I have, in the past, been given a key piece of information, put it in my pocket and left it there.
This is unforgivable, I know. But if the key is important enough you will have to either go through you pockets or be given another copy.
I am grateful to the rather unpleasant episode with Stephan as it allowed someone to supply me with that replacement key.
Metabolic flexibility is a slight misnomer, it describes a defect in fat metabolism.
I thank Stephan for getting me off my arse.
I thank Nick Lane for Power Sex and Suicide.
I thank M. for getting me to mention metabolic flexibility in comments.
I deeply thank J Staton for doing all of the work for me, reading Hyperlipid and taking the trouble to get the key cut then posting it to me via the comments. Go read.
There is no need to re invent the wheel. After reading the yellow box warning you can read this perfect quote
"This is a long and detailed article, but it’s very important".
And from elsewhere, if the post hasn't been taken down:
"A defect in fat metabolism?" Cracking quote, that one.
This fits with so many things which have become very, very obvious to me over the years. Neatly, logically, tidily.
Thanks all
Peter, the shoe-horner with the inappropriate prefix.
The gnolls satiety series is fascinating stuff. If you have any interesting in any of this, do yourself a favor and follow Peter's advice to "go read". Very interesting and I could waste another week following the links from it. I just bought the Nick Lane book as well. I've got a few 4 hr flights at the end of the month and a kindle waiting in my travel bag.
ReplyDeleteI have a basic question about impaired fat oxidation. What is the effect of high basal insulin levels on fat oxidation in cells between meals?
ReplyDelete(and yes I type faster than I think.. where oh where is that edit button...)
I will use the example of the feral pigeons in my backyard to explain the concept of satiety.
ReplyDeleteAccording to every famous pigeon fancier and avian veterinarian pigeons "need" a diet with 15% protein and <4% fat.
Pigeons are obstinate and invariably ignore expert advice. Offered a choice of seeds pigeons eat a diet with only ~8-10% protein and ~10% fat.
Why would a pigeons choose a high fat diet?
A pigeon is capable of flying very long distances (up to 1000km) at cruising speeds of 100-120km/h. To do this it must be as light and powerful as possible. A gram of fat offers twice as much energy as gram of carbohydrate or protein. Even a few grams weight saved makes a huge difference in efficiency for a 400g bird.
Why low protein?
A pigeon eats about 40g of seeds per day. This is about 30g carbohydrate and 10g of protein and fat. If it eats a 15% protein diet it will get ~7g protein. This is equivalent to around 17g/kg bodyweight which is probably far in excess of it's needs.
I had a look at the Gnoll 'Perfect Diet'. The guy is apparently some sort of whacky vegetarian because 3/4 of his plate is covered in various plant materials.
ReplyDeletePeter:
ReplyDeleteIt's mildly disconcerting to see the elephant in the room...but it's sort of a relief, isn't it? "So that's what I've been bumping into all this time..."
I've been calling attention to lack of metabolic flexibility as a major factor in weight gain for some time - but the mitochondrial dysfunction papers (particularly Rogge, which really is an excellent review) not only explain the mechanism by which met flex is impaired, they tie it together with so much other observed data, both scientific and anecdotal.
I hope that I've inspired you (and others) to explore the implications, and that the information will help us fit together some of the awkwardly-shaped puzzle pieces that remain. And as a longtime reader of Hyperlipid, I'm glad I can contribute something in return.
JS
The problem with studying the formerly obese is that confounding variable of leptin insufficiency, which has been documented in weight reduced subjects. What I mean by leptin insufficiency is that many observations of post obese people as compared to non dieted people can be completely and permanently fixed simply by giving the ex fatties a little leptin.
ReplyDeleteSo, this factor may be clouding these findings, as it may be purely an effect of fixing obesity and not causative in the obesity itself.
This is an important distinction because this so called defect can be reversed with theraputic leptin replacement after weight loss - it is not an innate part of being obese.
Low grade nutrient deficiencies after weight reduction, like not eating enough calories or zinc, can also cause leptin suppression... and many people lose weight in stupid ways, like not eating red meat.
It would be similar to someone who has had cancer treated with radiation, afterward finds that she needs to take synthroid in order for her thyroid to work. Sometimes, in resolving one abnormal physiological condition, you develop another, and this is true especially in endocrinology because of how so many hormones have feedback loops to one another.
Regarding the observation that fat people do not use energy the same as lean ones, most evidence suggests that obesity and metabolic syndrome feature a metabolic preference for fat. Greater metabolic flexibility - easily switching between glucose and fat - would be expected of inappropriate insulin dynamics in the obese, and also the central d2 receptor downregulation.
http://ajpendo.physiology.org/content/291/5/E1038.full
::"THE METABOLIC SYNDROME comprises a cluster of metabolic anomalies that are well-established risk factors for type 2 diabetes and cardiovascular disease including insulin resistance, abdominal obesity, dyslipidemia, and hypertension. Their concomitant occurrence suggests that a common pathophysiological denominator underlies these distinct metabolic features. Seasonally obese birds, fish, and rodents spontaneously develop virtually all components of the metabolic syndrome in preparation for wintertime. A wealth of data indicate that fluctuations of dopaminergic neurotransmission in various brain nuclei are involved in these seasonal metabolic adaptations (24).::"
d2 receptor downregulation is part of subsequent development of obesity, hibernating animals preparing for hibernation exhibit this as well, and one crucial change that occurs at the cell level from a lack of a d2 receptor to bind to dopamine literally causes a shift in how the cells in your body use glucose vs fat. The results are that the cells prefer fat in a reversal of the usual metabolic hierarchy, and this paradoxically results in an inability to use glucose with symptomatic higher insulin output, favoring storage of nutrients. It is part of seasonal/ hibernation adaptation, completely reversible in hibernating animals. Furthermore, this can be suppressed in hibernators by giving them bromocriptine.
As I have said many times before, I believe many forms of obesity are a conserved trait to exploit seasonal carbohydrate excesses, not a disease in so much as a tendency that can easily be controlled by not feeding on carbohydrate too often. But that's tangential. The overlaps between hibernating animals and obese people are striking, and I am surprised fewer people argue this position. Just me, hi.
So, really, it's kinda exactly wrong to say fat people do not oxidize fat well. I mean, the evidence suggests that obesity, metabolic syndrome, is often involving an inappropriate preference for fat, with an inability to use glucose, even when it would be metabolically appropriate to do so.
Again, regarding the lack of fat oxidation in post obese women, this, I would be $$$ on, is probably just a result of leptin insufficiency and would rapidly reverse itself if these women were given a nice wonderful dose of leptin in their bellies, to trick their bodies into thinking they never went on that diet at all.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840850/
Conclusion: In congenital leptin-deficient subjects, leptin replacement prevented the decrease in energy expenditure and fat oxidation often observed after weight loss.
im ok with the eat sfa part and the need for nutrients. the rest is conventional wisdom bullshit:
ReplyDeleteeat slowly, eat no dairy. eat no milk. no sugar. fructose is bad. better eat plants and starches, etc.
explain to me why i can drink / eat 1 liter of milk, use a bit of sucrose here and there, lots of chocolate as fast as i want, exactly about 3 minutes. yet i don't really know what hunger is, eating 15 minutes a day?...
could it be the 60% SFA in the form of, yolks, butter, cheeses, and meat that i eat next? ;) or maybe is my 65 mg/dl fasting blood sugar? maybe is all the fasting? or the moderate daily training? that could explain my current 6% body-fat. how knows.
blogblog:
ReplyDeleteI have no idea what you're referring to. My current dietary exegesis is titled Eat Like A Predator...
...and I just put over 100 pounds of dry-aged, grass-fed beef (which I helped to butcher - today's work involved meathooks, bone saws, and very sharp knives) in my freezer.
That's interesting data about pigeons, though. One wonders how the 15% PRO/<4% FAT figure was arrived at.
JS
This comment has been removed by the author.
ReplyDelete@J Stanton,
ReplyDeleteI was having a bit of a joke about your diet.
AFAIK the pigeon feeding "science" seems to be based on diets devised for raising chickens commercially. However the natural diet of chickens is mostly invertebrates and leafy greens. This is totally different to the seed diet of pigeons.
Pigeons also eat 2-3x as much food as chickens on a weight/weight basis.
Feeding high protein pelleted food to pigeons causes the chicks to grow faster than normal. This is known to cause problems in chickens including skeleten defects.
@J. Stanton
ReplyDeleteI noticed this in the fat-oxidation study you cited (Ranneries, et al):
"The excessive weight was lost by a conventional dietary energy restriction program..."
Do you think the results might have been different if the subjects had lost weight via carbohydrate restriction rather than calorie restriction?
@pablo DLS
ReplyDeleteMy Dad smoked three packs of cigarettes a day until he was sixty-years-old, then lived to be ninety-nine.
This suggests that smoking increases longevity.
The fact that I have also smoked cigarettes and have not died confirms it.
Peter,
ReplyDeleteI just read J Stanton's article on metabolic flexibility. In my opinion, it invalidates the carbohydrate-insulin hypothesis.
"First, this is not the 'greedy fat cells' theory of obesity, which posits an inability of the obese to retrieve fat from fat cells into circulation. That ability appears to be intact. What is indisputably damaged is the mitochondrial function of the obese, the formerly obese, and the soon-to-be-obese, and their ability to oxidize fat for energy."
