Have Seed Oils Caused a Multi-Generational Obesity Epidemic?

In 2006, Drs. Gerard Ailhaud and Philippe Guesnet hypothesized that industrial seed oils such as corn, soybean, safflower, sunflower and cottonseed oil are at least partially responsible for the current obesity epidemic (1). These oils were not a significant part of the human diet until very recently, yet they have been promoted due to their supposed ability to prevent cardiovascular disease. The Western world has been living a massive uncontrolled experiment ever since.

Linoleic acid is an omega-6 polyunsaturated fatty acid (PUFA) that makes up a large proportion of seed oils. It's a very bioactive molecule, in part because it's the precursor of two classes of signaling molecules (eicosanoids and endocannabinoids), some of which influence the development of fat tissue and regulate appetite.

Dr. Ailhaud and his colleagues pointed out that not only are people eating far more linoleic acid than ever before; that very same linoleic acid is accumulating in our fat tissue and showing up in breast milk. Here are a few graphs to illustrate the point. The first graph is of PUFA consumption in the US over the last century, primarily reflecting seed oil intake (based on USDA food disappearance records):

Here's a graph of added fat intake based on USDA data. Added animal fats such as butter and lard have remained stable since 1970 (although total animal fat intake has declined), while seed oil consumption has gone from high to higher:

The following graph shows linoleic acid accumulation in human body fat over the last few decades in Western nations (mostly the US). I put this together based on two references (2, 3). I didn't find any data from the US past 1986. Linoleic acid, unlike most other fatty acids, accumulates disproportionately in body fat (4):

And finally, linoleic acid in the breast milk of US mothers, from Dr. Ailhaud's 2006 paper (the black dots):

In 2009, Dr. Ingeborg Hanbauer published a paper showing that when mice are fed a diet with a poor omega-6:3 balance (77:1), after three generations they develop adult obesity (5). Mice fed the same diet with a better omega-6:3 balance (9.5:1) did not develop obesity, and remained smaller overall. This shows that PUFA imbalance can cause multi-generational effects resulting in obesity and excessive tissue growth. Cmdr. Joseph Hibbeln, a collaborator of Dr. Bill Lands, was an author. The thing I don't like about this paper is they didn't quantify the obesity by measuring fat mass, so we have to take the authors' word that they had more fat.

This week, Dr. Florence Massiera and collaborators published a similar paper titled “A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations” (6). Drs. Ailhaud and Guesnet were both on this paper. They showed that a 35% fat diet with an omega-6:3 ratio of 28 caused obesity that progressively increased over four generations of mice. Although this study was more detailed than the study by Dr. Hanbauer and colleagues, it lacked a comparison group with a more favorable omega-6:3 balance to show that the obesity was specifically the result of omega-6:3 imbalance, rather than the fact that the diet was higher in fat overall or some other aspect of its composition.

Both studies have serious problems. Nevertheless, together they suggest that PUFA imbalance is capable of causing obesity in mice that worsens over several generations.

If this is true in humans, it would be a straightforward explanation for the obesity epidemic that has plagued the Western world in recent decades. It would explain why the epidemic began in children around 1970, but didn’t show up in adults until about 1980. It would explain why the epidemic is less severe in Europe, and even less so in Asia. And of course, it correlates well with trends in seed oil consumption. This graph is based on US NHANES survey data:

We already know that a number of prenatal factors can have an effect on adult body fat levels in rodents, and observational studies have suggested that the same may apply to humans. If a mother’s body fat is full of linoleic acid, she will pass it on to the fetus as it grows, and after birth in breast milk, influencing its development.

As long-time followers of Whole Health Source know, I suspect industrial seed oils contribute to many of our modern ills. I can’t say for sure that seed oils are responsible for the current obesity epidemic, but the evidence certainly gives me pause. In any case, seed oils are an unnatural part of the human diet and it won’t hurt anyone to avoid them. The half-life of linoleic acid in fat tissue is about two years, so reducing it is a long-term prospect.

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12.53 | 0 comments

Full-fat Dairy for Cardiovascular Health

I just saw a paper in the AJCN titled "Dairy consumption and patterns of mortality of
Australian adults". It's a prospective study with a 15-year follow-up period. Here's a quote from the abstract:

There was no consistent and significant association between total dairy intake and total or cause-specific mortality. However, compared with those with the lowest intake of full-fat dairy, participants with the highest intake (median intake 339 g/day) had reduced death due to CVD (HR: 0.31; 95% confidence interval (CI): 0.12–0.79; P for trend = 0.04) after adjustment for calcium intake and other confounders. Intakes of low-fat dairy, specific dairy foods, calcium and vitamin D showed no consistent associations.

People who ate the most full-fat dairy had a 69% lower risk of cardiovascular death than those who ate the least. Otherwise stated, people who mostly avoided dairy or consumed low-fat dairy had more than three times the risk of dying of coronary heart disease or stroke than people who ate the most full-fat diary.

Contrary to popular belief, full-fat dairy, including milk, butter and cheese, has never been convincingly linked to cardiovascular disease. In fact, it has rather consistently been linked to a lower risk, particularly for stroke. What has been linked to cardiovascular disease is milk fat's replacement, margarine. In the Rotterdam study, high vitamin K2 intake was linked to a lower risk of fatal heart attack, aortic calcification and all-cause mortality. Most of the K2 came from full-fat cheese. In my opinion, artisanal cheese and butter made from pasture-fed milk are the ultimate dairy foods.

From a 2005 literature review on milk and cardiovascular disease in the EJCN:

In total, 10 studies were identified. Their results show a high degree of consistency in the reported risk for heart disease and stroke, all but one study suggesting a relative risk of less than one in subjects with the highest intakes of milk.

...the studies, taken together, suggest that milk drinking may be associated with a small but worthwhile reduction in heart disease and stroke risk.

...All the cohort studies in the present review had, however, been set up at times when reduced-fat milks were unavailable, or scarce.

The fat is where the vitamins A, K2, E and D are. The fat is where the medium-chain triglycerides, butyric acid and omega-3 fatty acids are. The fat is where the conjugated linoleic acid is. So the next time someone admonishes you to reduce your dairy fat intake, what are you going to tell them??

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18.30 | 0 comments

Copper and Cardiovascular Disease

In 1942, Dr. H. W. Bennetts dissected 21 cattle known to have died of "falling disease". This was the name given to the sudden, inexplicable death that struck herds of cattle in certain regions of Australia. Dr. Bennett believed the disease was linked to copper deficiency. He found that 19 of the 21 cattle had abnormal hearts, showing atrophy and abnormal connective tissue infiltration (fibrosis) of the heart muscle (1).

