The house mouse Mus musculus is an incredible research tool in the biomedical sciences, due to its ease of care and its ability to be genetically manipulated. Although mice aren't humans, they resemble us closely in many ways, including how insulin signaling works. Genetic manipulation of mice allows researchers to identify biological mechanisms and cause-effect relationships in a very precise manner. One way of doing this is to create "knockout" mice that lack a specific gene, in an attempt to determine that gene's importance in a particular process. Another way is to create transgenic mice that express a gene of interest, often modified in some way. A third method is to use an extraordinary (but now common) tool called "Cre-lox" recombination (1), which allows us to delete or add a single gene in a specific tissue or cell type.
Studying the relationship between obesity and insulin resistance is challenging, because the two typically travel together, confounding efforts to determine which is the cause and which is the effect of the other (or neither). Some have proposed the hypothesis that high levels of circulating insulin promote body fat accumulation*. To truly address this question, we need to consider targeted experiments that increase circulating insulin over long periods of time without altering a number of other factors throughout the body. This is where mice come in. Scientists are able to perform precise genetic interventions in mice that increase circulating insulin over a long period of time. These mice should gain fat mass if the hypothesis is correct.
I attended an interesting talk this week by Dr. John S. Parks, who studies lipid metabolism at Wake Forest University. He described data from a mouse missing a protein called ABCA1 specifically from the liver (generated using Cre-lox recombination). For reasons that I won't get into here, when fed an obesity-promoting diet, these mice develop heightened insulin resistance in the liver that results in substantially increased circulating insulin relative to normal mice fed the same diet. This suggests that insulin resistance in the liver can lead to whole-body insulin resistance, which is interesting. However, these mice do not become fatter than normal mice; to the contrary, at older ages they weigh slightly less.
Another interesting model is the liver-specific insulin receptor knockout (LIRKO) mouse. These mice lack the insulin receptor specifically in the liver. Although they have more than ten times as much circulating insulin as normal mice, their leptin sensitivity and body fatness are normal (2). Chris Masterjohn commented on this a while back (3).
Then there's the liver-specific IGF-1 knockout (LID) mouse. They maintain the same body weight as normal mice over time, despite having nearly four times more circulating insulin (4, 5).
Another model is the LIKK mouse, which has a modest overexpression of the inflammatory gene NF-kB in the liver specifically. This mouse has elevated circulating insulin yet has a "normal overall appearance, body weight and food intake" (6).
In an interesting 2002 study, researchers orally administered a small molecule insulin mimetic (drug that mimics insulin action) to mice and placed them on an obesity-promoting diet. Mice that received this treatment gained less fat than mice that were not given the drug over the course of six weeks (7), consistent with insulin's ability to constrain fat mass by acting in the brain (8).
These studies suggest that insulin sensitivity in the liver is important for whole-body insulin function, and that low-grade inflammation can impair insulin signaling in the liver, just as it does in other organs. Together with studies showing that preventing the increase in circulating insulin that occurs on fattening diets has no impact on the rate of fat gain in rodents or dogs (9), this suggests that high circulating insulin per se is neither necessary nor sufficient to cause body fat accumulation.
* This does have some hypothetical basis, which centers around the proposal that high circulating insulin causes leptin resistance in the brain. In cultured fat cells, insulin exposure increases SOCS3 expression (10), raising the possibility that the same could happen in other cell types. The reason this is relevant is because in the hypothalamus, SOCS3 is one of the main negative regulators of leptin signaling during the development of obesity. However, I'm fairly certain that insulin has not been shown to suppress leptin signaling in the hypothalamus, and the studies reported above would suggest it does not do so under normal circumstances.
Assuming that high circulating insulin causes Leptin reistance in the bain, is it possible that the study did not run long enough to create this effect, therefore no weight gain resulted?
Peter at Hyperlipid has written about the LIRKO mouse. As one might expect, his interpretation is quite different:
"Does this massive hyperinsulinaemia inhibit lipolysis? Well, yes it does.
Interestingly FFAs are only reduced by about 40% compared to the control mice. But they are reduced. So why don't these mice become obese?
Ultimately they don't become obese because they cut calories. They are ad lib fed, they must cut calories because they're not hungry. Gasp."
I have a feeling the other experiments with genetically mutilated mice are subject to alternative interpretations as well.
It is formally possible. However, these studies lasted more than long enough for the mice to become obese, so if it does have an effect, it would have to be a mild late-onset effect. I haven't seen any evidence that it occurs, although it's a formal possibility that something like that could occur if you followed them to old age.
Peter's ad hoc speculation does not line up with the evidence. LIRKO mice have a normal food intake, as reported in the study I cited.
When I've read about it in the past I've found the LIRKO mouse's enormous beta cell mass especially interesting.
Casts an interesting light on the old
"pancreas gets tired of producing so much insulin"
popular guess/explanation of type II diabetes and metabolic syndrome.
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What about the effects of cortisol on leptin receptors, promoted by elevated insulin? Just saying.
Ok, so give these mice free access to food and see what happens with them vs. the control group. :)
Do these animals the LIRKO mice exhibit insulin resistance in the brain? Did the small molecule insulin mimics cross the BBB? Curious and I don't have access to the literature right now.
"Ok, so give these mice free access to food and see what happens with them vs. the control group. :)"
The LIRKO mice in the cited study were fed ad libitum.
Unless you deny that mouse metabolisms are different than human metabolisms with respect to insulin, the LIRKO mouse pretty much shuts down the typical Carbohydrate-Insulin Hypothesis. Under that hypothesis, high insulin impairs lipolysis and leads to "internal starvation" that then leads to hyperphagia which itself leads to obesity.
LIRKO mice have huge amounts of insulin and impaired (though not completely blocked) lipolysis, and yet they do not exhibit hyperphagia or obesity.
As alluded to by WIlliamS, Peter has posted on the LIRKO mice too. His second blog post on the subject is particularly interesting and provides an alternative interpretation of the study:
The carbohydrate-insulin theory of obesity has become a multi-headed, ad hoc hydra. The advocates defend it from criticism by continuously changing it to the point that it no longer really means anything.
To be clear:
"Low carb diets work"
Does not equal
"The carbohydrate-insulin theory is correct"
The data in this post is incredibly damning for the CIH, but the proponents of the CIH just continue to advance corrective theories that totally undermine the CIH.
For example, Taubes wrote a book and a half advancing the idea that carbs -> insulin -> insulin resistance -> impaired lipolysis -> internal starvation -> hyperphagia -> obesity.
Then, at AHS, he casually mentions three-quarters of the way through his talk that he now thinks excess fructose consumption causes insulin resistance. News flash: that's not the CIH, that's the fructose-insulin theory of obesity. There's an enormous difference. And yet, people still defend the CIH, usually in his name. It doesn't make any sense.
Low carb diets work, but not because post-postprandial insulin surges lead to insulin resistance that then leads to hyperphagia and obesity. The details matter.
The reason I have been a fan of Taubes is that he put forward to a broad audience the idea that endocrinology is the field most likely to explain why we are in the middle of an obesity epidemic. I see this as his central insight. While the vast majority of the nutrition/public health community views overweight and obesity as best viewed as problems of psychology or resource economics, Taubes has waged a tireless campaign to say that maybe the way the body regulates fat might give us important insights.
There have always been big gaps in his message as far as what are the salient underlying mechanisms. But I think that he has always been clear that he is saying that the CIH is a hypothesis which needs to be tested instead of ignored.