There's your proposed mechanism of action going down in flames. I think it's time to reevaluate.
@ sam your analogy utterly fails to explain why im perfectly able to fast for so long without a single hint of hunger or craving, specially consuming teh evil refined sugars plus liquid carbohydrates...also stop smoking u dummy.
ReplyDelete@blog blog.
ReplyDeleteInteresting observation regarding your feral pigeons. We just conducted a food preference study in my lab, and found that all the pigeons tested preferred sunflower hearts and cracked peanuts over sunflower seeds, sorghum, peas, corn, breadcrumbs, or meal worms. Sunflower seeds and peanuts are both much higher in fat and lower in carbs than the other seeds/grains tested. I think the pigeons are on to something!
@Geoff,
ReplyDeleteIt's never time to stop thinking. I feel it's far too early for me to have a decision there and, at the moment, it's reading the papers that comes first. My current interest is that here we have a problem which primarily drives hyperinsulinaemia in people with metabolic damage.
There is a great deal to consider, I'm not going to rush.
Peter
@PAblo,I think that the article explains well why you are able to go for long time with no hunger at all eating sucrose.Your body is very adapted to burning fat.For me its another story where I am foraging all day for carbs but if I eat Optimal diet and adapt after agfew days I can really control my hunger well.
ReplyDeleteAnd about the smoking and cancer,look online for people curing themselves with baking soda at high doses....of bone cancer.;)I think it shows that PH of the body is of supreme importance and feel that people who drink alot of very hard water will be immune to negative effects of habits that lower body PH.Just theory mind you though.....
pablo, the only reasonable explanation is that you are in fact the christ reborn. once you take your lithium you'll realize you're not special.
ReplyDeleteIf, as Woo says, the obese do oxidize fat well enough, why are they hungry? Whether it's sugar or fat, they must not be oxidizing enough of something, as inhibitors of either increase "feeding behaviors." Unless, are obese, weight-stable people hungry, or is it only during fat gain?
ReplyDelete...to me it looks like: bad diet/toxins/etc leads to decreased fuel oxidation leads to high insulin (to protect against hyperglycemia or lipotoxicity?) leads to fat storage--with insulin levels staying ahead of adipocyte resistance during fat gain. Why do adipocytes become insulin resistant though if obesity per se is no problem...is it just a matter of being outside "evolutionary" conditions? That is, is there a tight correlation between adipocyte IR and adipose tissue amount, or is it only seen after significant gain?
ItsTheWoo2,
ReplyDeleteI have a lot of time for your thoughts, especially as we go looking for what breaks and what happens after the break. As you say, two quite different problems.
But I'm stuck with the respiratory quotients of the obese. They are running on carbohydrate at rest. Their mitochondria obviously process pyruvate perfectly well. I would guess they process ketone bodies even better. But for LCSFAs, my favourite fuel, metabolism has to be kicked and does not always seem to respond. I would fully agree that relative leptin deficiency is a major confounder. Is it leptin which controls the mitochondria?
I can't help but go back to Art Sayers and gut bacteria. If you don't have the right bacteria you can't generate them. This may be as easily fixed as eating unwashed root vegetables raw. But if we have selected against fat burning mitochondria and left only sugar burning mitochondria in the oocyte, where do the offspring get decent mitochondria from?
There is a great deal to read and think about and I've just just finished another late shift and will go to bed in 45 minutes time. Never forget that we have to read the full papers rather than the conclusions alone, and we may not always agree with the conclusions. It has happened before.
Peter
@Peter,
ReplyDeletethere is always the option of getting a stool "transplant". Early trials indicate that they are spectacularly successful at
treating clostridium difficile infections.
ItsTheWoooo2:
ReplyDeleteYou might find page 360 of Rogge et.al. interesting, as it proposes a role for leptin signaling and leptin resistance. I'm interested to hear what you think, because the proposal seems to agree with the results of the leptin study you cited.
"most evidence suggests that obesity and metabolic syndrome feature a metabolic preference for fat."
Can you provide references for this assertion? It's directly counter to the literature I'm familiar with. For instance:
http://www.ncbi.nlm.nih.gov/pubmed/21881161
"Carbohydrate oxidation rates (mg/kgFFM/min) adjusted for % predicted VO2max, were higher for prepubertal OW [overweight] children than pubertal children (p < .03). Fat oxidation rates were higher for NW [normal weight] prepubertal boys compared with other boys."
Note that it is important to distinguish between oxidation rates, which combine measurements of REE and resting RER/RQ, and the RER/RQ itself. So we may not be disagreeing: it's quite possible to have increased fat oxidation rate and increased RER/RQ if metabolic rate increases. The problem is high resting RER causing a metabolic "need" for carbohydrate in order to keep the lights on.
And this is a rat study, but it appears to support an epigenetic link:
Maternal Obesity during Gestation Impairs Fatty Acid Oxidation and Mitochondrial SIRT3 Expression in Rat Offspring at Weaning
http://www.ncbi.nlm.nih.gov/pubmed/21901160
blogblog:
Didn't realize you were joking. And no, chickens are definitely not the same as pigeons.
Sam Knox:
I suspect so, but I don't know for sure. There's a lot to learn here, and I hope that bringing this to the attention of the community leads to fruitful investigation and better knowledge.
Geoff:
Impaired mitochondrial fat oxidation does not by itself invalidate the insulin hypothesis. One could cause the other, one could be a side effect of the other (i.e. they're really the same thing), they could be complementary but unrelated, or one might not actually exist.
I don't know - which is why I disclaim my statement with "appears to be unimpaired". What I do know is that the mitox issue is not simply a restatement of carb/insulin, so I wanted to draw that distinction clearly. And it is very important to note that even if carb/insulin vanished tomorrow, it would still be much closer to practical truth than hypotheses based on "carbs are fine for everyone".
Again, I'm looking forward to seeing how Peter and others build on this information.
Peter:
The specific defect seems to involve the carnitine shuttle...which points us in a very interesting direction.
JS
@john
ReplyDeleteIt's not that fat people oxidize fat "well", it's that they do NOT oxidize glucose, even when they eat a big bag of low reward potatoes. This is a result of genetics as well as d2 receptor downregulation. D2 receptor downregulation, fyi, is a result of eating a high carb diet (yes, it is a cycle, and appears quite intentional, and so I have come to the conclusion that most cases of obesity are nothing more than an evolutionary trait to grow fatter on seasonal carbohydrate excesses, not dissimilar to the fact that some humans become very dark in the summer and very light in the winter).
It is abnormal to continuously oxidize fat, even in the presence of glucose, and this is how metabolic syndrome happens. When you attempt to feed on glucose, the body overproduces insulin and shunts it back into fat tissue, metabolic switcharoo.
Fat people are then hungry, because the insulin excess in response to the carbohydrate they tried to eat causes relative drops in blood sugar and other blood nutrients which make you hungreeeee.
Regarding his whole point that fat people have a lower fat oxidation rate, using studies of weight reduced people, this is a result of relative leptin insufficiency which is why all of his evidence of studies using weight reduced humans is irrelevant. The problem would be reversed if they were given corrective leptin replacement, as I posted above.
@pablo DLS
ReplyDeleteI can explain it easily. You are very metabolically healthy, do not have the genetic potential to develop obesity, and are also quite young with excellent glucose tolerance. Food does not cause these problems, it merely triggers them in people who have the vulnerability (me, hi!)
Healthy , non-obese people will never become obese from eating sugar or milk, unless they have the genetic metabolic potential to become obese. If you do, then no, you cannot binge eat milk and sugar and expect to fit through the door. That "daily meal" will soon just become dinner.
Want to trade serotonin/dopamine receptor profiles, and insulin receptor/fat cell genetics? No backsies, remember, all sales final ;).
The issue is caloric density. There are no obese hunter gatherers, whether they eat a predominantly animal or plant-based diet, because whole foods only provide so much caloric density.
ReplyDeleteThe industrialized world has huge surplusses of corn, soy and wheat. It stands to reason that avoiding processed foods equates mainly to processed and refined carbohydrates.
Those are the foods that are most easily processed and manipulated into unnatural, dense caloric foods. And that is also why HFLC and Paleo tends to work for weight loss in so many people.
@john
ReplyDeleteFat cell insulin resistance develops because some people are better at getting fat than others. We all have different white fat genetic potential. Women especially, due to progesterone and estrogen, are quite good at becoming obese as progesterone literally enhances fat cell growth. This is why any obesity ridden lower economic society will show enormously fat women, but men don't fatten as easily. Go to the local ghetto, you'll see many women who are 300+ pounds but not as many men, and men often remain thin even when eating badly. THis is the estrogen/progesterone difference.
Very bad diabetics, contrary to myth, are rarely hugely fat.
Mild diabetics can be quite fat, but severe "my sugar is like 450" diabetics are usually just a bit pudgy in the white fat, with thin, undermuscled, flabby limbs...and it is all belly. If they had better fat cell capacity to obesity they would probably be a huge tub of lard but at least they would have feet/kidneys/legs/not die of a heart attack or cva or severe infection.
Now what prevents diabetes is having the fat cell potential for your legs and arms to grow to the size of small children, like me. My sugar is always low, even while fat, my blood pressure was great, no visceral fat, all my obesity was in my white fat which is really awesome at being like WOW INSULIN TIME TO GROW HUGE AND INCREASE IN NUMBER. I would probably have been classified as "metabolically healthy", lol.