In 1963, Dr. W. F. Coulson and colleagues found that 22 of 33 experimental copper-deficient pigs died of cardiovascular disease. 11 of 33 died of coronary heart disease, the quintessential modern human cardiovascular disease. Pigs on a severely copper-deficient diet showed weakened and ruptured arteries (aneurysms), while moderately deficient pigs "survived with scarred vessels but demonstrated a tendency toward premature atherosclerosis" including foam cell accumulation (2). Also in 1963, Dr. C. R. Ball and colleagues published a paper describing blood clots in the heart and coronary arteries, heart muscle degeneration, ventricular calcification and early death in mice fed a lard-rich diet (3).

This is where Dr. Leslie M. Klevay enters the story. Dr. Klevay suspected that Ball's mice had suffered from copper deficiency, and decided to test the hypothesis. He replicated Ball's experiment to the letter, using the same strain of mice and the same diet. Like Ball, he observed abnormal clotting in the heart, degeneration and enlargement of the heart muscle, and early death. He also showed by electrocardiogram that the hearts of the copper-deficient mice were often contracting abnormally (arrhythmia).

But then the coup de grace: he prevented these symptoms by supplementing the drinking water of a second group of mice with copper (4). In the words of Dr. Klevay: "copper was an antidote to fat intoxication" (5). I believe this was his tongue-in-cheek way of saying that the symptoms had been misdiagnosed by Ball as due to dietary fat, when in fact they were due to a lack of copper.

Since this time, a number of papers have been published on the relationship between copper intake and cardiovascular disease in animals, including several showing that copper supplementation prevents atherosclerosis in one of the most commonly used animal models of cardiovascular disease (6, 7, 8). Copper supplementation also corrects abnormal heart enlargement-- called hypertrophic cardiomyopathy-- and heart failure due to high blood pressure in mice (9).

For more than three decades, Dr. Klevay has been a champion of the copper deficiency theory of cardiovascular disease. According to him, copper deficiency is the only single intervention that has caused the full spectrum of human cardiovascular disease in animals, including:

• Heart attacks (myocardial infarction)
  
• Blood clots in the coronary arteries and heart
• Fibrous atherosclerosis including smooth muscle proliferation
• Unstable blood vessel plaque
  
• Foam cell accumulation and fatty streaks
  
• Calcification of heart tissues
  
• Aneurysms (ruptured vessels)
• Abnormal electrocardiograms
• High cholesterol
• High blood pressure
  

If this theory is so important, why have most people never heard of it? I believe there are at least three reasons. The first is that the emergence of the copper deficiency theory coincided with the rise of the diet-heart hypothesis, whereby saturated fat causes heart attacks by raising blood cholesterol. Bolstered by some encouraging findings and zealous personalities, this theory took the Western medical world by storm, for decades dominating all other theories in the medical literature and public health efforts. My opinions on the diet-heart hypothesis aside, the two theories are not mutually exclusive.

The second reason you may not have heard of the theory is due to a lab assay called copper-mediated LDL oxidation. Researchers take LDL particles (from blood, the same ones the doctor measures as part of a cholesterol test) and expose them to a high concentration of copper in a test tube. Free copper ions are oxidants, and the researchers then measure the amount of time it takes the LDL to oxidize. I find this assay tiresome, because studies have shown that the amount of time it takes copper to oxidize LDL in a test tube doesn't predict how much oxidized LDL you'll actually find in the bloodstream of the person you took the LDL from (10, 11).

In other words, it's an assay that has little bearing on real life. But researchers like it because for some odd reason, feeding a person saturated fat causes their LDL to be oxidized more rapidly by copper in a test tube, even though that's not the case in the actual bloodstream (12). Guess which result got emphasized?

The fact that copper is such an efficient oxidant has led some researchers to propose that copper oxidizes LDL in human blood, and therefore dietary copper may contribute to heart disease (oxidized LDL is a central player in heart disease-- read more here). The problem with this theory is that there are virtually zero free copper ions in human serum. Then there's the fact that supplementing humans with copper actually reduces the susceptibility of red blood cells to oxidation (by copper in a test tube, unfortunately), which is difficult to reconcile with the idea that dietary copper increases oxidative stress in the blood (13).

The third reason you may never have heard of the theory is more problematic. Several studies have found that a higher level copper in the blood correlates with a higher risk of heart attack (14, 15). At this point, I could hang up my hat, and declare the animal experiments irrelevant to humans. But let's dig deeper.

Nutrient status is sometimes a slippery thing to measure. As it turns out, serum copper isn't a good marker of copper status. In a 4-month trial of copper depletion in humans, blood copper stayed stable, while the activity of copper-dependent enzymes in the blood declined (16). These include the important copper-dependent antioxidant, superoxide dismutase. As a side note, lysyl oxidase is another copper-dependent enzyme that cross-links the important structural proteins collagen and elastin in the artery wall, potentially explaining some of the vascular consequences of copper deficiency. Clotting factor VIII increased dramatically during copper depletion, perhaps predicting an increased tendency to clot. Even more troubling, three of the 12 women developed heart problems during the trial, which the authors felt was unusual:

We observed a significant increase over control values in the number of ventricular premature discharges (VPDs) in three women after 21, 63, and 91 d of consuming the low-copper diet; one was subsequently diagnosed as having a second-degree heart block.

In another human copper restriction trial, 11 weeks of modest copper restriction coincided with heart trouble in 4 out of 23 subjects, including one heart attack (17):

In the history of conducting numerous human studies at the Beltsville Human Nutrition Research Center involving participation by 337 subjects, there had previously been no instances of any health problem related to heart function. During the 11 wk of the present study in which the copper density of the diets fed the subjects was reduced from the pretest level of 0.57 mg/ 1000 kcal to 0.36 mg/1000 kcal, 4 out of 23 subjects were diagnosed as having heart-related abnormalities.

The other reason to be skeptical of the association between blood copper and heart attack risk is that inflammation increases copper in the blood (18, 19). Blood copper level correlates strongly with the marker of inflammation C-reactive protein (CRP) in humans, yet substantially increasing copper intake doesn't increase CRP (20, 21). This suggests that elevated blood copper is likely a symptom of inflammation, rather than its cause, and presents an explanation for the association between blood copper level and heart attack risk.

Only a few studies have looked at the relationship between more accurate markers of copper status and cardiovascular disease in humans. Leukocyte copper status, a marker of tissue status, is lower in people with cardiovascular disease (22, 23). People who die of heart attacks generally have less copper in their hearts than people who die of other causes, although this could be an effect rather than a cause of the heart attack (24). Overall, I find the human data lacking. I'd like to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper.

