemia / fat storage / high caloric intake similarly as carbohydrate food might?
I tend to react to very high MSG processed foods in this fashion even if the carbohydrate content is low.
I have a reflexive aversion to food such as canned broths and low carb high fat canned/jarred dips, or any "spice packet" type crap that usually contains salt + MSG. The aversion is garnered from knowning that putting these things in my mouth will lead to feeling very hungry and having unstable blood glucose and fighting urges to eat. Mood tends to suffer as well. Taking acid (apple cider vinegar) can help terminate the malaise , presumably by correcting the excessive insulin levels and increasing fat burning appropriately. (FYI, taking vinegar is a great way to help quickly terminate/attenuate insulinogenic dietary mistakes - hunger abates and energy improves).
I am not one at all to shy away from processed foods and fully advocate using low carb protein bars and splenda and such things. So it's not a neurotic reaction to fear of processed food that is evoking these feelings.
I find it funny that people will avoid splenda (which is insulin and metabolism neutral) but they will eat tons of MSG food, thinking it is better because it does not taste sweet. I NEVER have a problem with the sucralose molecule, or protein bars which are sufficiently low glucose (e.g. atkins bars). But give me some near zero carb canned soup broth, a zero carb "flavor packet" which is powdered MSG and some salt, or some type of dip or dressing that is excessively high in MSG, and I am HUNGRY AS GET OUT shortly later. This response is very abnormal for me given the trace carbs in the food. I can correlate it well with MSG content.
I think we who believe in the insulin hypothesis of obesity can become overly focused on carbs that we neglect the big picture: the problem is INSULIN; the level is either too high or there is an imbalance of receptor sensitivity.
The problem is not carbs. Carbs are only important because they produce a very great insulin response in those individuals who have disordered glucose metabolism.
Restricting carbs to zero and neglecting every other factor that affects insulin is an unproductive way to manage weight. See Jimmy Moore for evidence.
http://www.ncbi.nlm.nih.gov/pubmed/18827336
Abstract
Monosodium L-glutamate (MSG) elicits a unique taste termed umami and is widely used as a flavor enhancer in a variety of cuisines. Recent studies suggest the existence of L-glutamate (GLU) receptors and its transduction molecules in the gut mucosa as well as in the oral cavity. The vagal gastric afferent fibers respond specifically to the luminal stimulation of GLU in the stomach. GLU administration in the stomach also activates several brain areas (insular cortex, basal ganglia, limbic system, and hypothalamus). Ingestion of MSG enhanced secretion of digestive juices and insulin. Spontaneous ingestion of an MSG solution at the most preferred concentration (1% (w/v)) reduced weight gain, fat deposition, and plasma leptin levels without affecting food intake, naso-anal length (an index of somatic development), and lean mass in rats. These results suggest that umami signaling via gustatory and visceral pathways may play an important role in the process of digestion, absorption, metabolism, and other physiological functions via activation of the brain.
(though it states MSG inhibits fat gain in rodents, it should be noted that this is accomplished via increased insulin as rodents respond to trivial increases of insulin with satiety , as Guyenet is prone to point out... things are probably quite different in obese prone humans, where in which I would imagine increased insulin would contribute to fat gain, nutrient sequestering from the blood and hunger... as is my experiences with heavily MSG treated food items, and my vulnerability to relative hypoglycemia under trivial insulin stimulus)
Ahhh sorry for posting spam.
Yes, if MSG stimulates increased/exaggerated digestive responses, which are insulinotropic and promoting of hypoglycemic phenomena/hunger, it stands to reason that vinegar would be an antidote as vinegar accomplishes the opposite. I have naturally, intuitively taken to counteracting MSG with Vinegar.
Food Chem Toxicol. 1993 Dec;31(12):1019-35.
Monosodium L-glutamate: a double-blind study and review.
Tarasoff L, Kelly MF.
Source
Department of Chemistry, Faculty of Business & Technology, University of Western Sydney, Campbelltown, NSW, Australia.
Abstract
71 healthy subjects were treated with placebos and monosodium L-glutamate (MSG) doses of 1.5, 3.0 and 3.15 g/person, which represented a body mass-adjusted dose range of 0.015-0.07 g/kg body weight before a standardized breakfast over 5 days. The study used a rigorous randomized double-blind crossover design that controlled for subjects who had MSG after-tastes. Capsules and specially formulated drinks were used as vehicles for placebo and MSG treatments. Subjects mostly had no responses to placebo (86%) and MSG (85%) treatments. Sensations, previously attributed to MSG, did not occur at a significantly higher rate than did those elicited by placebo treatment. A significant (P < 0.05) negative correlation between MSG dose and after-effects was found. The profound effect of food in negating the effects of large MSG doses was demonstrated. The common practice of extrapolating food-free experimental results to 'in use' situations was called into question. An exhaustive review of previous methodologies identified the strong taste of MSG as the factor invalidating most 'blind' and 'double-blind' claims by previous researchers. The present study led to the conclusion that 'Chinese Restaurant Syndrome' is an anecdote applied to a variety of postprandial illnesses; rigorous and realistic scientific evidence linking the syndrome to MSG could not be found.
@blogblog: Have you gotten sand in your v*gina?
How about citing studies to support what you write instead of making stuff up and constantly using "Appeal to Authority" & "Straw Man" arguments? E.G. Where have I written that exercise is good for weight loss?
Anyway, I'm done with you, as [irony]you know everything and I know nothing[/i].
@Woo: "I think we who believe in the insulin hypothesis of obesity can become overly focused on carbs that we neglect the big picture: the problem is INSULIN; the level is either too high or there is an imbalance of receptor sensitivity.