Okay, here is how I explain the paradox. This is a two part post, sorry.
ReplyDeletePt1:
There is a fault in reasoning here...
Just because obese people oxidize relatively less fat than carbohydrate, does not logically equate to obesity being a state where in which the primary disorder is an inability to oxidize fat.
D2 is a major metabolic controller, this is true in animals and humans. "Neurotransmitters" don't just affect mood and motivation, but energy and metabolism at the cell level.
Prior research of d2 dopamine signaling (which is very relevant to human obesities, as obesity is always found with significant functional d2 downregulation in response to glucose) shows that obesity does feature poor metabolic flexibility, but the problem is that the body continues to prefer fat over glucose - the body refuses to switch to a high glucose oxidation state after eating a meal. There are also genetic traits, unrelated to d2, possessed by obese people which mean that they are always more apt to prefer fat over glucose.
Result? Hyperinsulinemia and excessive insulin production after eating a "normal" meal with carbohydrate in it.
However, once hyperinsulinemia is set in place (due to eating a mixed food diet, when one is glucose intolerant as described above), the skeletal muscles will no longer oxidize fat effectively as a result of the carbohydrate portion of the diet causing excessive insulin release.
Insulin is known to inhibit lipolysis - the available of fatty acids for oxidation - but what is lesser known is it directly inhibits fatty acid oxidation, even if FFA are available.
http://www.jci.org/articles/view/17303
:::"
Thus, hyperinsulinemia...drastically limits the availability of FFA to muscle, further inhibits LCFA oxidation even if LCFAs enter the cell, and makes available more glycerol-3-phosphate for LCFA esterification into triglyceride.
The opposite situation occurs in circumstances such as starvation, where plasma insulin concentrations drop dramatically. Plasma FFA concentrations can increase dramatically (4) (3,000 μmol/l is not unheard of), and FFAs are readily taken up by muscle (5). The reduced uptake of glucose by muscle is thought to lower malonyl-CoA concentrations (2), permitting greater LCFA entry into the mitochondria.":::
This comment has been removed by the author.
ReplyDeletePt 2:
ReplyDeletehttp://www.jci.org/articles/view/15715
:::"Physiological hyperglycemia with hyperinsulinemia reduces fat oxidation in skeletal muscle. The mechanism responsible for this decrease in fat oxidation in human muscle is not known and may contribute to the development of insulin resistance. We hypothesized that the transfer of long-chain fatty acids (LCFAs) into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1) in human muscle during hyperglycemia with hyperinsulinemia.
...
We conclude that hyperglycemia with hyperinsulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and shunts LCFA away from oxidation and toward storage in human muscle.
:::"
This explains the RQs, that the presently obese are inappropriately oxidizing glucose at rest when they should be oxidizing fat (cause: high insulin levels, suppressing LCFA entry into the mitochondria), and it also explains why they overproduce insulin in response to carbohydrate (cause: inappropriate metabolic preference for fat before glucose mean a "normal" meal is inappropriately insulinogenic resulting in hunger/sugar swings, and more carb consumption, like pouring gas on a fire).
The RQs of obese people showing high glucose oxidation at rest, reflects inappropriate hyperinsulinemia, and would therefore correlate with hyperinsulinemia, not obesity per se.
This is consistent with evidence that intramuscular lipid buildup correlates with insulin resistance and NOT BMI. Insulin resistance would lead to high insulin particularly eating carbohydrate, which then leads to suppression of CPT1 and LCFA entry into mitochondria, leads to FAT STORED IN MUSCLES. The problem is not obesity, although obesity is often the result (if your fat cells hog up on insulin well).
The evidence Stanton provided showing that overall mitochondrial functioning was low in obese people compared to normal subjects is to be expected as well (not using glucose well, and also not using fat well as a secondary effect of not using glucose well).
This all reflects in subjective experiences & testimonies of real live obese people - " I am always hungry and lethargic, until 2 days into a low carb diet, then my energy improves and I stop wanting to eat all the time, and I lose weight" which is very common. This all correlates with the reduction of insulin from stopping the dietary carb they can't process properly, which then removes the break from fat oxidation. SO, now, even if you do have this "trait" of refusing to prioritize glucose over fat, it doesn't matter because glucose is such a small portion of your diet that you won't become hyperinsulinemic inappropriately, and therefore will not suppress fat oxidation inappropriately.
The problem is not a defect in oxidizing fat. That is only secondary to hyperinsulinemia, and the way to correct it, is to remove the glucose, as the obese metabolism will NOT oxidize glucose preferentially as it should, resulting in high insulin inappropriately that impairs fat oxidation as a secondary effect.
In summary the obese are in a situation where they abnormally oxidize fat before glucose, HOWEVER because they are overproducing insulin while eating a "normal" high carb diet due to this inappropriate metabolism, their overall capacity to generate energy of any kind is significantly impaired due to symptomatic hyperinsulinemia from eating the carbohydrates they cannot oxidize normally (i.e. as long as they eat a "normal" diet with carbs in it).
Woo,
ReplyDeleteCompared to lean, obese people don't oxidize as much glucose (and obviously secrete more insulin) in response to a meal, but their fasting respiratory quotient is higher. I've seen that in skeletal muscle, fatty acid uptake is about 50% higher in obese, while fatty acid oxidation is 50% lower; and of course glucose oxidation is higher [in obese]. Obese do less DNL and more glycogenesis than lean. As JS says, they're "inflexible."
What are the differences between fat people still getting fatter and weight-stable obese?
My assumption has been for a while that a fructose intake outside of evolutionary bounds coupled with a sedentary lifestyle drove leptin resistance via an increase in plasma triglycerides (that block leptin's passage across the blood brain barrier) and hepatic insulin resistance (relative to the periphery) which caused lipolysis to be restricted via insulin's action upon HSL, and thus a preference for glycolysis in the muscle mitochondria (including the heart).
ReplyDeleteIt therefore seems to me that the best course of action would be an avoidance of fructose coupled with a marked increase in activity (specifically a high volume of low intensity activity like walking, easy cycling etc.) that is performed in the fasted state. This would decrease plasma triglyceride and insulin levels and maximize lipolysis.
If the individual remained active and continued to avoid fructose, the level of starch in the diet (provided that it wasn't too much greater than what is needed for glycogen repletion) would be largely irrelevant and the mitochondria would again be able to rapidly switch between energy substrates on the fly.
J. Stanton has done a great job here, but the implication (and it may be a false inference on my part) seems to be that this is an insuperable congenital defect or something of that nature, when a perfectly good explanation is the considerable increase in fructose intake and decrease in activity that has paralleled the rise in obesity. Those who consume the most fructose and are least active would be the most affected, but some could be totally inactive without appreciable increases in triglycerides/insulin resistance (due to their small fructose intake) or eat massive amounts of fructose but be so active that it is irrelevant (except for glycation etc.). Reading an NHANES report would definitely mislead you on this point.
Woo,
ReplyDeleteOkay, those last couple comments is a good explanation. So the excessive insulin comes before respiration inefficiency (I tentatively suggested the reverse above) because certain people can't handle glucose. Now you say it's strongly genetic, which would somewhat imply susceptibility even with boiled potatoes; or, does the hyperglycemia in those susceptible need some type of "toxin," and those resistant are resistant to the toxins, with everyone being okay, at least to start, with potatoes?
Travis,
ReplyDeleteYou said, "If the individual remained active and continued to avoid fructose, the level of starch in the diet (provided that it wasn't too much greater than what is needed for glycogen repletion) would be largely irrelevant and the mitochondria would again be able to rapidly switch between energy substrates on the fly."
Perhaps, but is it [starch/glucose] irrelevant?...Peter did mention Nick Lane this post and c. elegans is the last. With that sentiment, maybe we should just stick with fat!
John: I don't believe that starch is a problem, but if it is consumed during times of activity, the fed state and subsequent insulin spike will decrease lipolysis and fail to decrease plasma triglycerides. It is therefore much more conducive to fat loss if one were to eat starch much before and/or after greatest activity so that muscle mitochondria can use their preferred substrate. I don't know if there is an amount of starch intake that could lead to the same problems associated with fructose intake mentioned above, but if so, it would be a massive amount and would require even less activity.
ReplyDeleteWoo, very interesting part 1 and 2. Where does ASP fit in?
ReplyDelete@J. Stanton
ReplyDeleteRe: the reference for an inability to switch to glucose oxidation after fat feeding...
Fat people oxidize fat after feeding, even in a mixed meal. RQs are depressed after fat people eat, suggesting they are not oxidizing as much carbohydrate, which would be consistent with an inability to respond properly to a rise in glucose (with high oxidation at this time). This is all part of insulin resistance and once again, as is boring and unexciting and old hat as it is, the treatment is not to eat carbs as this will circumvent the defect by eliminating hyperinsulinemia.
http://www.jci.org/articles/view/25758/version/1
"The patterns of glucose and fat oxidation during insulin-stimulated conditions are also shown. In skeletal muscle of a lean, aerobically fit individual (C), insulin strongly suppresses fat oxidation and induces a high reliance upon glucose oxidation, whereas in skeletal muscle of an obese, sedentary individual (D), there is less stimulation of glucose oxidation by insulin and blunted suppression of fat oxidation. Thus, in skeletal muscle of obese, sedentary individuals, there is a constricted range in switching between fat and glucose oxidation compared to the dynamic switching evident in aerobically fit, lean individuals. This constrained homeostatic adjustment to the transitions between fasting and insulin-stimulated conditions in obese, sedentary individuals has been described as “metabolic inflexibility” of skeletal muscle."