According to a 2001 study, the majority of Americans may have copper intakes below the USDA recommended daily allowance (25), many substantially so. This problem is exacerbated by the fact that copper levels in food have declined in industrial nations over the course of the 20th century, something I'll discuss in the next post.

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20.00 | 0 comments

New Review of Controlled Trials Replacing Saturated fat with Industrial Seed Oils

Readers Stanley and JBG just informed me of a new review paper by Dr. Dariush Mozaffarian and colleagues. Dr. Mozaffarian is one of the Harvard epidemiologists responsible for the Nurse's Health study. The authors claim that overall, the controlled trials show that replacing saturated fat with polyunsaturated fat from industrial seed oils, but not carbohydrate or monounsaturated fat (as in olive oil), slightly reduces the risk of having a heart attack:

These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs [how do you like the acronyms?]. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD.

Looking at the studies they included in their analysis (and at those they excluded), it looks like they did a very nice job cherry picking. For example:

• They included the Finnish Mental Hospital trial, which is a terrible trial for a number of reasons. It wasn't randomized, appropriately controlled or even semi-blinded*. Thus, it doesn't fit the authors' stated inclusion criteria, but they included it in their analysis anyway**. Besides, the magnitude of the result has never been replicated by better trials, not even close.
  
• They included two trials that changed more than just the proportion of SFA to PUFA. For example, the Oslo Diet-heart trial replaced animal fat with seed oils, but also increased fruit, nut, vegetable and fish intake, while reducing trans fat margarine intake! The STARS trial increased both omega-6 and omega-3, reduced processed food intake, and increased fruit and vegetable intake! These obviously aren't controlled trials isolating the issue of dietary fat substitution. If you subtract the four inappropriate trials from their analysis, which is half the studies they analyzed, the result disappears. Those four just happened to show the largest reduction in heart attack mortality...
  
• They excluded the Rose et al. corn oil trial and the Sydney Diet-heart trial. Both found a large increase in total mortality from replacing animal fat with seed oils, and the Rose trial found a large increase in heart attack deaths (the Sydney trial didn't report CHD deaths, but Dr. Mozaffarian et al. stated in their paper that they contacted authors to obtain unpublished results. Why didn't they contact the authors of this study?).

The authors claim, based on their analysis, that replacing 5% of calories as saturated fat with polyunsaturated fat would reduce the risk of having a heart attack by 10%. Take a minute to think about the implications of that statement. For the average American, that means cutting saturated fat nearly in half to 6% of energy, which is a real challenge if you want to have a semblance of a normal diet. It also means nearly doubling PUFA intake, which will come mostly from seed oils if you follow the authors' advice.

So basically, even if the authors' conclusion were correct, you overhaul your whole diet and replace natural foods with bland unnatural foods, and...? You reduce your 10-year risk of having a heart attack from 10 percent to 9 percent. Without affecting your overall risk of dying! The paper states that the interventions didn't affect overall mortality at all. That's what they're talking about here. Sign me up!


* Autopsies were not conducted in a blinded manner. Physicians knew which hospital the cadavers came from, because autopsies were done on-site. There is some confusion about this point because the second paper states that physicians interpreted the autopsy reports in a blinded manner. But that doesn't make it blinded, since the autopsies weren't blinded. The patients were also not blinded, so the study overall was highly susceptible to bias.

** They refer to it as "cluster randomized". I don't know if that term accurately applies to the Finnish trial or not. The investigators definitely didn't randomize the individual patients: whichever hospital a person was being treated in, that's the food he/she ate. There were only two hospitals, so "cluster randomization" in this case would just refer to deciding which hospital got the intervention first. Can this accurately be called randomized?

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10.53 | 0 comments

Fatty Liver: It's not Just for Grown-ups Anymore

The epidemic of non-alcoholic fatty liver disease (NAFLD) is one of my favorite topics on this blog, due to the liver's role as the body's metabolic "grand central station", as Dr. Philip Wood puts it. The liver plays a critical part in the regulation of sugar, insulin, and lipid levels in the blood. Many of the routine blood tests administered in the doctor's office (blood glucose, cholesterol, etc.) partially reflect liver function.

NAFLD is an excessive accumulation of fat in the liver that impairs its function and can lead to severe liver inflammation (NASH), and in a small percentage of people, liver cancer. An estimated 20-30% of people in industrial nations suffer from NAFLD, a shockingly high prevalence (1).

I previously posted on dietary factors I believe are involved in NAFLD. In rodents, feeding a large amount of sugar or industrial seed oils (corn oil, etc.) promotes NAFLD, whereas fats such as butter and coconut oil do not (2). In human infants, enteric feeding with industrial seed oils causes severe liver damage, whereas the same amount of fat from fish oil doesn't, and can even reverse the damage done by seed oils (3).

So basically, I think sugar and industrial oils are major contributors to NAFLD, and if you look at diet trends in the US over the last 40 years, they're consistent with the idea. Industrial oils are harmful due (at least in part) to their high omega-6 content, which is problematic partially because it disturbs normal omega-3 metabolism. A potential solution to fatty liver is to reduce sugar, replace industrial oils with natural fats, and ensure a regular source of omega-3. I've posted two anecdotes of people rapidly healing their fatty livers using diet changes* (4, 5).

I recently came across a study that examined the diet of Canadian children with NAFLD (6). The children had a high sugar intake, a typical (i.e., high) omega-6 intake, and a low omega-3 intake. The authors claimed that the children also had a high saturated fat intake, but at 10.5% of calories, they were almost eating to the American Heart Association's "Step I" diet recommendations**. Busted! Total fat intake was also low.

High sugar consumption was associated with a larger waist circumference, insulin resistance, lower adiponectin and elevated markers of inflammation. High omega-6 intake was associated with markers of inflammation. Low omega-3 intake was associated with insulin resistance and elevated liver enzymes. Saturated fat intake presumably had no relation to any of these markers, since they didn't mention it in the text.

These children with NAFLD, who were all insulin resistant and mostly obese, had diets high in omega-6, high in sugar, and low in omega-3. This is consistent with the idea that these three factors, which have all been moving in the wrong direction in the last 40 years, contribute to NAFLD.


* Fatty liver was assessed by liver enzymes, admittedly not a perfect test. However, elevated liver enzymes do correlate fairly well with NAFLD.

