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Disclaimer: I love and respect many low-carbers and low-carb researchers, and think low-carb diets are very appropriate and perhaps necessary for many people.

Many in the low-carb field seem to think that insulin resistance is what is making us fat and even that insulin resistance is caused by… insulin.  Too much carb makes too much insulin and the insulin receptors get scared and run away.  Intriguing theory, but very simplistic.  During the Q&A session of my Wise Traditions talk this weekend, I made the following quip:


Saying that insulin causes insulin resistance is like saying that childhood mortality is caused by children.

Melissa McEwen caught this quote on her live twitter feed.  Melissa also live tweeted many other excellent talks from the conference, including Stephan Guyenet's masterpiece on the traditional diet of the Pacific islands.  He uncovered islands where the traditional diet was over 90% carbohydrate and other islands where the traditional diet was mostly fat, including a whopping 50% of calories just from saturated fat alone.  Neither of the populations had insulin resistance, diabetes, or cardiovascular disease, and none of either island's inhabitants were fat.  In came refined foods, and they became vulnerable to all of these diseases.

Lots of other people live tweeted talks and other events from the conference, and you can see a hodge podge of these tweets here.

In this blog post, I'd like to review a couple animal models that strongly suggest that between insulin resistance and leptin resistance, leptin resistance is much more critical to the development of obesity.

The mainstream often cries “eat less and exercise more” whenever someone has trouble losing weight.  Well in fact there's a little molecule called leptin that our fat tissue makes, which slips into our brain, acts on the hypothalamus, and makes us… *drumroll*… eat less and exercise more. Well, at a minimum it makes us eat less and expend more energy when we exercise.

Even though leptin appears to decrease food intake and increase energy expenditure, obese people have very high levels of leptin compared to lean people (1).  When they lose weight, leptin levels go down, but stay way above what you'd find in a lean person. The drop in leptin is accompanied by a drop in thyroid hormone (2, 3), muscular utilization of glucose (3), sympathetic nervous system activity (3), and adrenaline (3), and by changes in the pattern of brain responses to food (4), all of which are reversed by injections of leptin.  These studies have been very small and preliminary, but they support the widely held belief that obese people are leptin resistant.

Insulin has a century or so more research behind it than leptin has, so insulin resistance is a much more well defined phenomenon than leptin resistance.  Recent data suggest that about 39% of overweight Americans have either diabetes, impaired fasting glucose, or elevated fasting insulin (5), which are the clinical manifestations of insulin resistance.

These numbers are pretty similar to what Zelman reported in 1952 (6).  Zelman wrote long before the obesity epidemic emerged and it took him 18 months, a full year and a half, to find 20 obese people who weren't alcoholics.  He reported that about half of these people were glucose intolerant, meaning that when they were given a load of glucose, their insulin couldn't work fast enough to prevent an abnormal spike in blood sugar.

Zelman's finding was similar to what had already been reported in larger groups.  His new contribution was to show that upon liver biopsy, all patient but one — a full 95% — showed signs of at least mild to moderate liver damage.  The longer the people had been obese, the more damaged their liver was.  Long before the discovery of leptin, a hormone that acts on the hypothalamus, Zelman hypothesized that damage to the hypothalamus caused obesity and cravings for nutrient-poor sweets and fats, that the consumption of too much sugar and fat without sufficient choline, protein, and other nutrients led to liver damage, and he cited another researcher's suggestion that liver damage led to glucose intolerance.

Why would liver damage lead to glucose intolerance?  The liver not only contributes to clearance of glucose from blood, but, more importantly, the liver produces glucose from protein in a process called gluconeogenesis.  Ordinarily, the liver stops making glucose in response to insulin.  However, if liver damage prevents this response, the liver will keep making glucose even when we don't need any more of it.  More glucose in the blood will cause the pancreas to make more insulin, but the insulin will fail to stop the liver from making more glucose, and a vicious circle will ensue.  With increasing levels of glucose and insulin in the blood, many other tissues such as skeletal muscle and fat may deliberately stop responding to insulin themselves in order to prevent glucose overload in their own cells.