Short story: fatties use fat for fuel inappropriately, all the time, even after eating a BIG FAT GIANT bag of low reward boiled potatoes.
Skinny healthy people like Guyenet stop fat oxidation after a nice meal of low reward potatoes, and so do not overproduce insulin in response. This means that their fasting , late post feeding fat oxidation is not suppressed by inappropriate hyperinsulinemia. LCFA nicely enter the mitochondria and RQ drops. Fatties do not see this quite as much, halp insulin done stole my CPT1.
Peter,
ReplyDeleteI suspect that this issue of why do people with "inflexible" metabolism burn preferentially glucose (using too much insulin) over fat and have low fat metabolism, may have something to do with the idea (you know whose...) that they tend to metabolise glucose through an unusual "pentose phosphate pathway" and that they also may reduce the excessive glucose rather than oxidising it, using it as the oxidant for fats. Is it plausible? The question would be (if that is true) what does enforce or trigger such metabolism? Dr. K's idea is that it is the high carb diet containing also an intermediate amount of fat (40%), other factors being mentioned: hypoxia and Mg deficiency. Perhaps this is worth looking into it.
@ItsTheWoo2,
ReplyDeleteThe paper referenced inside the paper you quoted in your comment above seems to corroborate Dr.Kwasniewski's idea ("pentose phosphate pathway" - PPP theory, see my previous comment).
Quote: "Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164-180%) encoding mitochondrial proteins (P less than 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P less than 0.05).
RNA and protein synthesis is the hallmark of pentose phosphate path (PPP).
Interestingly insulin acting upon mitochondria seems to be driving it, whereas in healthy individuals insulin seems to be mostly driving glucose metabolism in the cellular plasma outside of the mitochondria.
I am not a biochemist, perhaps my picture is a bit incomplete (or wrong) but it seems that the key action is driven by insulin:
1) healthy cells - insulin acts upon the cellullar membrane regulating glucose transport through it; a relatively small insulin concentration is required.
2) metabolically "inflexible" cells: higher concentration of insulin is needed to maintain glucose transport; higher insulin concentration acts upon mitochondrion forcing it to process glucose through PPP.
This is the part which I don't understand:
- why do the fatty acids enter the cells together with glucose (in metabolically "inflexible" cells, which does not happen in healthy), what is the mechanism, what triggers it, and why such fats may be oxidised inside mitochondria through glucose reduction? Does PPP force it? (this is assuming that Kwasniewski's theory is correct, I am not 100% sure).
Wooo2, thanks for the info... i only know a guy like that: my old man. He is tall and "relative" lean eating the most terrible SAD you could possibly conceive - with abysmal blood sugar levels and under medication- the thing is... 5 years ago i used to be FAT (and sick) eating regular SAD, (several times per day) so im def not immune at all. something changed. I -think- is the removal of grains or maybe vegetable oils. Most fat people that i know are grain eaters. (ok maybe is not that simple but there is a strong correlation) Anyway i dont consider myself "healed" just A LOT better than before.
ReplyDeleteChris your explanation also looks solid, but the lithium joke is getting kinda old and i really don't take drugs. in fact i haven even taken food since my first post (training now) but as you def know by now that's normal for me :)
@Sue -
ReplyDeleteI have not read much of ASP, I know there was some talk months/years ago how THAT invalidated the "carbohydrate hypothesis". Like most every other research finding purported to "defeat" the insulin / carb hypothesis, it just ends up corroborating it or being misinterpreted somehow.
Side note: Why do people want to invalidate the insulin/insulin resistence/theraputic LC diet hypothesis of obesity so badly? Beats me. Perhaps, and I think this is the reason as Pablo D epitomizes, people just poorly understand the implications, e.g. they think it must mean that "carbs make people fat" or "the world needs to eat low carb" or such, when in no way are these valid leaps of logic.
If a person grows fat on carb, that does not mean carb causes fatness, only that in many types of obesities carbs are the triggering factor. If you are like Pablo D and have no glucose intolerance/obesity, then carbs cannot make you obese.
Most of the resistance to the theraputic LC diet seems to be from indiviuals who are not reasoning correctly ("BUT MY GWAMPA EATS CARBS AND HE WAS NEVER FAT!") That's good for grandpa, now lets have your family switch genes with mine, then tell me what you think of potatoes and rice?
When I google 'acylation stimulating protein" it seems to be a factor which contributes to obesity, but like I said, I have no opinion either way about it or what affects it or how important it really is.
@Pablo DLS
ReplyDeleteWell, I am glad you are at a low body fat now, I had assumed you were just a regular young person who has never had a weight problem, based on your inability to relate to the fact that some people do grow obese based on the type of foods they eat... perhaps it is all a language barrier as I assume your primary language is spanish. There are a lot of ways to get your metabolism in order, and one daily meal of crap, is certainly much better than multiple meals of crap, because you have 23 hours to use glycogen and body fat and keep insulin low. But, meh, we are all different. Arguging for intermittent fasting is basically arguing for low carb anyway. It's a different approach to handle the same problem (do not use glucose normally - do not make insulin normally ... solution: eat glucose once per day, deal with one insulin surge, do not eat again until the next day).
It would be like two vegetarians arguing over whether hemp protein is better than soy protein. They both ultimately agree that meat protein is not possible.
Woo: What are your fasting triglycerides? Is it possible that they are high enough to cause leptin resistance?
ReplyDeletehttp://diabetes.diabetesjournals.org/content/53/5/1253.short
Pablo, the lithium is not a joke. You seem quite seriously hypomanic verging on manic. If you've not been prescribed lithium, consult a physician for a proper diagnosis.
ReplyDelete@Travis
ReplyDeletePrior to leptin therapy my TGs were ~30, my HDL ~95 and my LDL ~110.
My leptin, upon measurement, was <2.
My LH was ~2 and my FSH ~4
I am clearly leptin insufficient, and presently metabolically healthy.
I respond well to a very low dose leptin replacement (0.04mg/kg), and even better to a high-physiologic replacement (0.06-0.08mg/kg).
Every 0.04mg/kg brings the blood leptin level up by a measure of 10.
A fit healthy female with low body fat has a leptin level about that.
An average body fat (not thin but not obese) female has a leptin level circa 20ish.
So, forgive me if I do not at all take stock in the prevailing theory that leptin resistence has anything to do with obesity, and it seems to me this "leptin resistance" idea is only popular because leptin is the last important thing we discovered in obesity research. That was 15 years ago, and guess what, leptin is not even important to obesity (although it is important to obesity CORRECTION which is a different matter all together, much in the way synthroid is important to cancer correction).
@Chris
Pablo doesn't seem manic to me, he just seems enthusiastic and young, plus there is a language barrier.
@john re: comment @ 1:10am
ReplyDeleteI think, and this is all boring and old hat, it all starts with glucose intolerance.
I think the vulnerability to glucose intolerance, as well as obesity, is genetic as well as environmental.
Our nutrition is horrible. Magnesium deficiency worsens insulin resistance. So does chromium deficiency. There are so many micronutrients requried to process glucose normally , lack of which causes that nice low reward potato meal to turn you into a fat stack. Omega 3s. Carnitine deficiency. Inositol. These are depleted by a diet of captain crunch. You are asking your body to process absolutely epic glucose loads, and you are not replacing the nutrients required of it. What do YOU think will happen? Deficiency, and very bad glucose tolerance.
People routinely go without sleeping normally, as if it was somehow physiological to just run on 5 hrs of sleep for a week. They wonder why they get fat.
I have been, over the past few months, reading and supplementing various glucose tolerance enhancing nutrients - the results have been phenomenal. My carb tolerance is so much better, as is my weight gain reistance. I HAVE gained a lot of weight these past few weeks, but that is mostly related to stopping leptin therapy (I am still "thinner" than before I took leptin, so..). If I tried to "diet" right now, it would be so much easier to lose weight than it was before I started taking these supplements, because I much more easily enter ketosis and do not fatten as quickly when eating carbs. My blood sugar does not become unstable as easily (read as: I do not overproduce insulin as easily in response to carbohydrate, indicating my insulin resistance/ glucose tolerance is better).
But anyway, once you are there, and you are glucose intolerant, your body cannot stop burning fat normally, even when you eat taters, you still burn fat, which causes hyperglycemia/hyperinsulinemia in response to any attempt to eat a mixed meal/carb meal, which then suppresses your fat oxidation a few hrs after the meal by suppressing CPT1 due to high basal insulin and higher blood glucose.
The problem is still glucose intolerance, the solution is still low carb, this removes the break on fat oxidation by reducing glucose and insulin, which increases CPT1 allowing LCFA to enter mitochondria for oxidation, making the metabolism somewhat more normal, improving the low energy state, reducing hunger, improving sugar stability, etc. You lose weight then.
ItsTheWooo2 @ 2:21:
ReplyDeleteWe're talking about two different ends of the same phenomenon. Impaired metabolic flexibility means a failure to adapt in both directions.