** Steps I and II were replaced by new diet advice in 2000. The AHA now recommends keeping saturated fat below 7% of calories. Stock up on those skinless chicken breasts! Make sure there isn't any residual fat sticking to the meat, it might kill you. I do have to give the AHA credit however, because their new recommendations focus mostly on eating real food rather than avoiding saturated fat and cholesterol.

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09.00 | 0 comments

Corn Oil and Cancer: Reality Strikes Again

The benefits of corn oil keep rolling in. In a new study by Stephen Freedland's group at Duke, feeding mice a diet rich in butter and lard didn't promote the growth of transplanted human prostate cancer cells any more than a low-fat diet (1).

Why do we care? Because other studies, including one from the same investigators, show that corn oil and other industrial seed oils strongly promote prostate cancer cell growth and increase mortality in similar models (2, 3).

From the discussion section:

Current results combined with our prior results suggest that lowering the fat content of a primarily saturated fat diet offers little survival benefit in an intact or castrated LAPC-4 xenograft model. In contrast to the findings when omega-6 fats are used, these results raise the possibility that fat type may be as important as fat amount or perhaps even more important.

The authors seem somewhat surprised and pained by the result. Kudos for publishing it. However, there's nothing to be surprised about. There's a large body of evidence implicating excess omega-6 fat in a number of cancer models. Reducing omega-6 to below 4% of calories has a dramatic effect on cancer incidence and progression*. In fact, there have even been several experiments showing that butter and other animal fats promote cancer growth to a lesser degree than margarine and omega-6-rich seed oils. I discussed that here.

I do have one gripe with the study. They refer to the diet as "saturated fat based". That's inaccurate terminology. I see it constantly in the diet-health literature. If it were coconut oil, then maybe I could excuse it, because coconut fat is 93% saturated. But this diet was made of lard and butter, the combination of which is probably about half saturated. The term "animal fat" or "low-omega-6 fat" would have been more accurate. At least they listed the diet composition. Many studies don't even bother, leaving it to the reader to decide what they mean by "saturated fat".


* The average American eats 7-8% omega-6 by calories. This means it will be difficult to see a relationship between omega-6 intake and cancer (or heart disease, or most things) in observational studies in the US or other industrial nations, because we virtually all eat more than 4% of calories as omega-6. Until the 20th century, omega-6 intake was below 4%, and usually closer to 2%, in most traditional societies. That's where it remains in contemporary traditional societies unaffected by industrial food habits, such as Kitava. Our current omega-6 intake is outside the evolutionary norm.

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19.00 | 0 comments

Lindeberg on Obesity

I'm currently reading Dr. Staffan Lindeberg's magnum opus Food and Western Disease, recently published in English for the first time. Dr. Lindeberg is one of the world's leading experts on the health and diet of non-industrial cultures, particularly in Papua New Guinea. The book contains 2,034 references. It's also full of quotable statements. Here's what he has to say about obesity:

Middle-age spread is a normal phenomenon - assuming you live in the West. Few people are able to maintain their [youthful] waistline after age 50. The usual explanation - too little exercise and too much food - does not fully take into account the situation among traditional populations. Such people are usually not as physically active as you may think, and they usually eat large quantities of food.

Overweight has been extremely rare among hunter-gatherers and other traditional cultures [18 references]. This simple fact has been quickly apparent to all foreign visitors...

The Kitava study measured height, weight, waist circumference, subcutaneous fat thickness at the back of the upper arm (triceps skinfold) and upper arm circumference on 272 persons ages 4-86 years. Overweight and obesity were absent and average [body mass index] was low across all age groups. ...no one was larger around their waist than around their hips.

...The circumference of the upper arm [mostly indicating muscle mass] was only negligibly smaller on Kitava [compared with Sweden], which indicates that there was no malnutrition. It is obvious from our investigations that lack of food is an unknown concept, and that the surplus of fruits and vegetables regularly rots or is eaten by dogs.

The Population of Kitava occupies a unique position in the world in terms of the negligible effect that the Western lifestyle has had on the island.

The only obese Kitavans Dr. Lindeberg observed were two people who had spent several years off the island living a modern, urban lifestyle, and were back on Kitava for a visit.

I'd recommend this book to anyone who has a scholarly interest in health and nutrition, and somewhat of a background in science and medicine. It's extremely well referenced, which makes it much more valuable.

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17.18 | 0 comments

Dissolve Away those Pesky Bones with Corn Oil

I just read an interesting paper from Gabriel Fernandes's group at the University of Texas. It's titled "High fat diet-induced animal model of age-associated obesity and osteoporosis". I was expecting this to be the usual "we fed mice industrial lard for 60% of calories and they got sick" paper, but I was pleasantly surprised. From the introduction:

CO [corn oil] is known to promote bone loss, obesity, impaired glucose tolerance, insulin resistance and thus represents a useful model for studying the early stages in the development of obesity, hyperglycemia, Type 2 diabetes [23] and osteoporosis. We have used omega-6 fatty acids enriched diet as a fat source which is commonly observed in today's Western diets basically responsible for the pathogenesis of many diseases [24].

Just 10% of the diet as corn oil (roughly 20% of calories), with no added omega-3, on top of an otherwise poor laboratory diet, caused:

• Obesity
• Osteoporosis
• The replacement of bone marrow with fat cells
  
• Diabetes
• Insulin resistance
  
• Generalized inflammation
• Elevated liver weight (possibly indicating fatty liver)
  

Hmm, some of these sound familiar... We can add them to the findings that omega-6 also promotes various types of cancer in rodents (1).

20% fat is less than the amount it typically takes to make a rodent this sick. This leads me to conclude that corn oil is particularly good at causing mouse versions of some of the most common facets of the "diseases of civilization". It's exceptionally high in omega-6 (linoleic acid) with virtually no omega-3.

Make sure to eat your heart-healthy corn oil! It's made in the USA, dirt cheap and it even lowers cholesterol!

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17.43 | 0 comments

The Body Fat Setpoint, Part III: Dietary Causes of Obesity

What Caused the Setpoint to Change?

We have two criteria to narrow our search for the cause of modern fat gain:

1. It has to be new to the human environment
   
2. It has to cause leptin resistance or otherwise disturb the setpoint
   

Although I believe that exercise is part of a healthy lifestyle, it probably can't explain the increase in fat mass in modern nations. I've written about that here and here. There are various other possible explanations, such as industrial pollutants, a lack of sleep and psychological stress, which may play a role. But I feel that diet is likely to be the primary cause. When you're drinking 20 oz Cokes, bisphenol-A contamination is the least of your worries.