The fact that insulin resistance is not found in all obese people does not mean it plays no causal role, because obesity does not necessarily have the same cause in every person.

Nevertheless, a look at the genetic animal models of leptin and insulin resistance would suggest that leptin resistance has a much more prominent role in causing obesity and that insulin resistance without leptin resistance may not cause obesity at all.

The agouti yellow mouse was the first genetic animal model of obesity, systematically described as far back as the 1920s, and it later turned out to be leptin resistant (7).  Another early model of obesity was neither dietary nor genetic, but rather involved the removal of the hypothalamus, the principal (but not only) site of leptin action (8).  The common modern genetic models of obesity include the ob/ob mouse (9), the db/db mouse (10), and the fa/fa rat (10).  The ob/ob mouse doesn't produce leptin at all, while the db/db mouse and the fa/fa rat have defects in the leptin receptor.  All three types of animals become insulin resistant and fat.

It's a little bit harder to study the effects of genetic insulin resistance, because mice with no insulin receptors die 2-3 days after birth (11).  Nevertheless, mice can be developed with deletions of the insulin receptor in specific tissues. Deletion of the insulin receptor from liver tissue results in whole-body (systemic) insulin resistance (12).  As predicted above, the insulin resistance in the liver can cause systemic insulin resistance by causing the liver to continue making glucose and sending it out into the blood stream even when it isn't needed.

But, surprise surprise!  These mice become neither leptin resistant nor fat (13).  In fact, while the effect is not statistically significant, they are slightly more sensitive to leptin and slightly more lean.

Although glucose metabolism tends to normalize after six months, fasting glucose is initially higher.  Feeding them glucose produces much higher blood glucose peaks and dosing them with insulin produces much less effective declines in blood glucose.  What is particularly remarkable, however, is their high insulin levels.  These dramatic changes persist even through adulthood.

In the fasting state, insulin levels are over 7-fold higher:


In the fed state, insulin levels are 23-fold higher:

Their insulin receptors are only knocked out in their liver.  So if high insulin levels are what act on our adipose tissue to make us fat, these mice should be really, really, really fat.

On the contrary, they are quite lean:


Why aren't they fat?  This study showed that they were just as sensitive to leptin, perhaps slightly more sensitive, than controls. Thus, while leptin resistance and insulin resistance often go together, it seems that leptin resistance is a much more important contributor to obesity.

These data should not be considered evidence that insulin resistance can never lead to leptin resistance in humans.  In fact, human hepatic insulin resistance (insulin resistance of the liver) looks nothing like what happens in the hepatic insulin receptor knockout mice.  The livers of these mice don't respond to insulin at all.  In humans, this insulin resistance is “selective.”  The livers of “insulin resistant” humans continue to manufacture fat and send it out into the blood as triglycerides in response to insulin, but fail to suppress the production and export of glucose in response to insulin.

In humans, insulin resistance of the liver leads to increased triglycerides in the blood.  One theory that has some experimental support, but is still questioned by some experts, is that increased blood triglycerides decrease the transport of leptin into the brain.  For this and perhaps other reasons, insulin resistance as it occurs in humans could, perhaps, cause leptin resistance.  However, if it does not cause leptin resistance, it is very unlikely to make people fat.

In describing this selectivity, Dr. Robert Lustig recently made the following remark (14):

The reason for this uncoupling of insulin's two main hepatic signaling pathways remains unclear.

I propose that the explanation may be rather simple.  Rather than a result of gluocose toxicity or fat toxicity or fructose toxicity, the development of insulin resistance may be a natural, protective, homeostatic response to energy overload.  It certainly has adverse consequences down the line, but the selectivity does seem to suggest a deliberate attempt of the liver to alter its energy metabolism.  Moreover, the liver is clearly modifying its energy metabolism in a consistent way that exports energy.  In this case, it is exporting both glucose and fat at the same time, rather than suppressing one whenever it engages in the other.