The problem is not carbs. Carbs are only important because they produce a very great insulin response in those individuals who have disordered glucose metabolism."
I know that we don't agree on a lot of stuff, but I mostly agree with the above.
So, what causes high insulin levels or an imbalance of receptor sensitivity? Insulin resistance in muscle and/or liver. And what causes that?
Muscle:- over-full and/or inactive cells.
Liver:- over-full cells.
Both of the above are helped by low-carb hypocaloric diets and increased activity.
@Nigel
There is not one answer.
Hypothalamic damage, as shown here by Peter, destroys a critical CNS site for adipocyte feed back (from leptin) and so shifts physiology toward thriftiness. All effects of leptin insufficiency/deficiency induce body fat growth by altering insulin dynamics. People with Praeder Willi syndrome have hypothalamic obesity, for example. As blogblog linked earlier, ketogenic low carb diets help circumvent the CNS driven to obesity via hypothalamic damage in prader willi syndrome but it does not cure them or totally make them normal. This is a special type of obesity to be discussed sepertaely from common obesity, because this obesity only manifests because of a break in physiology: the body is in a chronic state of starvation even though food is plentiful. The body is incapable of orienting physiology appropriately to a high nutrition environment, because the brain is destroyed and cannot receive fat tissue feedback (leptin) any longer. Note, the fact hypothalamic and leptin deficient obesity is so different than garden variety ordinary obesity is one reason I am so adamant against the "leptin resistance" hypotheiss of obesity. It is obviously wrong.
The most commonly occurring type of obesity is probably that which is related to absolute mitochondrial insufficiency, or specific defects in oxidizing glucose, manifesting as glucose intolerance and later as insulin resistance. Mitochondrial insufficiency has many causes, it is partially acquired from your mother's health during gestation, genetics, and environment (toxins/damage) play a role as well. Nutrition and nervous system status also affect glucose oxidative capacity and insulin sensitivity. Sleep status and stress status will also affect these things. Low CNS dopamine will result in specific temporary glucose intolerance, but the effect is exactly the same as mitochondrial insufficiency (cells cannot process glucose without adequate dopamine; keep using fat for energy; hyperinsulinemia results during food intake).
One could write a TOME of all the things that may adversely affect glucose tolerance and insulin sensitivity. It will not and never will be one thing, and if someone argues you just need to take a magic vitamin mineral or follow the right diet, they are ignorant or crazy or lying.
Anyway, take home message: obesity occurs because loss of ability to oxidize glucose normally, orchestrate normal insulin response, leads to hyperinsulinemia to process glucose in tissues; fat tissue is typically relatively more sensitive to insulin (compared to other tissues), so while this level of insulin is barely adequate to lower the blood glucose and use it for metabolic processes, it is driving a process of pathological growth at the site of the fat tissue.
Think of it like this... two people are in a snowstorm. One is wearing a bathing suit, one is wearing a snowsuit. Who will exhibit the effects of a high level of snow? Snowsuit man, or bathing suit? Who do you anticipate developing the effects of excessive exposure to cold?
LOGIC PUZZLE! PATHOPHYSIOLOGY QUIZ! DEDUCE AN ANSWER!
Patent has metabolic disorder.
Patient has very insulin resistant muscle tissue, very resistant liver, but fat tissue like, only sort of resistant to insulin. Patient is only semi-fat and genetically speaking his fat tissue has quite a ways to go before maximal insulin resistance is inducted (maximal hypertrophy/hyperplasia).
Obviously the patient's insulin level is a billionty plus one, because his liver and muscle tissue are wearing an insulin snow suit. This drives the insulin level up considerably, just to half-assed process nutrition.
Knowing what you know of this patient, do you anticipate this insulin resistance mediated hyperinsulinemia will lead to:
a) Body fat atrophy; duh insulin is an anorexigenic hormone! Hello, guyenet is a genius!
b) No change in body fat
c) Body fat hypertrophy
Regarding your belief that willful sloth causes glucose intolerance ("Muscle inactivity causes insulin problems"), this is moralizing bullcrap. Sorry. You need to get over your belief in gluttony and sloth, Nigel. You really don't want to, it seems, but the evidence is UBER CLEAR that inactivity cannot and will not cause pathological insulin resistance in normal people. Just because activity can slightly reduce IR in already diseased people is totally not the same thing as a lack of activity causing the illness in the first place.
@Woo: Will you please stop using the words gluttony and sloth. The reasons why people eat too much and move too little have sweet F/A to do with gluttony and sloth. I have never used those words, so stop putting them in my mouth!
I know that there isn't one answer. There are loads of factors that cause excessive fatness. I'm working on a new blog post that lays my cards on the table. Please read it and feel free to leave comments.
Muscle inactivity does cause muscular IR. It's basic physiology. Morals have nothing to do with it!
See Change of energy expenditure from physical activity is the most powerful determinant of improved insulin sensitivity in overweight patients with coronary artery disease participating in an intensive lifestyle modification program.
Jesus wept.
Jesus is about to weep some more.
See The effects of high-intensity intermittent exercise training on fat loss and fasting insulin levels of young women.
It seems that the KO model was not working as intended. The updated model, using an AdipoQ-Cre mediated KO, found that FIRKO behaves very similar to humans with lipodystrophy. Which makes perfect sense.
https://www.researchgate.net/publication/303180350
That's a very interesting and logical development. Thanks for posting. My biggest concern is what to do about the term "FIRKO-ise", a word dear to my heart but clearly no longer applicable to describe the changes on induction of ketogenic weight loss.....
Ta greatly, sigh.
Peter
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