In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:

• Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
  
• Low-carbohydrate diets are effective for fat loss and lower triglycerides
• Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
• Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
  

Inflammation in the hypothalamus, with accompanying resistance to leptin signaling, has been reported in a number of animal studies of diet-induced obesity. I feel it's likely to occur in humans as well, although the dietary causes are probably different for humans. The hypothalamus is the primary site where leptin acts to regulate fat mass (3). Importantly, preventing inflammation in the brain prevents leptin resistance and obesity in diet-induced obese mice (3.1). The hypothalamus is likely to be the most important site of action. Research is underway on this.

The Role of Digestive Health

What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.

Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.

Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).

A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.

Overall, I think gut dysfunction probably plays a major role in obesity and other modern metabolic problems. Insufficient dietary fiber, micronutrient deficiencies, excessive gut irritating substances such as gluten, abnormal bacterial growth due to refined carbohydrates (particularly sugar), and omega-6:3 imbalance may all contribute to abnormal gut bacteria and increased gut permeability.

The Role of Fatty Acids and Micronutrients

Any time a disease involves inflammation, the first thing that comes to my mind is the balance between omega-6 and omega-3 fats. The modern Western diet is heavily weighted toward omega-6, which are the precursors to some very inflammatory substances (as well as a few that are anti-inflammatory). These substances are essential for health in the correct amounts, but they need to be balanced with omega-3 to prevent excessive and uncontrolled inflammatory responses. Animal models have repeatedly shown that omega-3 deficiency contributes to the fat gain and insulin resistance they develop when fed high-fat diets (9, 10, 11).

As a matter of fact, most of the papers claiming "saturated fat causes this or that in rodents" are actually studying omega-3 deficiency. The "saturated fats" that are typically used in high-fat rodent diets are refined fats from conventionally raised animals, which are very low in omega-3. If you add a bit of omega-3 to these diets, suddenly they don't cause the same metabolic problems, and are generally superior to refined seed oils, even in rodents (12, 13).

I believe that micronutrient deficiency also plays a role. Inadequate vitamin and mineral status can contribute to inflammation and weight gain. Obese people typically show deficiencies in several vitamins and minerals. The problem is that we don't know whether the deficiencies caused the obesity or vice versa. Refined carbohydrates and refined oils are the worst offenders because they're almost completely devoid of micronutrients.

Vitamin D in particular plays an important role in immune responses (including inflammation), and also appears to influence body fat mass. Vitamin D status is associated with body fat and insulin sensitivity in humans (14, 15, 16). More convincingly, genetic differences in the vitamin D receptor gene are also associated with body fat mass (17, 18), and vitamin D intake predicts future fat gain (19).

Exiting the Niche

I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.

In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.


* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.

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The Body Fat Setpoint, Part II: Mechanisms of Fat Gain

The Timeline of Fat Gain

Modern humans are unusual mammals in that fat mass varies greatly between individuals. Some animals carry a large amount of fat for a specific purpose, such as hibernation or migration. But all individuals of the same sex and social position will carry approximately the same amount of fat at any given time of year. Likewise, in hunter-gatherer societies worldwide, there isn't much variation in body weight-- nearly everyone is lean. Not necessarily lean like Usain Bolt, but not overweight.

Although overweight and obesity occurred forty years ago in the U.S. and U.K., they were much less common than today, particularly in children. Here are data from the U.S. Centers for Disease Control NHANES surveys (from this post):

Together, this shows that a) leanness is the most natural condition for the human body, and b) something about our changing environment, not our genes, has caused our body fat to grow.

Fat Mass is Regulated by a Feedback Circuit Between Fat Tissue and the Brain

In the last post, I described how the body regulates fat mass, attempting to keep it within a narrow window or "setpoint". Body fat produces a hormone called leptin, which signals to the brain and other organs to decrease appetite, increase the metabolic rate and increase physical activity. More fat means more leptin, which then causes the extra fat to be burned. The little glitch is that some people become resistant to leptin, so that their brain doesn't hear the fat tissue screaming that it's already full. Leptin resistance nearly always accompanies obesity, because it's a precondition of significant fat gain. If a person weren't leptin resistant, he wouldn't have the ability to gain more than a few pounds of fat without heroic overeating (which is very very unpleasant when your brain is telling you to stop). Animal models of leptin resistance develop something that resembles human metabolic syndrome (abdominal obesity, blood lipid abnormalities, insulin resistance, high blood pressure).

The Role of the Hypothalamus

The hypothalamus is on the underside of the brain connected to the pituitary gland. It's the main site of leptin action in the brain, and it controls the majority of leptin's effects on appetite, energy expenditure and insulin sensitivity. Most of the known gene variations that are associated with overweight in humans influence the function of the hypothalamus in some way (1). Not surprisingly, leptin resistance in the hypothalamus has been proposed as a cause of obesity. It's been shown in rats and mice that hypothalamic leptin resistance occurs in diet-induced obesity, and it's almost certainly the case in humans as well. What's causing leptin resistance in the hypothalamus?

There are three leading explanations at this point that are not mutually exclusive. One is cellular stress in the endoplasmic reticulum, a structure inside the cell that's used for protein synthesis and folding. I've read the most recent paper on this in detail, and I found it unconvincing (2). I'm open to the idea, but it needs more rigorous support.

A second explanation is inflammation in the hypothalamus. Inflammation inhibits leptin and insulin signaling in a variety of cell types. At least two studies have shown that diet-induced obesity in rodents leads to inflammation in the hypothalamus (3, 4)*. If leptin is getting to the hypothalamus, but the hypothalamus is insensitive to it, it will require more leptin to get the same signal, and fat mass will creep up until it reaches a higher setpoint.

The other possibility is that leptin simply isn't reaching the hypothalamus. The brain is a unique organ. It's enclosed by the blood-brain barrier (BBB), which greatly restricts what can enter and leave it. Both insulin and leptin are actively transported across the BBB. It's been known for a decade that obesity in rodents is associated with a lower rate of leptin transport across the BBB (5, 6).

What causes a decrease in leptin transport across the BBB? Triglycerides are a major factor. These are circulating fats going from the liver and the digestive tract to other tissues. They're one of the blood lipid measurements the doctor makes when he draws your blood. Several studies in rodents have shown that high triglycerides cause a reduction in leptin transport across the BBB, and reducing triglycerides allows greater leptin transport and fat loss (7, 8). In support of this theory, the triglyceride-reducing drug gemfibrozil also causes weight loss in humans (9)**. Guess what else reduces triglycerides and causes weight loss? Low-carbohydrate diets, and avoiding sugar and refined carbohydrates in particular.