I'll expand on these ideas in an upcoming post arguing that the main culprit preventing the liver from correctly handling its energy is suboptimal intakes of choline, and perhaps lipid peroxidation, which prevent the liver from being able to export the fat that it obtains from dietary fat or that in manufactures anew from things like fructose and ethanol.  Nutrient deficiencies and other issues that compromise the liver's ability to burn energy are also likely involved.

First, expect a brief review debunking some of the conventional ideas about the so-called “Receptor for AGEs (RAGE).”

Then we can go back to fruit and honey.

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  1. just a quick comment about the carbohydrate hypothesis (carbohydrates – raising insulin – causing insulin resistance). Simplistic or not, it has empirical support.
    long term exposure to chronically raised insulin levels eventually leads to insulin resistance. Here is the proof –

    Raising glucose, raises insulin, increases insulin resistance…
    Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.
    Diabetologia (2004) 47:31–39
    “Conclusion/interpretation. When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in “normal” glucose tolerant individuals.”

    Barbara B. Kahn and Jeffrey S. Flier, Harvard Medical School
    The Journal of Clinical Investigation, August 2000 | Volume 106
    “Hyperinsulinemia per se can cause insulin resistance by downregulating insulin receptors and desensitizing postreceptor pathways, as was confirmed by overexpression of insulin in livers of otherwise normal transgenic mice. This transgene resulted in an age-related reduction in insulin receptor expression, glucose intolerance, and hyperlipidemia without any primary genetic defect in insulin action or secretion.”
    And again…
    Alternative Approach to Treating Diabetes Tested
    ScienceDaily (June 10, 2011)
    From; Deletion of Insulin-Degrading Enzyme Elicits Antipodal, Age-Dependent Effects on Glucose and Insulin Tolerance.
    Plos One June 2011 | Volume 6 | Issue 6
    “It’s an example of too much of a good thing [insulin] becoming bad for you…chronic hyperinsulinemia seemed to actually cause diabetes. As they aged, the mice appeared to adapt to the chronically high insulin levels, for example, by reducing the number of receptors for insulin in their tissues. These adaptations make the mice less sensitive to insulin, which is the exact cause of type 2 diabetes.”
    And again…
    Insulin: In need of some restraint? Salk Institute
    Proceedings of the National Academy of Sciences,March 07, 2007
    “the study reveals the “dark side” of high insulin production, the kind that results from over eating and obesity. “Insulin is very effective at lowering blood sugar, and promotes fat storage, preparing the animal for times when food may not be available,” he says. “But when the hormone [insulin] is produced at too high a level for too long, the body becomes insulin resistant and blood sugar and certain blood lipids gradually creep up, which can cause progressive damage to multiple organ.”

    And of course insulin resistance goes hand in hand with leptin resistance. Gary taubes’ preoccupation with insulin was a tad myopic, and apparently he did not know how it interrelated with leptin resistance.
    But his conclusions were still probably sound.

    1. Hi Marcus,

      My main point here was that insulin resistance doesn't necessarily cause obesity, which is separate from whether excess insulin causes insulin resistance. I don't doubt that if you give an animal excess insulin, it will cause insulin resistance in certain tissues. But I think it is caused by cellular energy overload secondary to the insulin, not simply a result of the insulin per se. And in human liver, insulin resistance is selective, targeting the glucose-related pathways but not the lipid-related pathways, which means it doesn't occur primarily through a downregulation of insulin receptors, but occurs at a bifurcation in a downstream signaling pathway. I would like to see a longitudinal study in humans showing whether insulin resistance comes before or after hyperinsulinemia in common relevant disorders like obesity, metabolic syndrome, and type 2 diabetes. I think that would be hard to do but would seem to settle the issue.


  2. Chris,

    Sorry to be a johnny-come-lately.

    I've been engaged in a bit of back and forth on Stephan's blog on a recent post entitled "Fat Tissue Insulin Sensitivity and Obesity".

    One of my antagonists pointed me in the direction of this post. I've called into question one of your conclusions, and I'd really like to hear your your take on it.