The bulk of the nutrition/public health community continues to mostly ignore endocrinoloy as key to understanding the obesity epidemic. I think it's sad that it has fallen to a journalist to try to make sense of why the concept of consciously trying to achieve energy balance has failed us so calamitously. Rather than taking the questions Taubes raises and answering them, and helping the rest of understand where he fall short, nearly every critique of Taubes by academics or health professionals have show that they do not understand what he is saying or have not read him. Stephan's writing is the first place I've found that critiques the CIH that begins with an understand of what it says in the first place.
Taubes comes across as arrogant and he's a polemicist at heart, but I've always read him as saying at root - "The conventional wisdom makes know sense when you approach it as a scientist and let's figure this stuff out like scientists, rather than moralists." He has long said that fructose may play a special role, but has only recently started digging into that. Why is that damning?
Probably, the answer from the people or diabetic animals who receive insulin injections would be different.
Yes Galina L -- as a person with Type 2 Diabetes (Metabolic Syndrome) I have direct personal experience of significant excess fat mass gain (in excess of 100lbs over a 12 month period) while injecting insulin to control my Blood Glucose. And while my experience may be discounted: as I am not healthy but instead am metabolically disordered, I might say the same about the mice used in these studies. There is evidently a strong association between injecting insulin and fat mass storage.
Try injecting some healthy, normal unadultearted mice with excess insulin and feeding them ad-libitum on a diet rich in sugars and refined starches (AKA the SAD or Western diet) and see what happens.
A theory of obesity that can't explain how healthy people become obese is not a very good theory of obesity.
The CIH says that a high carbohydrate diet will make healthy people obese over time due to the downstream effects of repeated post-prandial insulin surges. There is ample evidence that this is not correct.
Does that mean that low-carb diets can't reverse or prevent obesity? Of course not.
Dr Robert Lustig still seems convinced about the relationship between chronically raised insulin and obesity...
The fact that people are not the same adds to the confusion. Not all healthy individuals on a SAD diet became obese, not all obese turned into diabetics 2. It is almost fanny, but some naturally thin ones get D2. So what if genetically modified mice are fine with high insulin level? Why it is the answer? Well , some people stay slim and healthy on a potato diet. It is wonderful, of course, but then such people start telling everyone that their diet is the answer to the question about how to cure an obesity in USA (it is enough to eat enough blueberries, sweet potatoes and cook your own food).
Unfortunately, we are not tested in order to determine what makes the difference between naturally skinny folks and easy-to-get chubby folks. Some thinks it is the insulin level. May be, may be not. We are not tested. However, insulin still looks quite suspicious for me. I based my dieting strategy on the insulin theory and got better weight and better health. Actually, my health got better much faster than my weight.Weight loss is a very small part of the health and well-being picture.
You say that (1) "the vast majority of the nutrition/public health community views overweight and obesity as best viewed as problems of psychology or resource economics" and that they (2) "mostly ignore endocrinoloy as key to understanding the obesity epidemic", and that these views mean that they (3) cannot "make sense of why the concept of consciously trying to achieve energy balance has failed us so calamitously".
No (1) is just plain false. The 'mainstream' view on obesity fingers food choices, portion size, and physical activity levels as the main drivers of obesity. Psychological factors and resource economics are given secondary importance by comparison.
(2)is arguable. While many mainstream voices do not focus on endocrinology, this does not mean that they are ignoring it. It reflects the fact that factors governing energy balance (e.g. food choices, portion sizes, exercise levels) have an immediate and profound impact on weight irrespective of the endocrine milieu of the client...so it's a matter of priority. Sure, there may be underlying endocrine mechanisms that influence weight flux, but the proximate cause is always about regulating energy balance one way or another.
As to (3), you seem to be conflating the idea that the 'correct' solution to a problem is a 'highly effective' solution to a problem. It does not follow that a high failure rate in people attempting to consciously affect energy balance means that seeking to do so is unsound. If (as is the case) the environment is particularly hostile to a solution, it stands to reason that even the best advice will not succeed very often. Life is like that; for instance, many people know the formula for success in business, but few have the dedication to achieve it...this does not call into question the formula, but the native dispositions of the subjects of that formula.
Also, it bears repeating that the causes of obesity for one individual may not be the causes for another. Prior to the precipitous rise in obesity post 1980, there were obese people. It therefore stands to reason that the factors that drive the modern obesity epidemic (I nominate the obesogenic environment; i.e. convenience foods, fast foods, the rise of the food-as-entertainment culture, hyper-palatable foods, portion sizes, sedentary lifestyles) are not necessarily the reasons that drive obesity for the sub-set of the population that would have become obese even in the absence of these novel drivers. It is feasible that endocrinology may have something to say about this sub-set of people, but as for the 'new obese', energy balance considerations driven by the obesogenic environment are perfectly adequate explanations.
I should have stipulated from the start that we are talking the weight gain in the population over the last 20 years and not individuals that would be overweight under nearly an conditions.
I would say that food choices and portion size as viewed by the mainstream are couched primarily as resource economic and psychological problems. I'm talking about Marion Nestle and Kelly Brownell primarily, but lectures and articles by many others. I'm also talking about the description of the problem and the advice in countless articles by RD's in magazines and around the web for the general public. I'm also talking about the UCSF min-med school lectures on youtube.
They argue that our industrial food system produces too many calories and that results in bigger portion sizes. Just last week we saw a study looking at the relationship between social status and portion size. The salients reasons we have drifted towards bigger portion size are explored mostly through psychology. If you strip away the public health lingo, they are talking resource economics - overproduction of commodity crops, portion size and cost per calorie; and marketing - psychology.
The mainstream view does point to food choice, but it is usually explained as the intersection of resource economic and psychology. Overproduction of commodity crop meets marketing. And this is true and important.
But it doesn't tell us why those calories are more fattening, when we've just been told that quantity of calories, not the quantity of calories is the problem.
On food choices they are just plain schizophrenic and I think that undercuts the message. They will say that it's all about calories one minute and that you can't get fat eating brussel sprouts the next because you can't eat overeat brussel sprouts. They will caution against eating fatty foods because fat has 9 calories per gram instead of 4 one minute and say "of course you eat less on a low carb high fat diet because fat is more sating. Etc, etc. It's a conflicting mix of messages on energy balance, glycemic load and set points.
They also give a very mixed message regarding quality of calories vs. quantity of calories. They portray the problem with junk food as the absence of nutritional value. I think that a message that "If you take care of the quality of the food, the quantity takes care of itself." both reflects what we know and is a more powerful message. That has it's limits, but for most people it's seems to be true.
The statement that people eat too much and don't move enough doesn't explain the increasing trend of overweight 6 month olds. Portion size is not the issue. Babies are fed when they are hungry and eat until they are full and they always have been. Why have they started to overeat in the last 10 or 20 years?
In low income communities the public health community is becoming interested in the "hunger-obesity paradox". Why are people who experience hunger and food insecurity the most vulnerable to obesity? Energy balance considerations are not adequate to explain why someone who doesn't have enough to eat the last week of every month has taken in more calories than they burn. The bland admonishment that they eat too much and don't move enough is just inadequate to explain what's going on, it's perverse.