I'm pointing out that we should be burning as much fat as possible whenever our body is not trying to dispose of excess blood glucose - but impaired met flex leaves us stuck burning significant amounts of carbs in that situation.
You're pointing out that we should be burning as much glucose as possible in the post-prandial state when we need to be disposing of excess blood glucose - but impaired met flex leaves us stuck burning significant amounts of fat in that situation.
Both are consequences of impaired met flex, most likely consequent to impaired mitochondrial function. Therefore, I don't believe we're actually disagreeing.
JS
Wooo, your analysis - a bit patronizing and all- seems correct - and yes some foods are + lipogenic than others.
ReplyDelete(but milk + chocolate =/= omg teh total crap. yes hormones @ denatured, etc but also extra saciety, aka SFA, calcium, slow digesting casein plus a bit ( ok a lot) of magnesium + steric @ palmitic acid, fiber, and glucose / fructose. i can use that. in my experience (year) that combo beats the hell some shitty potato and or rice. ( they used to make me want to eat MORE, + give me cravings)
@Chris i really do appreciate your honest concern, but like i said, keep your drugs to yourself mate, i don't think maniacs sleep 9 to 10 hrs like i do. keep trying :)
Pablo, having had a fair bit of professional experience with the mentally it, I strongly suggest get yourself checked out. Don't discount the lifesaving value of lithium just because you're afraid of taking "drugs."
ReplyDeleteWoo, you are young an enthusiastic, he's mentally ill.
ReplyDeleteChris, i think you are obviously trying way to hard and failing, are Hypo? go eat a banana or something, but please for the love of god just lay out the drugs...
ReplyDelete"Both are consequences of impaired met flex, most likely consequent to impaired mitochondrial function. Therefore, I don't believe we're actually disagreeing."
ReplyDeleteSo, that leaves us with the million dollar question - what causes "impaired met flex"? NAFLD?, micronutrient deficiencies?, micronutrient deficiencies causing NAFLD?, Stress and micronutrient deficiencies and excess fructose? All of the above?
So many fun possibilities to pick from!
It does seem that Paleo living does cover most bases in the possibility cloud though, so the impact of identifying the exact mechanism on the enthusiast crowd might be limited. The importance for the general population cannot be overestimated though.
Oh, needless to say: excellent series of posts + discussion!
@j. stanton
ReplyDeleteI suppose we are not disagreeing re: impaired met flex.
What I was disagreeing with, was your whole thesis seemed to be that obese individuals cannot oxidize fat properly and oxidize glucose relatively normally. This is the exact opposite of the truth, as fat oxidation abnormalities in obesity are downstream of the glucose oxidation ones. This is precisely why the low carb high fat diet is often palliative for obesity, whereas the low fat high carb diet makes things way worse for many fat people. This is why study after study supports the superiority of carbohydrate reduction over any other macronutrient manipulation, when speaking of obesity therapy.
Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity.
ReplyDeleteAlso, if im reading this study correctly it seems that closure of ATP-sensitive potassium channels helps preadipocytes divide and grow.
How do we close ATP-sensitive potassium channels?
"increased intracellular glucose, resulted from hyperglycemia, increases cytosolic ATP through glucose metabolism. This leads to closure of ATP-sensitive potassium ion channels"
im a lay-person in biochem so maybe ive missed something, but it does look like things are lining up to implicate carbs, as usual.
Lastly this study may lend a bit of credibility to the above, potassium ion channel deletion stops rodents getting fat in the face of over-eating.
The researchers attribute it to increased energy expenditure, but perhaps its also because they have an upper limit on the amount of fat cells they can get?
The Rogge paper is a fascinating read. Am I missing something key here or is the implication that the metabolic defect in the mitochondria has a genetic component?
ReplyDeleteIf so, it would explain why people with this defect become broken when exposed to a calorically dense industrial diet, mainly refined carbohydrates.
This genetic defect must have provided some evolutionary advantage, or it wouldn't be so prevalent.
I wonder whether beta alanine supplementation would improve mitochondrial efficiency in these people?
Woo: The LH and FSH seem normal unless you have secondary hypogonadism, which would decrease leptin secretion: http://joe.endocrinology-journals.org/content/154/2/285.short
ReplyDeleteDid you ever have estrogen tested?
Could these be of some interest?
ReplyDeletehttp://www.springerlink.com/content/n51218080847w6lr/
::Aim of the study
To study the relation between glycemic index (GI), glycemic load (GL), and fructose with insulin resistance in a predominantly rural population in the Canary Islands.
::Conclusions
There was a direct association between fructose intake and IR. There was no relationship between GI and IR. Although a direct association of GL with IR was detected, it was attributable to the consumption of fructose.
http://www.sciencedirect.com/science/article/pii/S1262363607002224
::Aims
The aim of this study was to investigate whether fructose may induce early molecular changes in skeletal muscle prior to the development of whole-body insulin resistance.
::Conclusion
HFrD led to alterations of SCD-1, GLUT-4 and PGC-1α, which may be early markers of insulin resistance.
@Makro,
ReplyDeleteMy bet would be that reduced mitochondrial function has a lot to do with thyroid (T3) levels entering the cells. Thyroid hormone is too super-crucial for respiration and energy production not to play a large part in metabolic defects.
Now why the T3 isn't making it to cells is another question- maybe autoimmune thyroid disease in some due to something like gluten, but I am convinced there is something to Peter's ideas that a "broken metabolism" starts in the liver. Fatty liver due to PUFA, lack of choline, etc. would likely have problems converting T4 to T3. Micronutrient deficiency is a logical explanation as well.
My own experience (and some members of my family) with supplementing T3-containing thyroid extract is a very apparent feeling of increased energy and ability to stay warmer in cold environments. Considering we were lean (BMI < 20) before starting and still noticed improvement, I find it hard to believe that any overweight or obese person wouldn't also notice an improved metabolism and metabolic flexibility.
Of course if you view dessicated pig thyroid as a supplement and not really a serious pharma drug, it's not a big deal to play around with different doses as you would selenium or B6. My logic is that if I were butchering and eating my own pigs I would consume the thyroid tissue, so taking it in pill form is akin to taking gelatin in powder form rather than eating cow tendons...
One other note is that extreme low-carb does seem to supress thyroid. B. Barnes mentioned I believe 40 g/day as being the minimum and I'm pretty sure most consume at least that.
@Travis
ReplyDeleteActually, the LH is very low, as is the FSH. A LH of 2 and a FSH of 4 indicates hypothalamic amenorrhea (which is a sign of leptin insufficiency). Hypothalamic amenorrhea is a form of hypogonadism, but it is entirely functional and reversible upon leptin replacement (or alternatively, regaining your lost body fat). If you are wondering I did regain all reproductive competency after low dose leptin replacement and estrogen/lh/fsh levels increased significantly.
This is what is irritating about all this "leptin resistence" nonsense. Body fat is only a small fraction of what leptin regulates - it is an antistarvation hormone, it probably isn't even involved in the pathogenesis of obesity, and as I said before we only talk of leptin resistance because it was the last exciting thing we discovered. We refuse to admit it isn't that important (it IS important to weight maintenance after a post obese state, it is NOT that important to developing obesity). If the obese were leptin resistant, they would fail to enter puberty and would have very low LH and FSH levels, as we observe in cogenitally leptin deficient humans.
This is not at all the case - obesity features precocious puberty and signs of sex steroid excesses (females have PCOS; males get gynecomastia and baldness). This is to be expected if you assume leptin signalling in common obesity is in tact, and insulin is very high.
@blogblog: You pigeon anecdote reminded me of years ago watching gray squirrels at a corn/maize feeder and my surprise that they would nibble out the germ/embyo and toss away the endosperm/starch bulk of the kernel. At the time I thought the squirrels profligate, but it seems squirrels know best.
ReplyDeleteWoo:
ReplyDeleteI wonder if it's possible that you are approaching the leptin insufficiency from the wrong end and that the reduced secretion of GnRH was actually due to a zinc deficiency. Perhaps exogenous leptin is capable of masking the issue at least with regard to the endocrine system. Have you ever been a vegetarian or vegan? Was your previous diet heavy in phytate and low in zinc?
Pablo, there's no need to be so defensive toward someone who's trying to help you.
ReplyDelete@Travis
ReplyDeleteI am way ahead of you. Before participating in a study for leptin replacement I did my research and started taking zinc, just to, you know, see if that was the issue. It made no difference what so ever. Odds are I am not zinc deficient - I lost weight the proper way by eliminating carbs, I did not eliminate red meat (which is why so many anorexics and weight reduced individuals are sicker than they should be).
Travis, trust me, I have done so much research in this area and have first hand lived it. It is indisputable that obese people are relatively leptin insufficient after weight loss. It is also a fat they become ABSOLUTELY leptin insufficient should they diet to a point where their body fat is "healthy" (i.e. myself - I weighed around 120 pounds at 5'5 when I started leptin therapy, and still had a leptin level similar to that of an actively sick anorexia nervosa patient, with a LH/FSH to match).
Please consider, perhaps, that the readings you have been digesting which talk of "leptin resistance" as a cause of obesity, may just be as wrong as the stupidity of the "food reward" hypothesis. It does NOT match up to real live endocrinology of currently and post obese individuals.