    Basically, you say that “… if high insulin levels are what act on our adipose tissue to make us fat, these [LIRKO] mice should be really, really, really fat?”

    But is that right? That's my question.

    Even if you adopt the position that the insulin hypothesis describes everything as far as overall fat mass is concerned, you still don’t necessarily conclude that higher insulin (in the LIRKO mice) implies higher fat mass, because insulin is only going to promote fat storage if there’s fat to be stored. In other words, you would expect the rate of fat storage to depend on insulin, yes, but wouldn't you also expect it to depend on the levels of circulating TGs and FFAs? In the LIRKO mice, TGs and FFAs are about half what they are in the controls.

    At a naïve level, you might then think that the insulin-promoted influx of FFAs into the fat tissue is going to be about half what you would expect so see in the controls. How would that explain away a seven-fold increase in fasting insulin? The answer could be that a 50% difference in plasma TGs and FFAs results in a huge difference in the FFAs leaving the cells because of an enormous difference in the relative concentrations of FFAs on either side of the cell membrane (if the difference is 20% in a normal person it becomes 140% when you reduce the plasma concentration by 50%: seven times as much).

    Where am I going wrong here?

  3. Part 2: I think… the endocrine system, it doesn't matter what breaks first. After one thing breaks, the whole thing comes apart bit by bit.

    You don't wind up diabetic and that's ALL that's wrong. Yes, you wind up with high rT3, adrenal issues, etc., etc. Unless you outright die beforehand, if you have an endocrine disorder, you're going to get a HOST of endocrine issues.

    It's all feedback loops… carb/insulin/glucagon was always an overly simplistic model.

    Still, for me IR… was first. Seems like THAT is what the "tune up" needs to fix.

    I got very interested in amylin for a while, was sure it was the wonder drug. It will make the liver stop making glucose! Woohoo!

    I used Symlin for a while (VERY expensive) and saw no difference in insulin needs. Far as I can tell, in my body, Symlin is equivalent to placebo. Nada.

    Also, wound up extremely adrenally insufficient for a while – to the degree of being bedridden. Hydrocortsione got me out of bed, but of course, doesn't improve glucose control. Still, I was lucky it didn't screw it up. But… that's weird, isn't it? That going from almost no cortisol to 40 mg HC per day would make NO difference to bg/insulin? Makes me wonder if my liver isn't MAXED OUT at producing glucose, just can't make more…

    My rT3 got so ridiculously elevated that I went on T3-only meds for a while to clear it. Greatly improved my well-being, but not my bg.

    Also interested in leptin and leptin resistance, have been fascinated since the Zucker rats…

    Your posts on choline have been interesting, and shall inspire me to eat a bit more egg and liver.

    But right now, I am most interested in microflora.

    We know what cures diabetes: gastric bypass surgery.

    That is… a massively confusing thing, that disabling a big chunk of one's digestive system would IMPROVE anything. Well, yeah, I can "lose weight" by amputating my leg too, doesn't seem like a good idea though. 😉

    WHY should that help, it's so nutty! I mean, it's nuttier than the idea that high colonics can somehow fix disease…

    Then there's the bit of giving the GI bacteria of fat, diabetic rodents to other rodents, and they go and become fat and diabetic.

    Seems like someone should try that the other way around. Seems like… someone should try that… taking diabetic mice, sterilizing their GI tract, and then giving them enemas of healthy mice poop.

    Course, it'll be a bit of a quandary if it WORKS, cause who the heck wants a treatment like that? 😉 Almost rather keep taking these insulin shots…

  4. Part 1: I did low-carb, mostly, for two decades after being diagnosed a T2, on the simple basis of looking at bg profiles of T1s, T2s, and nondiabetics after eating various macronutrients, which I looked up in a research library shortly after diagnosis. I was a PhD candidate in biochemistry, trying to figure out why veterinarians thought all animals with diabetes should be on high-protein diets, and the ADA said ONE animal, us, should eat low fat. This was… before Atkins, Bernstein, Eades, etc.