Coming back to the role of resource economics in the conventional wisdom. We are constantly told that the most energy dense calories are the cheapest and that is why low income people are the most vulnerable to obesity. But that doesn't explain why a person with scarce resources would continue to buy and consume calories after their energy needs are met. The marginal value of those calories goes down dramatically after energy needs are met and we would assume that there would be other pressing needs that that money could be used for. There is no question that overeating is taking place. The question remains why. Cheap calories (resource economics) is the explanation offered. But pursuing economic logic further tells us that the cheapness of the calories can't be the whole story. The answer seems to me some combination of the fructose insulin hypothesis and the hyper-palatable foods hypothesis. The two theories are reinforcing and the model works with other obesity epidemics.
The question is not why have Americans gotten fatter? The question is what causes human obesity epidemics. Food-as-entertainment culture, portion sizes, and sedentary lifestyles don't help us explain other, previous obesity epidemics. What we do know is that metabolic syndrome appears in populations after the arrival of refined sugar and flour (and maybe seed oils - I don't know if that's been looked at.)
There has been plenty of obesity among non-sedentary people. The Pima Indians in the early 1900's are the best example. We see plenty of overweight and obese construction workers, DOT workers, housekeepers, certified nurse's assistants, etc. People in low wage work who are on their feet and moving all day long are frequently overweight. One of the most perverse applications of the conventional wisdom that I've heard was the group that was trying to help with farm workers in California with their weight and health and they were trying to help them improve there diet and get more exercise, but they were finding it hard to get people that were working in the fields 10 hours a day to come to an aerobics class.
The data isn't clear at all that we are more sedentary than we were before 1980. And research hasn't been able to demonstrate that exercise in general helps with weight loss. Research indicates that exercising more than 50 a day 5 days a week seems to be effective. Very intense interval training seems effective. Both of those seem to be effective because they help the body return to healthy weight regulation - bringing insulin and/or leptin into balance, not because they burn calories. Kids are more sedentary and it may turn out that general exercise is key in preventing metabolic syndrome, but that very specific, fairly intense exercise is necessary for exercise to play a role in reversing it.
But that isn't the conventional advice. The conventional advice is to just exercise more. And it hasn't served us well because it is inadequate to address metabolic syndrome and help people lose weight.
What's clear to me is that humans, like any other animal, under normal conditions maintains a healthy weight homeostatic-ally even in the presence of access to excess calories and something profound has happened to alter that fact.
I don't think that consciously trying to maintain energy balance is unsound. I think it's ridiculous on it's face. People have no idea or way of knowing how many calories they burn in a day. People have no real way of knowing how many calories they are eating, no matter how sophisticated the iPhone app. The conventional wisdom treats them as independent variables and they are not.
I think your distinct between good advice and effective advice is insightful, but I think that the advice has failed because it is poor, not because it hasn't been followed. It is the role of nutrition researchers to discover and refine our understanding of the problem. It is the role of public health advocates to translate that into effective advice. There is no question that they have failed. I think the underlying premises of the eat less, move more advice are flawed and the results reflect that. The hyper-palatable foods premise is about the addiction feedback loops and the hijacking of the body's system of appetite regulation. The problem is not that junk food contains too many calories. It's that it changes how your body works so that it takes extraordinary willpower to stop over consuming. Yes, excess calories are leading to weight gain, but the animating force is the effect on dopamine, etc.
The recent ranking in US News of healthy diets shows the disconnect. A panel of experts ranked the top 20 healthy diets. What's interesting is that readers were allowed to rate whether the diets had worked for them. 16 of 20 including the top 5 were rated as wildly ineffective by readers. But 4 diets were rated as effective. The top 5 were distillations of the conventional wisdom, yet only 10-20% of readers found them effective. The 4 rated as effective by readers, Weight Watchers (#6) Vegetarian Diet (#9) Eco-Atkins (#15) Vegan (#16). Weight Watchers has a strong social element and was effective for around 60% of readers. The other three are meatless and were effective for around 90%. Unpacking what that means is off topic, but my point here is that effectiveness counts is what counts in advice. Advice that can't be followed isn't good advice. It may be correct, it may be wise but it's not good advice it's something else.
My message would be: 1.) Foods high in refined carbohydrate, especially fructose can cause your body to partition energy as fat rather than activity in vulnerable individuals.* 2.) Foods high in sugar, fat and salt can cause addiction in vulnerable individuals. 3.) Thirst signals the body's need for water. Liquid calories short circuit the body's system of satiety. 4.) There are good reasons to exercise moderately for 30 mins a few times a week, but to lose weight and keep it off it seems that that requires an hour a day at least 5 days a week to get results
I think the idea that we are gaining weight because our bodies are not functioning properly and good diet can help restore that function is a more powerful message than you we are gaining weight because we have become too lazy and undisciplined. I think it's more instructive, it's more motivating and it's has the virtue of being closer to the truth than eat less, move more.
* as a lay person, the fructose insulin hypothesis seems the most compelling, but I'm really agnostic. It remains to be worked out what combination of insulin, leptin, ghrelin, etc is driving disequilibrium. It's angels on the head of a pin to some extent. I'm clear that its a matter of faith at this point, but it seems the best reading of what we know is that something is driving a hormonal disequilibrium. We have a much clearer sense of what foods might and what foods don't and as a lay person that is really all that matters. I spend way more time that I'd like to worrying about insulin resistance in mice and the effect of fructose on satiety injected into rat's brains. But I'm clear that with my limited faculties, I'm trying to make sense of the research but mostly trying to find experts who I trust to make sense of it for me and tell me a compelling story about what it means and what to do about it. I haven't found anyone to connect all the dots, but Stephan has quickly become someone that I trust as an honest broker and an insightful researcher who thinks like a scientist with one eye on the big picture.
If we could only figure out what's blocking my brain's concision receptors.
"But I'm clear that with my limited faculties, I'm trying to make sense of the research but mostly trying to find experts who I trust to make sense of it for me and tell me a compelling story about what it means and what to do about it. I haven't found anyone to connect all the dots, but Stephan has quickly become someone that I trust as an honest broker and an insightful researcher who thinks like a scientist with one eye on the big picture."
Try Peter blogging as Hyperlipid here:
good stuff. thanks.
p.s. wow, I'm a bad writer unedited.
For what it's worth, I think Peter is a very smart guy (and occasionally very insightful) but I have a hard time with any so-called scientific objectivity that leads to very specific dietary recommendations.
I read all of your posts with interest...I'll respond to some of the salient points here.
As to your characterisation of the 'mainstream' dietary advice...I'm sorry, but I remain unconvinced that the academic postulations to wit 'an intersection between resource economics and psychology' are what the unwashed masses perceive as being the main message coming from the establishment (rather, the main message is still seen as being eat more fruits and veggies, eat less junk, move more). As a nutrition consultant and physical trainer, I run screening checks on clients, during which I query their pre-existing views on diet. I have NEVER received a response that mentions resource economics (e.g. food availability, cost) nor, surprisingly, have I ever received a response about the effects of advertising. Almost all the responses reflect the 'eat less, move more' paradigm and the 'eat healthier foods' paradigm.
You are right that there are garbled and mixed messages regarding food choices (food quality) and portion control (food quantity). But Marc, do you really expect things to be any different?
If, as is clear, obesity has a multi-factorial aetiology (and reflects individual and ethnic genetic differences, adding another magnitude of variability to the problem), then it is inevitable that the analyses of the problem, and the remedial prescriptions offered, will be equally complex!
Obesity is a wicked problem...it is not going to admit a neat solution.
So, yes...food quantity is a cause AND food quality is a cause. There's no need for forced bifurcations here.
Regarding infant and low income obesity. The obesogenic environment theory (which subsumes the reward theory as well as incorporating resource economics and psychological explanations) is perfectly adequate to explain the phenomena (no wide-spread endocrine disorders need be postulated).