It is all hypothetical, and as I stated before, the hypothesis is only in existence because we desperately want leptin to be important to the etiology of obesity because it is the last bit of progress we made. We do not want to admit leptin is an antistarvation hormone of little relevance to obesity.
@Travis
ReplyDeleteIf you are interested in seeing the full text of the study I participated in, I can provide it for you.
It is very interesting and highlights the real physiologic significance of the hormone leptin. It is all about starvation. It is not involved in obesity, and high levels merely suggest hyperinsulinemia and the attending process of abnormal adipocyte hypertrophia and hyperplasia triggered by the high insulin, secondary to glucose intolerance while eating dietary carbs.
High leptin in obesity does not imply resistance and obesity in spite of in tact leptin signalling does not imply resistence
This is the lynchpin logical error so many otherwise intelligent people cannot understand.
For example, I have tested this in myself... when on theraputic leptin replacement it was absolutely true I could eat a TON more carbohydrates before becoming overweight/glucose intolerance instability signs. This is because leptin insufficiency worsens your glucose tolerance in a myriad of ways (hence the reason post obese women and men are not study candidates for understanding metabolism of an obese person).
HOWEVER, it only took a relatively "normal" meal of carbohydrates to send me down the path to shakiness and hunger and lethargy and all that jazz.
This indicates, to me, that my obesity is totally separate from my leptin insufficiency, and in correcting one I caused the other. It also suggests, to me, that lack of leptin binding has no effect waht so ever in my metabolic problem that lead me to become obese in the first place - however, lack of leptin sets me up to make it worse (which is why , probably, people always get fatter than they were before after their diet - their insulin dynamics are even more poor and leptin insufficiency allows for adipocyte differentiation thus a higher minimum body weight after refeeding).
But all the same if you want to see the full text it is quite interesting, they measured numerous endocrine parameters, leptin insufficiency affects every single one, and all respond / normalize to a low dose replacement. The difficulty of maintaining a reduced weight is, tragically, as simple as a tiny hormone replacement, and it's a s hame fat people berate themselves for being weak and having no willpower when they can be cured instantly if they take leptin while following a glucose controlling diet.
haters gonna hate Chris... dont be mad, is really NOT my fault if you JUST CAN STOP EATING LIKE A PIGGY mate! XD
ReplyDeleteRAAAaage; omg you think u are cristh! lithium! (how does he do it, bastard!) just sad.
Woo: Yes, I'd be very interested in reading that study. My gmail account is simply my name if it needs to be e-mailed.
ReplyDeleteIs it your belief that leptin insufficiency would continue ad infinitum or if a formerly obese person could manage to keep the weight off by whatever means necessary, would it normalize on its own? Is there any possibility of you addressing some issue that allows you to not have to receive it (that may not appeal to you, but I'm just wondering).
Come on people,this is supposed to be an intelligent place to discuss nutrition and people are resorting to telling someone to get on lithium because he drinks chocolate milk?Pablo,if it works for you then god bless.Can you give details to what you eat everyday?
ReplyDeleteThe role of Leptin is very interesting indeed. Here is a link summarizing Leptin Deficiency after losing weight, based on a talk by Rudy Leibel from Columbia University.
ReplyDeleteIt reinforces what I think Woo is saying.
Here is the link:
ReplyDeletehttp://www.drsharma.ca/obesitywhy-is-it-so-hard-to-maintain-a-reduced-body-weight.html
Here is another link on the same topic, also summarizing some of Leibel's research:
ReplyDeletehttp://www.drsharma.ca/obesity-why-hyperleptinaemia-is-not-leptin-resistance.html
I find it pretty depressing if true. It means when you lose weight, you also get much lower leptin and lower energy expenditure than non-metabolically damaged people at the same weight. They say there is no known way to reverse the metabolic damage (without brain surgery), you can only make it worse.
An interesting question to me is if a ketogenic diet can somehow sidestep these problems? Or, maybe a ketogenic diet would just allow you to subsist with much lower energy expenditure without feeling hungry?
GoBears,
ReplyDeleteWhy would a ketogenic diet lower EE?
Woo or Peter,
Why are obese fasting RQs higher if they're supposed to be insulin resistant? So their insulin action is "strong enough" in the fasting state to encourage glucose oxidation, but not post-prandially? Why would obese have less DNL with an exaggerated insulin secretion?...It's as if a large carb meal triggers resistance?
@john
ReplyDeleteI just posted something that may address a similar question you asked me on Stephan's blog.
@Travis
ReplyDeleteSent :)
I have been maintaining weight for 9 years. I started the low carbohydrate diet at 20, and then rapidly cured my obesity. I am going to be 29 in a few days. I have, thus far, not resolved the relative leptin insufficiency, the only time I felt "normal" and "naturally thin" rather than post-obese, and suppressing my weight, was the 2 years I took leptin.
I lost my menstrual cycles at about 145 pounds, which is by no means a thin weight for me. It's not an obese weight, but it is a bit chunky. I'm 5'5. I could settle for semi-fat, like so many other dieted obese people do... but why? If I am going to do it, might as well do it right and be properly thin.
The only time I had them back, was the two years I took leptin. My body is behaving as if it is starving to death, basically. LOL. It is a testiment to the efficacy of carbohydrate restriction that I am able to, with relatively mild difficulty, maintain my weight, in spite of the fact my body is like "NOOO YOUR STARVING lets shut everything down!"
No insulin spikes, no fat accumulation, thus no hunger/lethargy. That is the sequence of events in obesity. Regardless of what stubborn crackpots (ahem Guyenet) would blog at length to discredit, this is the reality of obesity. It is all about insulin in the context of a certain adipocyte genetic potential. (NOTE: this does not mean it is all about carbs, as more than carbs affect insulin, a lot more).
I have noticed that since having fat cell removal surgery (skin removal) that it is "easier" to maintain my weight now in the sense that I feel more comfortable/fed the way I did when I was taking leptin. I suspect that the primary defect causing post-obese leptin insufficiency is the fact that having years of hyperinsulinemia results in adipocytes abnormally replicating in number, this is not resolved by glucose stabilization and insulin reduction. The post obese person has 3 times the fat cells of a normal person, so when I am weighing "a healthy 120 pounds" it is like a normal woman weighing 90 or 100, at least in terms of my adipoctye size and leptin dynamics. So, for me to be a "healthy 120 pounds" i need to be more like, an "Unhealthy and obese 160 pounds".
Indeed, circa ~170 pounds is when I noticed my body started fighting me and the weight stopped melting off. I suspect that somewhere, around there, is where I would have had normal leptin dynamics/normal adipocyte size. But that is obese, FYI.
Our physiology never anticipated corn syrup, never anticipated extremely high glucose loads minus proper nutrients (e.g. magnesium/chromium). Our physiology never evolved with a situation where ABNORMAL adipocyte hyperplasia could ever occur. There is , therefore, absolutely no natural cure for obesity - we can, at best, regress it somewhat , and we can arrest its development, but we can't return a morbidly obese person to the same state they would have naturally been in, had they not been exposed to this.
There are known "cures" now - removal of fat cells after dieting , supplemental leptin replacement - but none of these are understood by the mainstream medical or research community, just a few fragmented people here and there and a few internet quacks like myself. I will, probably, never see the proper treatment in my lifetime.
@GoBears
ReplyDeleteSadly, it's true, and unlike other bloggers I won't lie to people and say they can cure or totally solve their obesity. Fact time: you can't. Obesity is a real disease like any other, your body permamently changes from hyperinsulinemia, your adipocyte tissue is FUBAR, and because unfortunately so many researchers are clueless, we won't see proper treatment for a really long time if ever. We will never cure obesity in the sense of allowing people to eat whatever they want and not get fat - there are too many distinct genetics, too many types of obesities, and the evidence amounts to it being a FUNCTIONAL TRAIT to capitalize on seasonal food excess that is being triggered abnormally in modern society.
However that' doesn't mean you should give up, and it is possible to maintain a reduced weight if you do it intelligently - by controlling and avoiding pathological insecretion, by eating a diet that agrees with your metabolism disorder, and supplementing the crucial nutrients required to properly metabolize food.
And, good news, it's probably much much easier for men to maintain reduced weight as female physiology evolved to be HIGHLY sensitive - and reactive - to nutrient trends. Testosterone largely replaces many effects of leptin. It takes much more severe levels of starvation for men to suffer the same way. This explains the common observation - women struggle to lose weight and keep it off, whereas men often just blast through and have few problems at the lower weight assuming he maintains the original diet that allowed him to lose weight.
Leptin is sexually dimorphic, it is almost an attending co-factor for female endocrine system. AT puberty, having testes means leptin levels drop from the prepubertal level, simply because testosterone production shuts down leptin. A lot of the things "leptin " does, like allow for normal dopamine stores/release and raise IGF1, are simply neatly replaced (and augmented) by testosterone. Men do require some leptin, and congentially leptin deficient males never enter puberty and are infertile, but they just require a lot less of it. The replacement dose for leptin in males is like 0.01-0.02. Very very low.
Having ovaries means that at puberty the opposite happens, your leptin levels rise a lot (women have 3 times the leptin of men), and there develops an involved feedback loop between leptin and estrogen, both in terms of serum levels and receptors. The lowest dose replacement of leptin for a female is 0.04, and upward.