In the next post, I'll get more specific about what factors could be causing hypothalamic inflammation and/or reduced leptin transport across the BBB. I'll also discuss some ideas on how to reduce leptin resistance sustainably through diet and exercise.


* This is accomplished by feeding them sad little pellets that look like greasy chalk. They're made up mostly of lard, soybean oil, casein, maltodextrin or cornstarch, sugar, vitamins and minerals (this is a link to the the most commonly used diet for inducing obesity in rodents). Food doesn't get any more refined than this stuff, and adding just about anything to it, from fiber to fruit extracts, makes it less damaging.

** Fibrates are PPAR agonists, so the weight loss could also be due to something besides the reduction in triglycerides.

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What's the Ideal Fasting Insulin Level?

Insulin is an important hormone. Its canonical function is to signal cells to absorb glucose from the bloodstream, but it has many other effects. Chronically elevated insulin is a marker of metabolic dysfunction, and typically accompanies high fat mass, poor glucose tolerance (prediabetes) and blood lipid abnormalities. Measuring insulin first thing in the morning, before eating a meal, reflects fasting insulin. High fasting insulin prevents the escape of fat from fat tissue and causes a number of other metabolic disturbances.

Elevated fasting insulin is a hallmark of the metabolic syndrome, the quintessential modern metabolic disorder that affects 24% of Americans (NHANES III). Dr. Lamarche and colleagues found that having an insulin level of 13 uIU/mL in Canada correlated with an 8-fold higher heart attack risk than a level of 9.3 uIU/mL (1; thanks to NephroPal for the reference). So right away, we can put our upper limit at 9.3 uIU/mL. The average insulin level in the U.S., according to the NHANES III survey, is 8.8 uIU/mL for men and 8.4 for women (2). Given the degree of metabolic dysfunction in this country, I think it's safe to say that the ideal level of fasting insulin is probably below 8.4 uIU/mL as well.

Let's dig deeper. What we really need is a healthy, non-industrial "negative control" group. Fortunately, Dr. Staffan Lindeberg and his team made detailed measurements of fasting insulin while they were visiting the isolated Melanesian island of Kitava (3). He compared his measurements to age-matched Swedish volunteers. In male and female Swedes, the average fasting insulin ranges from 4-11 uIU/mL, and increases with age. From age 60-74, the average insulin level is 7.3 uIU/mL.

In contrast, the range on Kitava is 3-6 uIU/mL, which does not increase with age. In the 60-74 age group, in both men and women, the average fasting insulin on Kitava is 3.5 uIU/mL. That's less than half the average level in Sweden and the U.S. Keep in mind that the Kitavans are lean and have an undetectable rate of heart attack and stroke.

Another example from the literature are the Shuar hunter-gatherers of the Amazon rainforest. Women in this group have an average fasting insulin concentration of 5.1 uIU/mL (4; no data was given for men).

I found a couple of studies from the early 1970s as well, indicating that African pygmies and San bushmen have rather high fasting insulin. Glucose tolerance was excellent in the pygmies and poor in the bushmen (5, 6, free full text). This may reflect differences in carbohydrate intake. San bushmen consume very little carbohydrate during certain seasons, and thus would likely have glucose intolerance during that period. There are three facts that make me doubt the insulin measurements in these older studies:

1. It's hard to be sure that they didn't eat anything prior to the blood draw.
2. From what I understand, insulin assays were variable and not standardized back then.
   
3. In the San study, their fasting insulin was 1/3 lower than the Caucasian control group (10 vs. 15 uIU/mL). I doubt these active Caucasian researchers really had an average fasting insulin level of 15 uIU/mL. Both sets of measurements are probably too high.
   

Now you know the conflicting evidence, so you're free to be skeptical if you'd like.

We also have data from a controlled trial in healthy urban people eating a "paleolithic"-type diet. On a paleolithic diet designed to maintain body weight (calorie intake had to be increased substantially to prevent fat loss during the diet), fasting insulin dropped from an average of 7.2 to 2.9 uIU/mL in just 10 days. The variation in insulin level between individuals decreased 9-fold, and by the end, all participants were close to the average value of 2.9 uIU/mL. This shows that high fasting insulin is correctable in people who haven't yet been permanently damaged by the industrial diet and lifestyle. The study included men and women of European, African and Asian descent (7).

One final data point. My own fasting insulin, earlier this year, was 2.3 uIU/mL. I believe it reflects a good diet, regular exercise, sufficient sleep, a relatively healthy diet growing up, and the fact that I managed to come across the right information relatively young. It does not reflect: carbohydrate restriction, fat restriction, or saturated fat restriction. Neither does the low fasting insulin of healthy non-industrial cultures.

So what's the ideal fasting insulin level? My current feeling is that we can consider anything between 2 and 6 uIU/mL within our evolutionary template, although the lower half of that range may be preferable.

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The Dirty Little Secret of the Diet-Heart Hypothesis

The diet-heart hypothesis is the idea that saturated fat, and in some versions cholesterol, raises blood cholesterol and contributes to the risk of having a heart attack. To test this hypothesis, scientists have been studying the relationship between saturated fat consumption and heart attack risk for more than half a century. To judge by the grave pronouncements of our most visible experts, you would think these studies had found an association between the two. It turns out, they haven't.

The fact is, the vast majority of high-quality observational studies have found no connection whatsoever between saturated fat consumption and heart attack risk. The scientific literature contains dozens of these studies, so let's narrow the field to prospective studies only, because they are considered the most reliable. In this study design, investigators find a group of initially healthy people, record information about them (in this case what they eat), and watch who gets sick over the years.

A Sampling of Unsupportive Studies

Here are references to ten high-impact prospective studies, spanning half a century, showing no association between saturated fat consumption and heart attack risk. Ignore the squirming about saturated-to-polyunsaturated ratios, Keys/Hegsted scores, etc. What we're concerned with is the straightforward question: do people who eat more saturated fat have more heart attacks? Many of these papers allow free access to the full text, so have a look for yourselves if you want:

A Longitudinal Study of Coronary Heart Disease. Circulation. 1963.

Diet and Heart: a Postscript. British Medical Journal. 1977. Saturated fat was unrelated to heart attack risk, but fiber was protective.

Dietary Intake and the Risk of Coronary Heart Disease in Japanese Men Living in Hawaii. American Journal of Clinical Nutrition. 1978.

Relationship of Dietary Intake to Subsequent Coronary Heart Disease Incidence: the Puerto Rico Heart Health Program. American Journal of Clinical Nutrition. 1980.

Diet, Serum Cholesterol, and Death From Coronary Heart Disease: The Western Electric Study. New England Journal of Medicine. 1981.