Put simply, the ubiquitous presence of hyper-palatable, cheap foods in the diet leads to passive overconsumption (this overrides satiety signals in babes as well as adults). The hyper-palatability mediates the changes in brain chemistry that override the satiety signals, while the cheapness/availability/cultural acceptance of the foods (contra pre-1980 conditions) allows for continued consumption.
You say that "humans, like any other animal, under normal conditions maintains a healthy weight homeostatic-ally even in the presence of access to excess calories". I beg to differ. Humans, when faced with an obesogenic environment will tend to overeat; witness the Kings and Queens of England for instance...food-as-entertainment - check, hyper-palatable foods - check, no limits on availability and cost - check; results = observe a portrait of Henry VIII or Queen Victoria !
The reality is that even low income people now have access to the obesogenic lifestyle that had been hitherto reserved for the very wealthy. Food is not ONLY hyper-palatable, it is also cheap; it is not ONLY cheap, it is everywhere; it is not ONLY everywhere, it is part of our accepted entertainment culture (to eat solely for fun). We are, in short, in the midst of a perfect storm. And none of this depends on the postulation of epidemic endocrine disorders.
As to your 4 messages, I agree with 2, 3 and 4...and I agree that fructose can have deleterious effects on fat metabolism. But, this only occurs in the context of the rest of the diet. Even a ridiculously high proportion of fructose in the diet (as per a fruitarian diet) will not cause dislipidemia. It is only when high levels of fructose are combined with high total calories that metabolic disregulation occurs. So again, its overconsumption relative to needs that's the proximate cause, not the consumption of a single (completely natural) saccharide like fructose.
It's all about context. And it's complex...and it's maddening.
hi Stephan ...
a suggestion on "rewarding foods", maybe a response to the accusations of tautologousness / circularity.
"if an animal trainer were trying to train YOU (a human), what foods would they use to reinforce the behaviour they wanted?
Would they use plain white rice or chocolate ice cream and baklavas (or even worse, some of the Indian sweets)? unsalted, unbuttered, boiled potato or thick, juicy steak with all the tastiest spices? "
There IS a circularity there - the PROCESS itself is circular - certain foods reinforcing the desire to eat those foods. How could there NOT be circularity? That doesn't mean the explanation itself is completely circular. There are reference points outside (fMRI, blinded tests).
Harry (Nov 9)
Excellent, clear presentation. Welcome change from the muddled, anedcdotal,overconfident usual fare. Thanks. I would add only one thing: the huge effect of individual state of health on pathology and metabolism.Would you agree?
Thanks for your kind comments.
Yes, indeed; broader health issues do impact on glucose, amino acid and lipid metabolism (and on appetite).
It is very important to view weight management holistically (i.e. in the context of broader health).
For example, trying to eat well and exercise vigorously on 3 hours sleep per night will meet with scant success. And sleeping like a log for 9 hours, eating a perfect diet, while smoking 2 packs a day will be similarly misguided.
Peter has made a comment on the LIRKO.
"Peter has made a comment on the LIRKO."
Under the CIH:
Hyperinsulinemia + ad libitum access to food + time = insidiuous fat gain
In this experiment:
Hyperinsulinemia + ad libitum access to food + time = no fat gain
Peter has talked about the LIRKO mouse several times, but he never seems to adequately address this issue. The fact that the LIRKO mouse would probably be healthier on a high-fat diet doesn't change the fact that the LIRKO mouse is not obese.
Look at the title of this post: "Does High Circulating Insulin Drive Body Fat Accumulation?" It's a very specific question. The CIH says yes, the LIRKO mouse says no.
Is the LIRKO mouse a perfect analogue for the human condition? No, and as such it's not the final word on the issue of obesity. But it's a compelling piece of evidence against the CIH, and even the fructose-insulin hypothesis.
Not only is the "...LIRKO mouse [NOT] a perfect analogue for the human condition..." but it is not even a perfect analogue for the mouse condition because it has been genetically modified.
Feed normal, healthy, unadulterated mice an ad-libitum diet rich in sugar and refined starches, inject 1/2 of them with insulin to simulate chronically raised circulating levels and if the study group do not gain at least higher levels of fat mass than the controls, then we can talk.
Why make the study more complex than it needs to be? Obfuscation perhaps?
@Marc: I don't think that consciously trying to maintain energy balance is unsound. I think it's ridiculous on it's face. People have no idea or way of knowing how many calories they burn in a day. People have no real way of knowing how many calories they are eating, no matter how sophisticated the iPhone app. The conventional wisdom treats them as independent variables and they are not.
Sorry but this is just a diversion. Nobody knows exacts, but it's not rocket science to log what you eat and see how that reflects on the scale. And nobody claims the variables are independent. But they are not perfectly compensatory or nobody would ever get fat to begin with.
@FrankG: Feed normal, healthy, unadulterated mice an ad-libitum diet rich in sugar and refined starches, inject 1/2 of them with insulin to simulate chronically raised circulating levels and if the study group do not gain at least higher levels of fat mass than the controls, then we can talk.
Do you see the problem with your experiment? Why can't we talk about whether the mice become fat from the physiologically produced insulin spikes? They do not. You're talking inducing hyperinsulinemia artificially. Not relevant.
@Evelyn -- "You're talking inducing hyperinsulinemia artificially. Not relevant."
By the same logic are you suggesting the the LIRKO mice are relevant?
Why are you so sure that the control mice woud not also gain fat mass? I expect that they would, just not as rapidly as the study group.
Another issue I have with using the LIRKO mouse in this context is the assumption that liver Insulin Resistance (IR) occurs before the chronic high levels of insulin. In my world the IR results from the high levels of insulin, in a down-regulation spiral -- much like folks living beside a busy road gradually get used to the noise.
Unlike these mice, I was not born with IR but I developed it slowly and insidiously over many years... alongside the other symptoms of my metabolic disorder -- including obesity -- which in turn worsened the IR and led to even higher levels of insulin to compensate.
Allow me to clarify -- neither is going to be directly relevant.
That said, all of the KO mice are helpful in elucidating pathways and mechanisms. It is interesting to see what happens when you just knock out the liver receptor but leave the fat receptors intact. In this regard it makes it even more damning for the insulin-hypothesis, because the LIRKO mouse should clearly be a porker if it holds. Because (1)fat should be trapped in the fat cells, and (2) the ensuing so-called "internally starved" mice should turn ravenous. No and no.
Now exogenous insulin in an otherwise normal mouse tends to increase appetite by inducing hypo episodes and increasing food intake. Is this relevant? No, because the CI hypothesis says that dietary carb creates the hyperinsulinemia from which all else follows. You create artificial HI in a normal animal with signalling intact? It eats more from hypoglycemia
Exactly as you say: all very interesting but not relevant as in both cases we are looking at artificial situations which do not directly mimic the human condition.
LIRKO mice have a much higher degree (almost absolute) of IR than humans with Metabolic Syndrome, and again in humans this condition does not happen overnight but over the course of many months or years -- this latter factor alone is tough to replicate in a relatively short-lived rodent, even a perfectly healthy one... let alone one that has been "designed" to be damaged from the outset.
Allow me to clarify: I'm not interested in interesting academic discussion that does nothing to further a practical human solution. In my personal experience I know full well the improved health I have enjoyed since switching to a diet that reduces my need for insulin; both exogneous and endogenous. CIH also makes sense of everything that I have experienced in the last few years -- perhaps it is not the full story but it was enough for me to be working with.