    Seemed to me that T2s got closest to normal bg by eating low-carb meals and the ADA was stupid. Couldn't test myself, there were no handy dandy bg meters around.

    Also, no internet back then, so we got ADA news in newspapers. A few months after my diagnosis, the ADA said… sugar was metabolized the same as other carbs, so… diabetics could eat sugar. I quit listening at that point.

    I have now almost two decades of bg data to look at and have progressed to the point that I take rather a large amount of Lantus and Humalong/Novolog daily.

    Unfortunately, most of my low-carb dieting was with so-called "healthy fats" so likely I am saturated with PUFA (only having switched to good fats in the past 3-4 years). I've been off most PUFAs for a while, consuming fullfat raw dairy, coconut oil, loads of butter, and pastured meats. And my insulin needs have decreased, but am nowhere near normal yet.

    I can state unequivocally that low-carb does not fix diabetes. And neither does low-PUFA, though it does improve it.

    My interpretation of the data I have is this… low-carb is like saying, my car runs badly, so if I don't drive it much, it will last longer. Yes, that is true. However, a tune-up would be better still.

    I'm not sure what the equivalent of a "tune up" is. Low-PUFA and good fats help. But it's not all.

    A few years ago, I had acute pancreasitis, which resulted in bg over 300 for a year, in spite of fasting. I came to the conclusion that I am VERY VERY good at gluceoneogensis.

    I can eat zero carb, zero ANYTHING, and have high bg… for days. It simply must be gluceoneogenesis, because after a few days, glycogen stores are gone. My body must be making glucose out of protein and fat cause that's all there is.

    I have joked… I think my body can make glucose out of air. Seems like it sometimes.

    At this point, I suspect that low-carb TRAINS the body to be good at gluceoneogenesis. So… in the long run, I think low-carb increases the problem that is diabetes.

    And yes, T2 diabetes is primarily a liver disease. So I take milk thistle.

  5. No, TSH does not rise. The idea that TSH is sufficient to diagnose thyroid problems is preposterous. In any case, leptin malfunction would blunt the ability to respond to a hypothyroid state with increased TSH, so TSH is particularly unable to diagnose the issue in this case.

    Hi there, so it would likely that TSH fall down. I have hypothyroid and haven't taking medicines for a quite while cause I am pregnant and I don't want to. Does it makes sense in bigger risks to my baby?

  6. Westie,

    Thanks! I'm glad; I like writing them but I like it more when other people like reading them. 🙂

    In certain animal models such as ob/ob mice adipose lipolysis and release of free fatty acids does seem to play a role. However, in humans, although free fatty acids are increased, the total production of triglycerdies in the liver from circulating free fatty acids is equivalent to healthy controls, while de novo lipogenesis is increased three-fold. Moreover, all of the dietary animal models depend on either dietary fat provided directly to the liver or on lipogenic substrates.

    I'm curious why you think otherwise. If you have evidence, I'd like to see it.


  7. Chris wrote:
    "prevent the liver from being able to export the fat that it obtains from dietary fat or that in manufactures anew from things like fructose and ethanol."

    Hi Chris,

    It's a real pleasure to read your posts, thanks!

    You didn't mention adipose tissue in your list. It is a largest source of free fatty acids.

    What do you think about an idea that liver fat accumulation and liver insulin resistance is caused by immune cell function in the liver and/or adipose tissue. Innate immunity activation may enhance lipolysis which will increase portal FA flux…..

    It's quite long story overall but I think that liver fat accumulation is mainly caused by increased lipolysis and not so much by dietary fat or de novo lipogenesis.

  8. What about cholesterol deficiency? At the WAPF conference, Stephanie Seneff said that fat cells that normally produce leptin become impaired by cholesterol deficiency, and can no longer produce leptin or do their other jobs, and that this causes obesity as well as the associated symptoms.

  9. Arg, google ate my long comment 🙁

    Chris, great great post and I can't wait to read more.