Diet and 20-year Mortality in Two Rural Population Groups of Middle-Aged Men in Italy. American Journal of Clinical Nutrition. 1989. Men who died of CHD ate significantly less saturated fat than men who didn't.

Diet and Incident Ischaemic Heart Disease: the Caerphilly Study. British Journal of Nutrition. 1993. They measured animal fat intake rather than saturated fat in this study.

Dietary Fat and Risk of Coronary Heart Disease in Men: Cohort Follow-up Study in the United States. British Medical Journal. 1996. This is the massive Physicians Health Study. Don't let the abstract fool you! Scroll down to table 2 and see for yourself that the association between saturated fat intake and heart attack risk disappears after adjustment for several factors including family history of heart attack, smoking and fiber intake. That's because, as in most modern studies, people who eat steak are also more likely to smoke, avoid vegetables, eat fast food, etc.

Dietary Fat Intake and the Risk of Coronary Heart Disease in Women. New England Journal of Medicine. 1997. From the massive Nurse's Health study. This one fooled me for a long time because the abstract is misleading. It claims that saturated fat was associated with heart attack risk. However, the association disappeared without a trace when they adjusted for monounsaturated and polyunsaturated fat intake. Have a look at table 3.

Dietary Fat Intake and Early Mortality Patterns-- Data from the Malmo Diet and Cancer Study. Journal of Internal Medicine. 2005.

I just listed 10 prospective studies published in top peer-reviewed journals that found no association between saturated fat and heart disease risk. This is less than half of the prospective studies that have come to the same conclusion, representing by far the majority of studies to date. If saturated fat is anywhere near as harmful as we're told, why are its effects essentially undetectable in the best studies we can muster?

Studies that Support the Diet-Heart Hypothesis

To be fair, there have been a few that have found an association between saturated fat consumption and heart attack risk. Here's a list of all four that I'm aware of, with comments:

Ten-year Incidence of Coronary Heart Disease in the Honolulu Heart Program: relationship to nutrient intake. American Journal of Epidemiology. 1984. "Men who developed coronary heart disease also had a higher mean intake of percentage of calories from protein, fat, saturated fatty acids, and polyunsaturated fatty acids than men who remained free of coronary heart disease." The difference in saturated fat intake between people who had heart attacks and those who didn't, although statistically significant, was minuscule.

Diet and 20-Year Mortality From Coronary Heart Disease: the Ireland-Boston Diet-Heart Study. New England Journal of Medicine. 1985. "Overall, these results tend to support the hypothesis that diet is related, albeit weakly, to the development of coronary heart disease."

Relationship Between Dietary Intake and Coronary Heart Disease Mortality: Lipid Research Clinics Prevalence Follow-up Study. Journal of Clinical Epidemiology. 1996. "...increasing percentages of energy intake as total fat (RR 1.04, 95% CI = 1.01 – 1.08), saturated fat (RR 1.11, CI = 1.04 – 1.18), and monounsaturated fat (RR 1.08, CI = 1.01 – 1.16) were significant risk factors for CHD mortality among 30 to 59 year olds... None of the dietary components were significantly associated with CHD mortality among those aged 60–79 years." Note that the associations were very small, also included monounsaturated fat (like in olive oil), and only applied to the age group with the lower risk of heart attack.

The Combination of High Fruit and Vegetable and Low Saturated Fat Intakes is More Protective Against Mortality in Aging Men than is Either Alone. Journal of Nutrition. 2005. Higher saturated fat intake was associated with a higher risk of heart attack; fiber was strongly protective.

The Review Papers

Over 25 high-quality studies conducted, and only 4 support the diet-heart hypothesis. If this substance is truly so fearsome, why don't people who eat more of it have more heart attacks? In case you're concerned that I'm cherry-picking studies that conform to my beliefs, here are links to review papers on the same data that have reached the same conclusion:

The Questionable Role of Saturated and Polyunsaturated Fatty Acids in Cardiovascular Disease. Journal of Clinical Epidemiology. 1998. Dr. Uffe Ravnskov systematically demolishes the diet-heart hypothesis simply by collecting all the relevant studies and summarizing their findings.

A Systematic Review of the Evidence Supporting a Causal Link Between Dietary Factors and Coronary Heart Disease. Archives of Internal Medicine. 2009. "Insufficient evidence (less than or equal to 2 criteria) of association is present for intake of supplementary vitamin E and ascorbic acid (vitamin C); saturated and polyunsaturated fatty acids; total fat; alpha-linolenic acid; meat; eggs; and milk" They analyzed prospective studies representing over 160,000 patients from 11 studies meeting their rigorous inclusion criteria, and found no association whatsoever between saturated fat consumption and heart attack risk.

Where's the Disconnect?

The first part of the diet-heart hypothesis states that dietary saturated fat raises the cholesterol/LDL concentration of the blood. This is held as established fact in the mainstream understanding of nutrition. The second part states that increased blood cholesterol/LDL increases the risk of having a heart attack. What part of this is incorrect?

There's definitely an association between blood cholesterol/LDL level and heart attack risk in certain populations, including Americans. MRFIT, among other studies, showed this definitively, although the lowest risk of all-cause mortality was at an average level of cholesterol. The association between blood cholesterol and heart attack risk does not apply to Japanese populations, as pointed out repeatedly by the erudite Dr. Harumi Okuyama. This seems to be generally true of groups that consume a lot of seafood.

So we're left with the first premise: that saturated fat increases blood cholesterol/LDL. This turns out to be largely a myth, based on a liberal interpretation of short-term feeding studies. In fact, it isn't even true in animal models of heart disease. In the 1950s, the most vigorous proponent of the diet-heart hypothesis, Dr. Ancel Keys, created a formula designed to predict changes in blood cholesterol based on the consumption of dietary saturated and polyunsaturated fats. This formula is extremely inaccurate and has gradually been dropped from the modern medical literature. Yet the idea that saturated fat consumption increases blood cholesterol/LDL lives on...

This is it, folks: the diet-heart hypothesis ends here. It's been kept afloat for decades by wishful thinking, puritan sensibilities and selective citation of the evidence. It's time to put it out of its misery.

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Butyric Acid: an Ancient Controller of Metabolism, Inflammation and Stress Resistance

An Interesting Finding

Susceptible strains of rodents fed high-fat diets overeat, gain fat and become profoundly insulin resistant. Dr. Jianping Ye's group recently published a paper showing that the harmful metabolic effects of a high-fat diet (lard and soybean oil) on mice can be prevented, and even reversed, using a short-chain saturated fatty acid called butyric acid (hereafter, butyrate). Here's a graph of the percent body fat over time of the two groups:

The butyrate-fed mice remained lean and avoided metabolic problems. Butyrate increased their energy expenditure by increasing body heat production and modestly increasing physical activity. It also massively increased the function of their mitochondria, the tiny power plants of the cell.