There isn't a single cause of obesity. There isn't a single cause of raised appetite. As long as everyone approaches the discussion as if there is you'll continue to cancel each other out.
For example -- what drives PICA? Appetite is a complicated thing.
I love the passionate battles between the Stephanites and the Peterites. :) I think Stephan and Peter both write interesting blogs, and intellectual competition breeds actual learning. Keep it up!
Stephan, Peter's most recent blog entry, though flip, does raise interesting counterpoints. Can you address them?
That blog entry being http://high-fat-nutrition.blogspot.com/2011/11/lirko-mice-3-mcq.html, by the way. It was mentioned above, but I thought it bore repeating.
"Allow me to clarify: I'm not interested in interesting academic discussion that does nothing to further a practical human solution."
This is the point I alluded to upthread. Dr. Guyenet, myself and lots of ther readers ARE interested in academic discussions, oftentimes on very specific points.
Saying "the CIH is probably wrong" is not the same as saying "don't cut carbs." I think the CIH is extremely incorrect in its traditional form, but I still eat a moderate to low-carb diet. I like it, and it works for me.
I just don't think it works for me for the reasons the CIH says it does.
Until something comes along that definitively shows my diet is manifestly unhealthy, I'm going to stick with it. But from a scientific perspective, I'm curious to know the mechanisms through which my diet is successful. I think the CIH does a poor job of that. I think food reward does a nice job, but an incomplete one. I'm curious to see what else comes down the pipe.
There's room for theory and practice in the world, and to paraphrase Robert Nozick, there is room for words other than last words.
He does actually, but I guess you didn't pick up on it.
You and others ignore the argument that FrankG and others continually make about IR to the point of having disinterest in what you say. You respond to many arguments with strawmen and consider everyone in defense of eating high fat to have the same exact ideas as Taubes.
Yes, I'll address them. There was really only one counterpoint, and the rest was speculation on his part (SFA feeding would improve LIRKO mice??-- give me a break-- this has never been tested).
The counterpoint was that the mice are "intensely diabetic". This argument doesn't hold water. It is true that they are very glucose intolerant when young, but their fasting blood glucose is only modestly elevated. Most papers have not referred to them as diabetic, and certainly not "intensely diabetic", although I do think you could argue that they qualify. I haven't been able to find a reference to support his claim that they excrete a lot of urinary glucose. It would be nice if he would supply references so that people can sort out facts from things he made up.
What he failed to mention is that at 4 months of age, these animals regain normal glucose tolerance, normal fasting glucose, yet continue to have grossly elevated insulin levels. So where is the obesity?
But let's assume for the sake of argument that Peter is right and the LIRKO mice are irrelevant. What about the liver-specific IGF-1 knockout and the ABCA1 knockout? What about the LIKK mouse? All referenced in my post. These are not diabetic, have high insulin, yet do not gain more fat mass than normal mice. I wonder why he didn't address those in his post?
I've noticed that Peter likes to make snarky comments and nitpick people who disagree with him, but these are no substitute for a rational and thorough consideration of the evidence. I just can't take his writing seriously since he began selectively throwing out data points from studies to make them fit his ideas.
"He does actually, but I guess you didn't pick up on it."
That's entirely possible. I freely admit that I find a lot of Peter's writing to be less than transparent.
The question I find myself asking more and more when reading his material is whether a lot of it seems like nonsense to me because I'm missing something (possible), or because HE's missing something (also possible).
I read his blog, and my diet looks a lot more like Peter's than Stephan's, so it's not like I want him to be wrong or something.
As Adam stated, it's difficult to read Peter's blog and separate speculation from sarcasm from science.
So Stephan and all, I'm not sure if I'm understanding him, but it seems he's offering up the following postulate for why they don't get fat: no LIR = liver can't use glucose so therefore liver burns most/all of the dietary fat leaving not much left to be stored. But insulin is not required for glucose transport into cells so this is not the case. Furthermore, all that carbohydrate "metabolic bullying" should force the fat cells to accumulate every fatty acid they can manage to get.
@john: Please tell me what strawman I set up. I have no idea what you're talking about here.
Hold up @Sane,
::"We conclude that IR and GLUT2
form a receptor-transporter complex in hepatocytes, which forms a mechanism of insulin-mediated hepatic glucose regulation."
(In rats, but ...)
Anyway, I thought Peter was saying that the liver won't be using the available glucose, not necessarily that it doesn't get into the liver. Having reread the post I'm now not sure, but if the liver's getting the glucose and not seeing the insulin, then there'll be no glycogen synthesis, there'll be a bias toward fat oxidation, and there'll be no DNL.
There's also the observation that the LIRKO mice have serum FFAs depressed by 40%. A hepatic bias toward fat oxidation together with no DNL could explain this. The question then becomes, if the IH/CIH is correct, which effect dominates? High insulin? Or low FFAs (and probably other TGs)? One works in one direction (insulin spares fat) and the other works in the other direction (there's no fat to be spared).
I think this is why the LIRKO mice might not be as diagnostic as has been suggested.
It's the IR, which a few people have mentioned.
FrankG and others like me are pointing out the high IR. This is why these mouse examples are bad. Not too long ago Stephan referenced mice with normoinsulinemia and high body fat, but they have abnormally high fat tissue insulin signaling, just as these have low. This is what would be expected. In response to that point, you simply repeat the fact that obese people have high FFAs, so insulin cannot be trapping fat in cells.
Insulinomas and the reverse [pancreas damage / insulin secretion inhibition like feeding of oxidized fats] support the, as Strontium pup says, the "weak" insulin hypothesis.
The fact that there is wide variance in fat storage with above-maintenance calorie intakes or even variance across maintenance calorie intakes should instantly tell us that there are explanations beyond the eating of more calories. My metabolism throughout my life has been such so that I can eat (I no longer do this) 1-2 pints of ice cream per day, cereal by the box with whole milk, enormous amounts of cake, candy, etc, yet I have never been above single-digit body fat %. Natsuko Sone claims to eat 5000 calories per day; Ramajit Raghav claims 7000. I'm not implying low carb or even low insulin enables this high calorie intake without fat gain, but any theory that centers around a calorie intake increase per se (however we get there) as the cause of obesity is absolutely wrong.
While "eat less, move more" (the logical product of the calories in calories out explanation of bodyweight flux) may not always work very well, the proposition that positive energy balance causes obesity is overwhelmingly supported by the evidence.
If you look at the results of free living trials versus metabolic ward trials, you find that the former sometimes seem to defy the energy balance explanation, while the latter almost always confirm it.
This is due to the fact that we all suck at estimating our calorie intake and energy expenditure, even when we're doing our best (this is leaving aside the possibility of deliberate deception).
When the trials are done in metabolic wards, this confounding variable is removed and the results become virtually homogeneous.
I have never seen evidence from a cross-over trial (metabolic ward, or at the very least, 3rd party documented) where folks lost weight after increasing their calories, or conversely, gained weight after decreasing their calories. Are there any that you are aware of?
P.S. I'm not saying that your claims and those of Natsuko Sone and Ramajit Raghav actually are B.S...but I am compelled to assume that they are if I want to take the scientific method seriously.
If LIRKO mice don't have reduced food intake, how does the insulin make them leaner?
I also wonder if one might think as a result of this claim that insulin resistance (and so too little insulin, in effect) in metabolic syndrome that contributes to obesity, rather than too much insulin?