    Ordinarily, the liver stops making glucose in response to insulin. However, if liver damage prevents this response, the liver will keep making glucose even when we don't need any more of it. More glucose in the blood will cause the pancreas to make more insulin, but the insulin will fail to stop the liver from making more glucose, and a vicious circle will ensue. With increasing levels of glucose and insulin in the blood, many other tissues such as skeletal muscle and fat may deliberately stop responding to insulin themselves in order to prevent glucose overload in their own cells.

    Peter at Hyperlipid has written a bit about this. I think this model is very tidy, but I wonder about things around it.

    I believe the liver doesn't just regulate blood sugar through gluconeogenesis, but it also buffers glucose directly and via glycogen, and titrates it out under the control of insulin. A lot (most? almost all?) of dietary carbohydrates leave the digestive system through the portal vein which is the express lane to the pancreas and liver.

    But what about the pancreas in that model? What if the pancreas is producing glucagon at the same time as insulin? My bet is the liver will prioritize the glucagon response over the insulin response, because hyperglycemia may kill you later, but hypoglycemia could kill you now. So what scenarios could lead to pancreas malfunction? This could be independent of liver malfunction.

    I like the diabetes model where diabetes is when your fat cells can't hold any more fat, and you have a surge in blood FFAs, and it ends up translating to uncontrollable blood sugar. I think Peter wrote a bit about that, and I think I also read it on Nephropal. I really need to read this again, I have a lot more to understand here.

    I am on board with the big-picture model of leptin being the key regulator of energy consumption and expenditure. But it remains very interesting after that point. If I eat 100 excess calories, does it go to building muscle or fat? What's the traffic cop there, is that leptin or something else? And if it goes to fat, where does the fat go? Is it peripheral or visceral? Hepatic? What controls that?

    I don't believe that carrying some extra fat is inherently bad. I understand that visceral fat can drive the sex hormones towards estrogen, and cause or participate in systemic inflammation, and that's bad. But peripheral fat doesn't seem to be particularly unhealthy, and I bet a small to moderate amount of visceral fat really isn't all THAT bad. So the leptin system might malfunction for someone and they might gain weight, but I don't think that guarantees that they will be unhealthy. I think there are other systems that would need to operate in a particular way to drive the resulting fatness towards being healthy or unhealthy.

    You may get to this in later posts, but I'm curious about the mechanisms of proper and improper leptin response in the hypothalamus.

    Thanks so much for this series, I can see that I might reach a deeper and more useful understanding of metabolism, endocrinology, and health.

  10. Chris,

    Very very good post. Thanks a ton. Do you believe that HcG injections could be a way to increasing endogenous leptin production and/or leptin sensitivity? I do recall one study where such was the case in embryonic cells.

    I am not one credit pop-science or con artists and those pushing the HcG diet are not very reliable personalities, but I have seen numerous examples of obese individuals responding very well to HcG injections and wonder if leptin is how HcG may be helping people lose weight.



  11. Hi Matt,

    Thanks! I haven't looked into the primary research too much yet, but there is a case for inflammation inducing cellular leptin resistance. I'll post more as I learn more.


    Maybe you should try more fat and less carb. 2 tsp is not much fat, in my opinion. On the other hand, if more fat does not help, perhaps you have some insulin resistance going on. Fat does not blunt glucose responses very much in type 2 diabetics. I do not know if this is because the blunting is insulin-dependent, or for more complicated reasons related to defects in gastric emptying.

    I'm looking forward to an upcoming post from Stephan Guyenet about plasma glucose spikes in response to carbohydrate among healthy 'primitive.'


    I find the triglycerides (TG) hypothesis compelling, even though some questions remain about it. In fact I have a suscpicion that elevated blood TG may be a signal of starvation to the brain.

    I need to do more research before I come to definitive answers, but I believe this post showed that excess insulin in and of itself absolutely does NOT cause leptin resistance. Insulin resistance in the brain may, but that's due to a loss of insulin signaling (i.e. resistance), not an excess of it. In a human with selective hepatic insulin resistance, insulin will stimulate increased blood TG. So if blocking insulin in humans resolves leptin resistance, it probably supports the TG hypothesis.