Male physiology is designed for leanness, and does not respond/freak out to weight loss quite as much as female physiology does. This is reflected everything you have ever read on any blog/forum of dieters.
As I wrote above, ketosis and tight insulin control will only sidestep the "fattening" part, meaning it controls hunger and arrests body fat gain in spite of leptin insufficiency. It does absolutely nothing else to remedy the leptin insufficiency associated with weight loss, as my lab works and pathetic lh/fsh/cortisol/free t3 levels support.
@GoBears
ReplyDelete(ugh sorry for posting so excessively, it's the caffeine)
Regarding Dr.Sharma, he only has half the picture.
They assume that a high CNS leptin set point is the reason that obese people are obese - this is false. The obese have a high leptin level because of glucose metabolism dysfunction, which is rarely related to leptin at all. The obese are actually "above" their weight set point. This is why when obese people go on low carb diets, OVER NIGHT they instantly and effortlessly lose weight. This would not at all be possible if they were at their ideal leptin set point. By removing the disorder of glucose/insulin/adipoctyes cycle, their leptin can work PROPERLY to return them to their minium body fat weight.
If I was leptin resistant, or if I had a "high leptin set point" I would not have lost 100 pounds in a few days, without any signs of starvation, simply by adopting a low carb keto diet.
I do think the obese have a higher body fat after losing weight, but the defect is not central, it is peripheral: Insulin mediated adipocyte hyperplasia results in a chronically insufficient level of leptin production when adjusted for body fat in kgs. The weight gain resistance people run into while still having high leptin, and still being very fat, probably have much more to do with inadequately controlled glucose/insulin dynamics. Basically, they are usually eating too many carbs, too much protein, and they are not adequately controlling the glucose metabolism disorder.
If Sharma could talk to Taubes, we might get somewhere.
Strontium,
ReplyDeleteOkay, that works [about the fasting RQ] I suppose, though I don't think insulin sensitivity is solely dependent on glut4 (is it even the dominant factor?). If the problem with the obese is insulin, then why would they do less DNL?
So I had a look at both the links posted by Go Bears.
ReplyDeleteI never really understood much about leptin and it's role in metabolism. For me it is much easier understanding the role of insulin.
Anyways, I am quite intrigued by what the article said combined with what Woo has to say.
So while the article may argue for a 'set point' and Woo says that the article is neglecting that this threshold is much higher in obese people (rather than obese people having a higher threshold which is considered normal---it must be physiologically abnormal at higher levels as evidenced by Woo being able to drop 100 pounds, which thereby lowers the leptin levels.) I therefore would agree with Woo, that the threshold is abnormally high in the first place in obese people. The article is a good starting point.
Woo, I'm curious what you think about periodic 'refeeding' in order to 'physiologically give the body a break from dieting'? *Note: this article seems to be discussing this within the context of caloric restriction. Assuming that obese people have broken metabolisms which clearly they do then wouldn't this refeeding (of carbs) be harmful? I'd love to know your opinion.
Btw, I would also like to have a copy of the study you participated in as well.
zorica.vuletic12@gmail.com
I definitely agree that a ketogenic diet sidesteps so many issues regarding impaired metabolism. (Whatever the root cause might be thought to be and/or so badly argued over---pretty much sidestepping hyperinsulinemia/abnormal glucose tolerance). I also ask, like John, how could ketogenic diet lower energy expenditure?
Peter, great post and good discussion here!
This comment has been removed by the author.
ReplyDelete@Wolf, sure no prob, drop me an email, and ill gladly give you some more input. (can't give you guarantees, but i did manage to help a few friends get lean @ healthier)
ReplyDelete@woo 29?.. im 5 years older that you! (adios age argument) the only consolation i have is that i look/ feel 15 years younger...
Travis Culp:
ReplyDeleteIn the article I deliberately avoided speculating how the mitox problems arise, because I'm not confident enough in any specific chain of causality to assign blame yet. What I'm hoping to do is bring the issue to the attention of the community so we can work on the problem.
I suspect there is genetic variation involved, but I doubt it's a specific mitochondrial defect...I suspect they're alterations in nutrient processing and conversion that make the system more brittle, so that mitox breaks more easily.
Svero:
Thank you! It's a huge subject, and I can't claim to be exhausting it.
Makro:
Exactly. From what I currently understand, the functional paleo model provides solid practical advice, which is why I advocate it.
However, it's important to know why these things work, both for our credibility, and to find improvements.
I'm glad you find my articles valuable!
ItsTheWooo2:
No, I agree that glucose oxidation is a problem too. I'm just not as confident in the chain of causality as you are.
Recall that the article's purpose is to analyze hunger, not to propose a hypothesis of how mitox becomes broken. When a healthy person's blood sugar drops after a post-prandial insulin spike, their metabolic switch falls towards "fat" and they're fine...whereas a damaged person will become ravenously hungry, because the switch is stuck partway over towards "glucose" while the glucose tide is receding.
Kindke:
Healthy rats are metabolically flexible, and I wouldn't expect changing the substrate oxidation ratio farther towards fat would have an effect anyway. The interesting part would come in if you pushed the ratio the other direction from control (towards glucose) or somehow clamped it in the middle to simulate loss of met flex.
allison:
Re: genetic variation, most likely you're correct - but I doubt it's directly in the mitochondria. See my comment to Travis above.
Also, caloric density is only one part of hunger. If it were the overriding factor, all anyone would need to lose weight is a big jar of sugar-free Metamucil.
Strontium Pup:
Yes, fructose has a big target painted on its back. I suspect that high fructose consumption will someday be proven causative (though not exclusively causative) to metabolic syndrome.
Owen:
Paul Jaminet, of Perfect Health Diet, recently wrote an excellent series of articles on low-carb and the thyroid which I highly recommend.
Everybody:
Thank you for your time and thoughts!
I know it's currently fashionable to impose bold new Grand Unified Theories of Obesity on everyone - but I think what the community needs now is a lot more patient investigation of the existing literature, and careful assembly of existing facts into hypotheses about causal connections. I'm glad to have your eyes on this issue...I've already seen some interesting connections made, and I hope to see more in the future.
JS
@john
ReplyDeleteI'm not sure about DNL, because according to this study:
http://www.ajcn.org/content/73/2/253.full.pdf
"Conclusion: After a high-carbohydrate, low-fat meal, overweight men had a lower fat oxidation and a higher fractional
hepatic fat synthesis than did lean men."
Obese individuals also exhibit higher fasting DNL:
http://www.ajcn.org/content/77/1/43.full.pdf
Do you have evidence of the contrary?
Stront,
ReplyDeleteI figured there was something that opposed http://www.nature.com/ijo/journal/v28/n10/full/0802760a.html
...guess I was too lazy too look.
This comment has been removed by the author.
ReplyDeleteThis comment has been removed by the author.
ReplyDeleteWoo,
ReplyDeleteThanks for the explanations, very helpful! I am still left with two big questions in my mind.
(1) For those with broken metabolism or formerly obese, is it universally known and accepted that after losing weight, their energy expenditure is lower than normal people at the same weight?
(2) In what way does low carb eating (lets say mildly ketogenic), change the picture? Does it allow easier maintenance of weight (after weight loss) by reducing hunger? Or does it allow higher energy expenditure then otherwise possible?
@J. Stanton
For question (2), I think your articles somehow argue that you can restore your ability to burn fat, so in fact low carb would allow you to keep weight down by increasing energy expenditure more than would otherwise be possible on a normal diet.
Would love to see some links to papers or blog posts for these 2 issues.
@john
ReplyDeleteGot it: Minehira et al. (your paper) use indirect calorimetry to derive "net" fasting DNL. The Schwartz paper discusses the limitation of this approach in the introduction. Instead, Schwartz et al. use mass isotopomer distribution analysis that yields a more realistic fasting DNL measurement (they say).
Re (1) For those with broken metabolism or formerly obese, is it universally known and accepted that after losing weight, their energy expenditure is lower than normal people at the same weight?
ReplyDeleteI don't know to what extent it is generally known but the Rogge paper The Role of Impaired Mitochondrial Lipid Oxidation in Obesity" J Stanton linked to has this to say
Higher RQs, indicating reduced fat oxidation, have been observed in preobese and reduced-obese participants compared to lean individuals (Astrup, Buemann, Christensen, & Toubro, 1994; Filozof et al.2000; Simoneau, Colberg,Thaete, & Kelley, 1995).
Preobese and formerly obese people have lower rates of fat oxidation and are more dependent on glucose use than normal-weight people. However, when pre-obese and reduced-obese people gain weight, their RQ declines to normal or below normal levels, indicating their fatty acid oxidation improves as their lipid stores increase. This means that an obese individual requires higher than normal endogenous lipid stores to achieve a more normal balance between fat and carbohydrate oxidation (Ruderman et al., 2003).
Re In what way does low carb eating (lets say mildly ketogenic), change the picture? A ketogenic diet may improve mitochondrial function and biogenesis (along with other strategies such as high fat diet, resistance training, endurance exercise) as set out in Mitochondrial Energetics
and Therapeutics
These speculations suggest that the ketogenic diet may act at multiple levels: It may decrease excitatory neuronal activity, increase the expression of bioenergetic genes, increase mitochondrial biogenesis and oxidative energy production,and increase mitochondrial NADPH production, thus decreasing mitochondrial oxidative stress.