Nice information. I will make it as reference for my website: http://www.mawared-international.com
You're misunuderstanding what I said. No sh*t "positive energy balance" is the "cause" of obesity (though this can even be altered: you know what happens when bodybuilders overeat during winstrol and test cycles?): it's implied/redundant. It's the notion that increased calorie intake per se is responsible is what is false...increased calorie intake does not necessarily equal positive energy balance...
...The people who look for reasons behind Americans' average 300 calorie increase to explain obesity are treating people with a low tendency to store fat like a random statistic, like the result of 9 out of 10 "heads" during a coin flip simulation, which is incorrect; there is a physiological explanation as to why some people store more fat than others. The answer as to why people eat more now helps us understand the cause of obesity, but the "why" is not itself the cause; otherwise, I would get just as fat as Itsthewoo or whoever after overeating on cake or anything else.
Stephan has said food reward is "a" dominant factor, so I don't know his complete thoughts, but many like Carbsane don't seem to recognize my argument above.
@Strontium: There is no doubt that insulin facilitates glucose transport and/or insulin/receptor binding regulates glucose. But insulin is not required for glucose transport. I've never heard of cells not using glucose at all even in the face of severe IR -- have you? This seems to be what Peter is implying.
Let's get back to the title of this post, can we? LIRKO is but one of many examples where the hyperinsulinemia drives fat accumulation just doesn't hold up. There wasn't much Peter said to counter that.
@john: (1) I repeat my request to please show me where I made a strawman argument in this thread.
I suppose your position is that CIH explains why you can pig out on carbs and not get fat while others can't -- you envision you have low insulin sensitivity/fewer receptors on your fat cells or something like that? Obese people heightened sensitivity/receptors?
That sounds reasonable until you flash back to the 70's and realize that this does not explain the obesity epidemic. Or is the claim now that certain modern foods alter the number of insulin receptors in different ways on fat, muscle and liver? If that's the claim, please do bring the evidence.
@Frank, etc.: I guess the insulin injection v. LIRKO relevancy comes down to this wrt the C-I hypothesis which states that carbs drives insulin drives fat accumulation. I Frank's scenario you're talking feeding mice carbs, injecting some with more insulin. If the injected mice got fat what does this tell you? Oh ... perhaps that postprandial endogenous insulin in response to dietary carb does NOT drive fat accumulation, but artificially elevated insulin does? The LIRKO on the other hand is endogenously overproducing insulin -- bigtime at that. Yet that this does NOT drive fat accumulation directly counters CI. Now put a mouse on a high carb vs. a high fat diet and see what happens. Oh ... we know. But mice aren't humans. OK, put humans on high carb vs. high fat diets -- when calories and protein are controlled, advantage goes slightly to carbs for higher lean lower fat mass.
...When you point to insulin not locking away fat cells--and also when you throw the CIH in my face as though I have ever claimed to accept it, which I have not.
Well I didn't propose that exactly, but it seems plausible. And yes, that would be my best guess, with some people resistant to the "damage." I don't have evidence on hand.
I don't see how your idea explains the obesity epidemic either--people got more gluttonous? Linoleic acid is too rewarding?...
Your hypothesis looks at calories themselves, but the fact that people store different amounts of fat than others immediately rejects it. Even if foods have no long term effect on that ability, which is highly unlikely, calorie intake intself still wouldn't explain obesity because the physiology of those different types of people is still different. Everyone with good reasoning skills should understand this.
John her name is Evelyn not Carb.
What are you, her mother? Is calling her Carb or CarbSane an insult, because I'm pretty sure she went by CarbSane for much longer than Evelyn; if she prefers Evelyn now, I'll call her Evelyn...happy?
"I don't see how your idea explains the obesity epidemic either--people got more gluttonous?"
Just so we're all on the same philosophical page, this is a clear example of the straw man fallacy. :-)
I'm interested in how Evelyn and Stephan might reply to your (and Strontium's)contentions, but combating perceived fallacies with the same is obviously unhelpful.
@Strontium: I just realized that after reading Peter's LIRKO (3), I went back and re-read 1& 2. This from (1) that solidified what I think he's saying:
These mice are eating CIAB and their liver wants nothing to do with the diet derived glucose. Nothing. The liver is utterly insulin resistant. No receptors, no response...
The mice eat Mouse Diet 9F which is 56.5% carbohydrate. Each mouthful of food pushes glucose toward the liver. The liver ignores it. Unharvested glucose hits the systemic circulation. The pancreas notices. The pancreas whispers insulin in to the portal vein and the liver ignores it. The pancreas speaks louder. The liver ignores it. The pancreas screams. The liver shrugs.
Where does the glucose go? With a blood glucose of 400mg/dl some goes down the loo (did I mention these mice were intensely diabetic? OK, they are intensely diabetic). The rest of the glucose tries its damnedest to get in to muscles. The muscles really don't want the glucose. They internalise their insulin receptors. Did I mention that these mice are intensely insulin resistant. OK, they are. Very. Whole body). The pancreas breeds extra beta cells then goes to the gym and pumps up those beta cells to steely muscled bulges of insulin hypersecreting islets. Insulin secretion goes up yet higher. It does no good. Not only do the beta cells multiply and hypertrophy, don't forget that the liver is the main sump for insulin degradation on a high carbohydrate diet. Not without insulin receptors it isn't. Hepatic insulin clearance is zero so insulin has almost nowhere to go. This too markedly contributes to the hyperinsulinaemia.
In this excerpt there are several statements by Peter that are at best speculation at worst outright inaccurate.
@john: I'm not offended by being called "Carb", but does seem a bit rude to address me that way especially since you addressed me by the full pseudo the other times. Either CarbSane, CS or Evelyn is fine.
Regarding " when you throw the CIH in my face as though I have ever claimed to accept it"
This is the comment section of a blog post addressing the hyperinsulinemia causes obesity portion of the CIH. I'm addressing that which Stephan was addressing and I don't recall addressing you. Your response to my exchange with Frank was: "You and others ignore the argument that FrankG and others continually make about IR to the point of having disinterest in what you say. You respond to many arguments with strawmen and consider everyone in defense of eating high fat to have the same exact ideas as Taubes."
What does defending eating high fat have to do with anything wrt this post? Nothing. Except that a high fat diet will, if anything, contribute to IR. Stephan (and I and others) are addressing specific tenets espoused -- for lack of a better term -- as LC Science. For better or worse, the hypotheses put forth by Taubes in GCBC and the watered down version in WWGF are the "prevailing wisdom" of low carb.
I was trying to figure out what your opinion is based on some exchanges we've had on my blog and comments you've made here. Sorry but that's not a lot to go on. Perhaps it's time for folks like you to start your own blogs and jot down some thoughts so you won't have to jump on people for not addressing phantom hypotheses.
It is NOT erecting a strawman to address the hypothesis under consideration as stated.
@Harry: Regarding the homeostasis, we so very much agree. Obesity used to be a disease of mostly the affluent. If the menagerie in my back yard (squirrels, birds of all feathers, chipmunks) is any indication, wild animals will overeat too if they find a dependable food source.
Just a casual friendly nickname...what if I call you Ev? Okay, but it's been a few times now where you've brought up a counterpoint to Taubes with which I already agree. I don't really have any innovative nutrition strategy that would warrant a blog, but you probably could guess I suspect high fat diets are superior for health--and that I don't think it should be necessary to ever have to consciously restrict calories per se(though some food choices need restricting).