    As far as I know, the current basis for the palmitate theory is largely related to infusing it into the brain, which I think is ridiculous. I do think it's possible that excess lipogenesis can cause some imbalances in fatty acids, but I'm not very convinced. The body is not stupid enough to make only palmitate. This happens initially and then it is largely converted to palmitoleic, stearic, and oleic acids. But again, it's possible, and I'll write more when I learn more.

    Thanks for your comments everyone,

  12. Chris,
    Great post. I'm not qualified to evaluate them but I've heard three theories on the cause of leptin resistance: excess triglycerides (Byron Richards), excess insulin (Ron Rosedale, Robert Lustig), and excess palmitic acid produced by the liver in response to excess carb intake (Robb Wolf in collaboration with, per Robb's comments, Matt Lalonde)
    I'd be interested in your thoughts, perhaps in future posts.

  13. Chris,

    I do eat butter with my oatmeal (about 2 tbsp's); however I also see spikes around 140 mg/dl when I eat bread/pasta products.

    I look forward to reading more.


  14. Excellent post Chris. I too have been strongly focused on leptin resistance more than any other, and have even found overfeeding (raising leptin) to improve glucose clearing tremendously. Although, it should be noted that the overfeeding is low-fructose, low-PUFA, and high-fiber which are all prominent factors.

    Anyway, I'm curious as to where you go with this. So far all of my research has led me towards IL-6, TNF-Alpha, and other inflammatory molecules responsible for overproduction of the known leptin-resistance inducers cortisol and SOCS-3.

  15. Hi, Chris.

    Since butter, coconut and chocolate are delicious, and since I occasionally like to get drunk, I've recently been reading your previous posts on the development of fatty liver in alcohol-intoxicated rodents.

    The other day I came across a very recent study on mice which appeared to contradict the other rodent studies:

    The mice weren't fed alcohol. Two groups were fed slightly hypercaloric 40%-fat diets that were otherwise identical (casein, sucrose, cornstarch etc.) except that the fat was provided by safflower oil (equal amounts of MUFAs and PUFAs) or butter. Both "high-fat" groups gained the same amount of fat, but the butter group accumulated more triglycerides in the liver.

    As I recall, saturated fat from both animal and plant sources protected the livers of alcohol-intoxicated mice as well as rats in other studies. Any idea how this apparent anomaly can be explained?

    I followed some of the links from the above study and came across this study on obese, non-diabetic female humans:

    The women followed two two-week diets in random order with no washout phase. One contained 61% carbs and 16% fat; the other contained 56% fat and 31% carbs. Protein intake was higher on the high-carb diet (19% versus 13%). Alcohol intake was said to be c. 1% on both diets, although logic/mathematics would suggest that it was 4% on the high-carb diet and practically zero on the high-fat diet. Liver fat content was reduced during the high-carb diet and increased during the high-fat diet!

    The women followed the diets (eucaloric) under free-living circumstances, being guided to achieve them by swapping isocaloric amounts of fat and carbs from their normal diet. Annoyingly (though predictably), the researchers didn't condescend to measure or report micronutrient intakes (or actual foods eaten) on either diet.

    I searched for other human research on this matter and found this study on obese, insulin-resistant, non-diabetics (mostly women) without liver disease (even though just over half of them were defined as having NAFLD):

    The diets were strongly hypocaloric, being fed on-site for the first four days and then followed freely until 7% weight-loss had been achieved (with no difference in time between diets). Those on the low-carb diet lost significantly more liver fat after 48 hours, but the difference evaporated over the course of the study. Once again, actual foods/micronutrients eaten were not mentioned.

    As for changes in enzymes thought to reflect liver damage, there's this amusing study on normally physically active males who were temporarily inactive while following three different eight-day diets (separated by two-week washouts):

    Compared to a hypocaloric diet with even amounts of fat and carbs (mostly sucrose rather than starch), their levels of alanine aminotransferase (and other liver enzymes) went through the roof (along with fasting blood triglycerides) on a hypercaloric high-carb diet (c. 640g of carbs per day, fairly evenly split between starch and sucrose). On a hypercaloric high-fat diet (almost 300g of fat per day, but also c. 325g of carbs mostly from starch rather than sucrose), alanine aminotransferase was a little elevated (still within what was considered the normal range) but other liver enzymes were little changed and fasting blood triglycerides were non-significantly lower than on the hypocaloric diet! Micronutrient intakes were again unrecorded.