I do urge everyone new to these ideas read both those papers very carefully.
There is much that can be done by formerly obese people that will help prevent weight regain while eating to satiety and drinking (red wine) in moderation.
@Peter
ReplyDeleteOff topic, but what do you think about the following:
In Paul Jaminet's book, he states on p.44
"Ideally, most cells should never metabolize glucose directly - they should obtain all energy either from fats or from glucose-6-phosphate peeled off in a controlled way from glycogen."
My understanding is that any oxidation of glucose, whether dietary glucose or from glycogen stores, will always pass through the glucose-6-phosphate stage.
Dietary glucose -> hexokinase -> glucose-6-phosphate -> many steps -> pyruvate
Glycogen -> glucose-6-phosphate -> glucose-1-phosphate -> glucose -> hexokinase -> glucose-6-phosphate -> many steps -> pyruvate
Is there any method by which glucose does not go through the intermediary stage of glucose-6-phosphate and is metabolized directly?
@john
ReplyDeleteWhen GobBears spoke of ketosis and EE, he was speaking of utilizing a ketogenic diet to circumvent the pressure to fatten (hunger/easy fat gain) which is levied by leptin insufficiency status post weight loss. He was speaking of EE in the context of being a sign/symptom of leptin insufficiency (energy inadequacy, and hunger).
There is evidence that ketosis can depress metabolic rate, which is probably secondary to insulin and leptin reduction, as both insulin and leptin increase ft3. Metabolic rate and thyroid hormones often decrease on such a diet, but this is functional, and one may argue that hypermetabolism observed in obesity is abnormal sign of insulin and leptin excesses. This also is yet more evidence that the undieted obese are not leptin resistant: thyroid axis is typically upregulated during obesity, and many (not all but many) obese complain of typical hyperthyroid symptoms (agitation, sweating, anxiety, discomfort, easily overheating, high blood pressure).
After dieting things change, so my statements about obesity and hypermetabolism only apply to the obese who are not manipulating or restricting food intake.
It's common for women who pathologically starve/restrict calories, without eating adequate protein, to develop functional hypothyroidism, but this is not the same as leptin deficiency, leptin resistance, OR hypothyroidism. It is dieting stupidly.
@gladina
ReplyDeleteRefeeding... I was skeptical from the outset when I first heard of it. I think refeeding is a good approach for people chronically in energy deficiency in an attempt to become very lean (e.g. body builders). I do not think it is helpful for leptin insufficiency status post obesity, because my leptin deficiency is not the result of inadequate energy intake as it is for someone like an athlete/body builder. Thos people are doing more work than they are taking in energy - the body suppresses leptin to prevent further fat tissue atrophy. I lay about and do no exercise, except walking and that which my body naturally compells me to do from having normal energy. I eat a ton of calories in fat and protein. My micronutrient status is quite good and my supplement list is exhaustive. I take tons of omega 3s, chromium, zinc, mag, so on.
My leptin is not suppressed, my leptin is what it is after being fourty million pounds, and now being waif-like. I have the body fat kgs of a teenager who has never been obese, but I have the fat cell numbers of an enormously obese person. My fat cells are atrophied abnormally, and so my lab work reflects this (leptin like an anorexia nervosa patient, with attending endocrine disorders - higher cortisol, very low LH + amenorrhea, low IGF1, high IGFBP, disordered RQ, symptomatic fatigue/hunger/relatively worse glucose tolerance etc).
So, I was highly skeptical that refeeds could help.
The few times I did "refeed", meaning to say, eat a ton of calories and carbs... not intentionally but merely due to pleasure ... I observe that the next day I feel absolutely replenished as can be expected of higher leptin levels. My appetite is far lower, and my energy is better. However, the effect is very temporary (like a day max) and the net influx of fat gain does not justify the temporary amelioration of leptin deficient symptoms.
If it takes 3000 calories for you to feel "normal" the next day... and the next day you naturally eat just like, 1700 and feel very full on that... this does not equal weight maintenance at all. You are still in a positive energy balance. You will need to still restrict, consciously, your energy intake and feel some hunger if you wish to avoid gaining body fat.
Perhaps a refeed ONLY on glucose would be better than a mixed meal refeed, but I doubt it, as evidence suggests mixed meals are more insulinogenic thus better at raising leptin than would be a pure carbohydrate meal. The idea is to spike insulin high, as that spikes leptin the best. The idea is to get your leptin up, and a high cal mixed meal does it better than anything. A pure carb meal would be superior for an athlete as that is the best way to replenish glycogen but this is of no concern to me as I am not an athlete, we are only concerned with spiking insulin and leptin here.
@gladina
ReplyDeleteI forwarded you the copy of the email I sent Travis, I hope it helps.
@J.Stanton
The reason people in early stage insulin resistance experience hypoglycemia after meals is because their liver is not very insulin resistant and easily suppresses glucose dumping/glucagon. This is the major reason reactive hypo happens - the insulin excess, prompted by the carb they can not tolerate, suppresses the counter regulatory response in the body, and so blood sugar drops more than it should 90 minutes postprandially at the insulin peak. This is a sign of early insulin resistance.
It disappears later, if/when the person progresses to diabetes, then we see the opposite disorder - high insulin resistance in the liver means the liver is spewing out sugar 24/7 with no ability to suppress it, and you find postprandial hyperglycemia with no hypoglycemia.
SO, hyperinsulinemia with reactive hypo is the first sign of insulin resistance, and hyperglycemia (frank,prolonged, diabetic) is later (if it develops at all - those with very rapid insulin prcoessing in fat tissue, with a good genetic potential to obesity, may remain "metabolically healthy" in spite of glucose intolerance).
So, it's less about mitochondria being inflexible postprandially, reactive hypo is more about insulin stopping the liver from making sugar while simultaneously ushering it into cells for storage. .. no different than what occurs when you inject a few units into someone with a syringe, the liver stops making sugar and the sugar currently in the blood dips. If the insulin overdose is extreme the only cure is glucagon (you then inject the counter regulatory hormone, which is presently suppressed by the injected insulin, and poof the diabetic comes to).
Great read. Love the blog. thanks, Vaporizer
ReplyDeleteThanks for the feedback on my questions. The question is not about the RQ or partitioning of energy expenditure between glucose & fat burning, but rather the total energy expenditure. I suppose the more specific questions about energy expenditure are:
ReplyDelete(1) Is resting metabolic rate (RMR) lower in formerly obese compared to healthy people at the same weight?
This paper did not observe any change in RMR:
http://www.springerlink.com/content/f8267542hl877222/
However, this meta-anlaysis found 3% to 5% lower RMR in formerly obese:
http://www.ncbi.nlm.nih.gov/pubmed/10357728
Seems its controversial.
(2) Same question but for activities like walking, running, etc...?
For my question about the effect of low carb diets, Dr. Eades had a post a few years ago which hypothesized that lower triglyceride levels in low carb diets allows leptin to work more effectively, sort of restoring your leptin sensitivity.
http://www.proteinpower.com/drmike/metabolism/leptin-low-carb-and-hunger/
The paper linking triglycerides and leptin resistance:
ReplyDeletehttp://diabetes.diabetesjournals.org/content/53/5/1253.long
On the SAD diet, many people have high TG, while on paleo or low carb, TG generally are much lower. My own personal experience was TG > 300 on SAD, and TG < 90 on paleo.
GoBears,
ReplyDeleteI think you'll find mixed results, as I have read a study that reviewed others with the criticism that there wasn't consideration for lean mass or lean mass lost. In it, the formerly obese had the same BMR as lean when adjust for lean mass. Sorry I can't find it, but I'm sure you can if you care to look.
GoBears,
ReplyDeleteLucas Tarfur of Ketogenic Nutrition recently wrote an interesting post on leptin and insulin signaling.
Hi all,
ReplyDeleteNice to see the discussion has been on going, sensible and pretty polite. Thanks all. People seem to have covered most of their bases and I don't see much for me to add.
Motzart, I don't know that there is any route for glucose other than glycolysis...
Stan, PPP is definitely on the list of "fitting in" to do, especially for the initial injury.
Ted, yes, very careful reading. Plus she never even dares consider the prompt and near immediate normalisation of appetite on LC eating. Or (gasp) ultra low fat eating either. We have to visit all of these scenarios. But looking for a physiological way to breed intramyocellular mitochondria is to be applauded. I'm not sure how successful it would be alone. Reminds me of CF/ME advice too much (probably the same problem). But definitely an adjunct.
Ta Woo. Where do you get the time? I can't do this.
Peter
@Peter
ReplyDeleteSome of it = Binge posting sessions after a good cup of coffee. The rest is just obsession from my weird brain.
I have been trying to avoid the binge posting as it reaches a point where everyone is annoyed. Feel free to delete anything that is ridiculous.
Srry. :(
Woo,
ReplyDeleteI mean I can't go through the detail you do. I'm not objecting. Obviously there is never 100% agreement between any two people but you do pretty well.
Peter
I will follow Peders advice on buying a vaporizer for weed.
ReplyDeleteJust to say I'm a big fan of "Itsthewoo2" too, although she does go on a bit :-)
ReplyDelete(But she gets me (and maybe others) thinking, which should be good).
@Woo: I think you are right about leptin. No idea about the other stuff though.
...
:-)