@john: Ev is fine :) ... and much shorter to type. I might suggest you change your profile name ... only because you post on a few blogs that Jack Kruse posts as "john" on. While viewing the blog I see your smiling face, I don't see it in my reader, and I presume I'm not the only one reading comments by that means.
In the past few weeks I'm finding that the evidence for high fat diets being healthier, let alone healthy for humans is scant, especially in the context of obesity/overweight.
Speaking of which, once someone becomes obese, I would venture to say that most will have to do something consciously to maintain a reduced weight. Indeed I would say that anyone who gains even a modicum of weight relying on their own homeostasis probably needs some attention to detail here.
The net is a huge place. Thus I believe the success of LC for weight loss/maintenance is unfortunately exaggerated. I say this because Atkins has been around since 1972 and LC diets since before that. There have also been huge booms especially circa 2003. If it were that simple ... because trust me, obese people are desperate not to be so. No amount of doctors/media/government telling you it's gonna kill you is going to stop them (formerly us) from doing it.
P.S. The high fat and health thing is causing a bit of cognitive dissonance for me of late. I'm no lipophobe, though I was never a dip prime rib in butter gal either. I just thank God I'm not diabetic or glucose intolerant, because it's not looking good for the high fat diets or even the middle-road like Zone or my beloved PHD-styled diet.
CS, what is inaccurate in Peters post you referenced ?
@majkinetor: There are too many to post here, not to mention I do not want to play woo here and post diatribes. I'm working on a blog post of my own and I'll post a link when I get it up, or you can check in at my blog ;)
"The net is a huge place. Thus I believe the success of LC for weight loss/maintenance is unfortunately exaggerated. I say this because Atkins has been around since 1972 and LC diets since before that."
The net is only a huge place for low carbers. That is why people that have success with all the other approaches are unable to accumulate significant numbers of success stories on the net. The vegan net is growing a little, but I don't see much of anything else. Low fat and eat less/exercise more were just invented and they haven't had time to develop their net.
In the clinic, low carb (particularly when food quality is emphasized) is metabolic magic for the vast majority of compliant patients. The why may be up for debate, but results are where the rubber meets the road. Success with low carb outnumbers all others 10 to 1 (leading to growth of their net).
Maintenance is an issue with any weight loss program. The doctors/media/government and, most importantly, family definitely have an impact on compliance. Environment and social factors are huge. If and when doctors/media/government and family encourage compliance, the low carb net will grow even more.
thanks for sharing such a nice information about body fat accumulation...its really wonderful and deserving topic...!!!
" Low fat and eat less/exercise more were just invented and they haven't had time to develop their net."
There are more experiments needed to reach at accurate facts. Diabetes could caouse the knee problems and thus Knee Arthroscopy
helps to knee treatment.
I agree that Peter is a master of hyperbole and other rhetorical devices, but as far as the LIRKO mice are concerned, I’m not basing my own thoughts on what he or any other commentator has to say.
You’ve noted in Stephan’s more recent post that the LIRKO mice have suppressed serum FFAs. They’re reduced by 40% or 50% depending on which study you read. Another interesting thing about the LIRKOs is that the TG content of VLDL, LDL and IDL is also reduced compared with control mice by ~50% (more for IDL). See Table 2 and figure 1D of “Hepatic Insulin Resistance Is Sufficient to Produce Dyslipidemia and Susceptibility to Atherosclerosis”, DOI 10.1016/j.cmet.2007.11.013.
The IH doesn’t simply hold that hyperinsulinaemia drives body fat accumulation. It holds that hyperinsulinaemia leads to increased LPL activity, that LPL goes to work on serum lipoproteins, thus increasing the extracellular FFA concentration and creating a FFA concentration gradient across the cell membrane that then drives the FFAs into the cell. When you look at it this way, you can see why there’s a problem with the LIRKO mice. Low serum FFAs mean that LPL has to work harder to create sufficient extracellular FFA concentrations to maintain a given adipocyte size, especially in view of the low TG content in the VLDL, and that in turn means higher insulin levels will be required.
Thus, given the blood lipid profile of the LIRKO mouse, the IH already predicts that normal adiposity will be accompanied by hyperinsulinaemia, and that is what we see.
Your comment on Stephan’s latest post:
“In the LIRKOs it appears the fat tissue remains insulin sensitive and the low circulating FA's would be consistent with insulin doing its job. Indeed I think the FA's are lower than normal, which would be consistent with hyperinsulinemia w/o enlarged fat cell mass.”
This seems to agree with what I’ve just said, so to be honest I don’t understand why we’re appearing to disagree. Of course, insulin doesn’t “regulate” the fat tissue if by that we mean that its biological function is to maintain a certain fat mass. That’s not the IH though. The IH allows that a side effect of insulin’s role in regulating BG is to encourage the accumulation of fat under certain conditions. I don’t see how we can conclude from LIRKO that this is false. As far as I can see, if it were not for the hyperinsulinaemia, these mice would be emaciated.
My blog post on LIRKO:
@Strontium: It gets frustrating trying to discuss CI hypothesis when it keeps changing or has different meanings to different people. For the past year or so Taubes has boiled it down to carbs drives insulin drives fat accumulation by focusing on how insulin regulates fat cells. Nothing else is significant in his latest version. Therefore, LIRKO and other hyperinsulinemic models directly refute this. We're told that if our fat is locked away, our cells are starving so we eat more. NEFA levels are supposed to be regulated on the release side of adipose tissue via suppression of lipolysis by HSL. This is clearly going on with LIRKO. But why don't they get fat like MIRKO? Perhaps it's because insulin ultimately regulates circulating glucose, NEFA (and the oft forgotten amino acid levels) and doesn't regulate fat tissue LEVELS.
@secox: The net is not littered with active forums of "moderate political views" either. You would think reading on the internet that the US is full of tons of raging liberals and conservatives.
There are a lot of weight loss blogs out there by folks following so-called conventional wisdom. What would be the point, however, of a "movement" to promote this?
The proof is in the pudding as they say, low carb has had it's surges and boons, yet the NWCR is dominated by those who have achieved longterm success through caloric restriction and regular exercise.
Re: Success with low carb outnumbers all others 10 to 1 (leading to growth of their net).
Says "secox" with no way of verifying how he/she came up with this ratio or verifying it. Meanwhile many of the more ardent promoters of low carb have had very limited success, one is even larger than she was when she started LC. The only reason Jimmy Moore is a weight loss success story at this point is because he used to weigh 410 lbs, but he is morbidly obese.
I'd already read your post on LIRKO. Quite entertaining.
It looks like our only disagreement is the nature of the insulin hypothesis. I say it has always been implicit in "insulin drives fat accumulation" that there is fat in the blood capable of being accumulated.
And it looks like LIRKO don't have that.
@Strontium: OK, now I think I understand what you're saying. Thanks for clarifying. This seems to be what Peter argued as well, that the liver was using whatever fat was in the diet to live/function. But actually, that didn't used to be the hypothesis -- it was that carbs were converted to fat to be stored, and in this regard, as in the MIRKO, the LIRKO should get obese through de novo lipogenesis. Still, even if it's about fat available to be stored, there is some fat in the mouse diet although the standard rodent diets are rather lower in fat than even low fat human diets. Just because fasting NEFA are low doesn't mean there's no fat available for storage. Actually according to the hypothesis, the fat cells should be hoarding any fatty acids they can get their grubby "hands" on thus "starving" the mice who should be ravenous when they wake up in the morning. As time progresses for these mice they are almost equally hyperinsulinemic, while their glycemia and fatty acids normalize -- e.g.they should get fat then, right?