    So, other than suggesting that it may be unwise to consume c. 350g of sucrose per day as part of a hypercaloric diet while being physically inactive, I guess that most of the above fits in with the notion that actual foods and micronutrients are more important than the macronutrient ratios that people often obsess over.

  16. Chris,

    I think there are a number of ways that refined foods could contribute to obesity or leptin resistance. Leptin resistance will lead to obesity. I'm not sure if obesity occurs without leptin resistance, but if it did it would ultimately cause leptin resistance anyway. I'm not ready to blame fructose from natural foods, but it's a possibility in excess. More on this in coming posts. Perhaps extreme obesity is more likely to be secondary to a genetic defect or glandular damage but I think ultimately, it's a similar phenomenon.


    While there are other possible explanations, that makes a lot of sense and I have another post on choline coming soon.


    Thanks! And you're welcome. I have some evidence under review that some of the effects of blood glucose fluctuations can be mitigated by boosting antioxidant status, but it is still an open question. Increases in blood glucose within the normal range do stimulate oxidative stress. Do you put butter in your oatmeal?


    You're welcome.


    I read Mastering Leptin years ago. I think some of the writing is frustrating to deal with but the content is excellent. The recommendations helped me with my sleeping problems big time. Thanks for passing it on.


  17. you need to read Byron Richards book called Mastering Leptin. Great read and well researched. Leptin resistance is manifest by a super high reverse T3. The total thyroid panel can be in normal range but the patient is still hypothyroid. Leptin reistance also slows conversion of t4 to t3. Interestingly you should clinically fix the leptin resistance and not alter the thyroid panel until the leptin issue is dealt with. I do this with patients everyday but so few docs understand this biochemistry and how to use it clinically

  18. Chris,

    First, thanks so much for your work. Out of all of the nutrition and health blogs I read, yours seems the most balanced.

    A general question about blood glucose levels: Is it ever the case that slightly elevated BG levels (90-95 mg/dl fasting and 140 mg/dl at 2 hours postprandial) are health positive (vs. my assumption that it is a negative)?

    I recently had an HbA1c test that came back with a reading of 5.5%; so I invested in a cheap BG meter and have been doing some testing to determine if I have spikes and the foods that cause them. I was surprised to see some spikes above 140 (when eating my breakfast oatmeal with honey). And fyi, my triglycerides were 64 mg/dl.



  19. Chris,

    this is very interesting for hardgainers like me. Eating the appropriate amount of food (of the SAD fashion) for my height, I could never gain a pound (unless trying really really hard, which would have had only short-term effect anyway).
    Since childhood, my liver had been producing slightly more bilirubin than is usual – you could see it in my eyewhites (eyeyellows). After several rounds of testing, no definitive cause could be found by my doctors.
    Now that I switched to paleo, this condition disappeared and I think it might be attributed to the greatly elevated intake of eggs and beef and chicken, which are, as I understand, excellent dietary sources of choline…
    Of course I might be wrong but this theory would dovetail with your post, what do you think?

  20. Chris–

    Given this, in your opinion is the insidious weight gain associated with middle age due to mild leptin resistance? Diet-wise then, are you of the opinion that this is from a lifetime of having eaten too much fructose? What about refined flour? Is there, in your opinion, a difference in cause between the man 20 lbs over weight versus the man 100 lbs over weight?

  21. Hi Todd,

    No, TSH does not rise. The idea that TSH is sufficient to diagnose thyroid problems is preposterous. In any case, leptin malfunction would blunt the ability to respond to a hypothyroid state with increased TSH, so TSH is particularly unable to diagnose the issue in this case.

    Leon, you're welcome.


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