I have a followup analysis of LIRKO in the works. This mouse pretty much decimates Taubes' hypothesis on it's own. One knockout, so many KO punches to the former amateur boxer!
Seems we've agreed to disagree. Cool.
I look forward to your next LIRKO post.
The political graveyard is littered with moderates. More political success seems to come from the extremes. More success equals more active forums. What have the cries for a moderate 3rd party accomplished?
Dietary success seems to come from the extremes as well. More success equals more active forums. A successful dieter is more than happy to share their success. They would be right here saying “this is the way” and nothing would stop them from doing it. Success seems to be the key to most “movements”.
NWCR is dominated by those who have achieved long term success through low fat, low calorie, decreasing their carbohydrate intake by at least 50% in many cases (there is a limit on protein and fat restriction over the long term - play with the numbers). My opinion is, if the low carbers had the support of family and doctors/media/government, they would dominate NWCR. Part of the low carb blogging is to try to convince themselves and family/friends that their approach is healthy. For some reason, many are not convinced by the studies showing improvements in so many biomarkers of health.
With no way of verifying, as in “one is even larger…” There are of course no failures with other approaches. You’re right; I can’t verify the numbers I have seen.
The term morbid obesity refers to patients who are 50 - 100% -- or 100 pounds above -- their ideal body weight. Alternatively, a BMI (body mass index) value greater than 39 may be used to diagnose morbid obesity. At 75 inches and 230 lbs, Jimmy seems overweight (Nearly obese, but far from morbid). It’s not nice to tell stories about a sensitive man’s weight. And really, "the only reason..." He is hugely successful due to his successful loss of close to 200 lbs and he is good at what he does.
@secox: FWIW, Jimmy is probably flirting back with the 300 lb mark at the moment. This is why the internet success stories are not very reliable to compare to others. Oprah is not her heaviest, but she's not her lightest either. Same with Jimmy, only the worrisome thing about Jimmy's regains is that he's remained pretty solidly LC.
I've just noticed something else that might interest you in the paper I previously mentioned:
In the section on "Dysregulation of PGC-1b, SREBP-1c, and SREBP-2", it says:
"After fasting and refeeding, which normally leads to a dramatic induction of SREBP-1c (Matsuzaka et al., 2004), nuclear SREBP-
1c, which represents the active form of SREBP-1c, was reduced
>95% in LIRKO livers relative to controls (Figure 2A)."
This suggests to me that when Peter says these mice are doing zero DNL, he might be onto something.
@Strontium: I don't think I addressed the DNL by the liver. That has nothing to do with whether the liver is able to utilize glucose for energy. It can contribute to the hyperglycemia b/c the glycogen storage and apparently DNL are lacking -- two means by which the liver clears glucose. According to Peter's paper glucose transport into muscle and fat was not impaired. Why doesn't LIRKO get obese?
I guess I misunderstood your comment that, "as in the MIRKO, the LIRKO should get obese through de novo lipogenesis."
@SP: Yeah, I meant by DNL in the adipose tissue, which apparently occurs in the MIRKO allowing them to become obese. I am tied up at the moment, but just posted an article in my library (carbsanitylibrary.blogspot.com) that discusses the contributions of DNL from liver and adipose tissue in lean and ob mice.
"Probably" is why the internet success stories are not very reliable to compare to others. Relating to a personal attack, probably means - an adverb used in any statement which is almost certainly false. The relevance of any 2 or 3 people and their weight is what?
@secox: I'm not telling stories about JM, he's posted pictures of himself and discussed his regain. Seen the pics of him from AHS? You are right about the "probably". But it is relevant when so many prominent low carbers remain overweight or downright obese while bragging on their wonderfully healthy diets. Jimmy's incredible yo-yoing over the past 5 years is also relevant. He's probably regained and relost over 300 lbs which HE has documented ... each time ending up with a few more regained pounds. So wouldn't you say his example -- at least with a name and public appearances to judge -- is more pertinent than all of these magical weight loss success stories we keep hearing?
Thanks for the clarification about MIRKO. I had a bit of a sniff around to see if I could find a reference showing adipose tissue DNL in MIRKO, and I came across:
"Cellular and Molecular Mechanisms of Adipose Tissue Plasticity in Muscle Insulin Receptor Knockout Mice"
I think this paper says MIRKO's adiposity is not associated with DNL, but with de novo adipogenesis, creation of new adipocytes.
One quote I have in mind is at the top of column 2, page 1930:
"Here, we show that the increased adiposity in MIRKO mice results from adipocyte hyperplasia, with individual adipocytes reaching the same size as in control mice and without increase in expression of the major lipogenic genes, i.e. leading to de novo triglyceride synthesis from glucose: PPAR , SREBP-1c, and FAS. Thus, unlike in the case of diet-induced obesity, the increased adiposity observed in MIRKO mice does not result from hypertrophy of preexisting adipocytes leading to enlarged insulin-resistant cells, but rather to the recruitment/differentiation of new small insulin-sensitive adipocytes."
I'm quite interested in getting to the bottom of this. Can you point me to something that establishes the adipose tissue DNL in MIRKO (or tell me if I've misinterpreted this reference)?
I've been visiting your blog BTW. I may post there if you'll have me.
Being a non-scientist, can anyone explain in simple terms why the LIRKO mouse does not get fat but the MIRKO mouse does?
If only ...
There's a big difference in the amount of fat in the blood. MIRKO mice show an increase in triglycerides and free fatty acids. LIRKO mice show exactly the opposite. This could limit the amount of fat the LIRKO mice can store.
I think this could well be part of the story, but it's not the whole story by any means.
@SP & poohstixxx: I've gotten my hands on an excellent review of knockout mice or two that may just hold the answer to the question. I'm just sort of backed up with other trains of thought at the moment. Some sort of cross-talk signaling between muscle and fat may well be at play. MIRKO muscles can't handle the glucose so they tell the fat to pick up the slack, and SP according to your paper they make more fat cells (still, if DNL per fat cell is the same, total DNL would increase so that might still be a possibility, otherwise where's all that glucose going?). LIRKO muscles seem to uptake just fine so no distress signals out to the fat cells.
@SB re your comment about my blog. The more the merrier! You're always welcome to pop on by. Gary Taubes will be debunking himself there for the next few days >:)
Excellent article and great series. You say “This is consistent with countless other studies showing that exposing cells to excess nutrients, particularly free fatty acids, causes insulin resistance”. Do you mean by “particularly FFA’s” that this is due to the 2.5 ratio of FFA: glucose caloric value ie once in excess the higher caloric value produces additional damage more quickly? Or is there an implication that FFA’s are inherently more damaging?
From a free article “The Costs of Breathing” by Nick Lane in Science, Oct 14/’11, p184: “Senescent cells survive by glycolysis, often with high mitochondrial ROS leak, which gives rise to oxidative stress. This drives epigenetic changes and the expression of proinflammatory factors (3) associated with chronic inflammatory conditions such as diabetes, and cancer” . The article is about evolutionary selection for ROS leakage rates in mitochondria. The quote implies that damaged cells limp along increased glucose metabolism. This view if I interpret correctly is not just blogosphere musing. My personal experience (ya I know) does not contradict this kind of process.
Hi stehphan guyenet.
I was just wondering, is it possible that hypothalmic insulin resistance might dirve obesity even if liver-insulin resistance doesn't? thanks.
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