Butyrate lowered their blood cholesterol by approximately 25 percent, and their triglycerides by nearly 50 percent. It lowered their fasting insulin by nearly 50 percent, and increased their insulin sensitivity by nearly 300 percent*. The investigators concluded:

Butyrate and its derivatives may have potential application in the prevention and treatment of metabolic syndrome in humans.

There's one caveat, however: the butyrate group at less food. Something about the butyrate treatment caused their food intake to decline after 3 weeks, dropping roughly 20% by 10 weeks. The investigators cleverly tried to hide this by normalizing food intake to body weight, making it look like the food intake of the comparison group was dropping as well (when actually it was staying the same as this group was gaining weight).

I found this study thought-provoking, so I looked into butyrate further.

Butyrate Suppresses Inflammation in the Gut and Other Tissues

In most animals, the highest concentration of butyrate is found in the gut. That's because it's produced by intestinal bacteria from carbohydrate that the host cannot digest, such as cellulose and pectin. Indigestible carbohydrate is the main form of dietary fiber.

It turns out, butyrate has been around in the mammalian gut for so long that the lining of our large intestine has evolved to use it as its primary source of energy. It does more than just feed the bowel, however. It also has potent anti-inflammatory and anti-cancer effects. So much so, that investigators are using oral butyrate supplements and butyrate enemas to treat inflammatory bowel diseases such as Crohn's and ulcerative colitis. Investigators are also suggesting that inflammatory bowel disorders may be caused or exacerbated by a deficiency of butyrate in the first place.

Butyrate, and other short-chain fatty acids produced by gut bacteria**, has a remarkable effect on intestinal permeability. In tissue culture and live rats, short-chain fatty acids cause a large and rapid decrease in intestinal permeability. Butyrate, or dietary fiber, prevents the loss of intestinal premeability in rat models of ulcerative colitis. This shows that short-chain fatty acids, including butyrate, play an important role in the maintenance of gut barrier integrity. Impaired gut barrier integrity is associated with many diseases, including fatty liver, heart failure and autoimmune diseases (thanks to Pedro Bastos for this information-- I'll be covering the topic in more detail later).

Butyrate's role doesn't end in the gut. It's absorbed into the circulation, and may exert effects on the rest of the body as well. In human blood immune cells, butyrate is potently anti-inflammatory***.

Butyrate Increases Resistance to Metabolic and Physical Stress

Certain types of fiber reduce atherosclerosis in animal models, and this effect may be due to butyrate production produced when the fiber is fermented. Fiber intake was associated with lower blood markers of inflammation in the Women's Health Initiative study, and has been repeatedly associated with lower heart attack risk and reduced progression of atherosclerosis in humans. Butyrate also sharply reduces the harmful effects of type 1 diabetes in rats, as does dietary fiber to a lesser extent.

Butyrate increases the function and survival of mice with certain neurodegenerative diseases. Polyglutamine diseases, which are the most common class of genetic neurodegenerative diseases, are delayed in mice treated with butyrate (1, 2, 3). Many of you have probably heard of Huntington's disease, which is the most common of the class. I did my thesis on a polyglutamine disease called SCA7, and this is the first suggestion I've seen that diet may be able to modify its course.

Yet another interesting finding in the first paper I discussed: mice treated with butyrate were more cold-resistant than the comparison group. When they were both placed in a cold room, body temperature dropped quite a bit in the comparison group, while it remained relatively stable in the butyrate group, despite the fact that the butyrate group was leaner****. This was due to increased heat production in the butyrate group.

Due to the potent effect butyrate has on a number of bodily processes, I believe it may be a fundamental controller of metabolism, stress resistance and the immune system in mammals, similar to omega-6:3 balance.

An Ancient Line of Communication Between Symbiotic Organisms

Why does butyrate have so much control over inflammation? Let's think about where it comes from. Bacteria in the gut produce it. It's a source of energy, so our bodies take it up readily. It's one of the main molecules that passes from the symbiotic (helpful) bacteria in the gut to the rest of the body. It's only logical that the body would receive butyrate as a signal that there's a thriving colony of symbiotic bacteria in the gut, and induce a tolerance to them. The body may alter its immune response (inflammation) in order to permit a mutually beneficial relationship between itself and its symbionts.

A Change of Heart

Butyrate has caused me to re-think my position on fiber-- which was formerly that it's irrelevant at best. I felt that fiber came along with nutrient-dense whole plant foods, but was not beneficial per se. I believed that the associations between fiber intake and a lower risk of a number of diseases were probably due to the fact that wealthier, more educated, healthier people tend to buy more whole grains, fruit and vegetables. In other words, I believed that fiber intake was associated with better health, but did not contribute to it. I now feel, based on further reading about fiber and short-chain fatty acids like butyrate, that the associations represent a true cause-and-effect relationship.

I also didn't fully appreciate the caloric contribution of fiber to the human diet. In industrialized countries, fiber may contribute 5 to 10 percent of total calorie intake, due to its conversion to short-chain fatty acids like butyrate in the large intestine (free full text). This figure is probably at least twice as high in cultures consuming high-fiber diets. It's interesting to think that "high-carbohydrate" cultures may be getting easily 15 percent of their calories from short-chain fats. Since that isn't recorded in dietary surveys, they may appear more dependent on carbohydrate than they actually are. The Kitavans may be getting more than 30 percent of their total calories from fat, despite the fact that their food is only 21 percent fat when it passes their lips. Their calorie intake may be underestimated as well.

Sources of Butyrate

There are two main ways to get butyrate and other short-chain fatty acids. The first is to eat fiber and let your intestinal bacteria do the rest. Whole plant foods such as sweet potatoes, properly prepared whole grains, beans, vegetables, fruit and nuts are good sources of fiber. Refined foods such as white flour, white rice and sugar are very low in fiber. Clinical trials have shown that increasing dietary fiber increases butyrate production, and decreasing fiber decreases it (free full text).

Butyrate also occurs in significant amounts in food. What foods contain butyrate? Hmm, I wonder where the name BUTYR-ate came from? Butter perhaps? Butter is 3-4 percent butyrate, the richest known source. But everyone knows butter is bad for you, right?

After thinking about it, I've decided that butyrate must have been a principal component of Dr. Weston Price's legendary butter oil. Price used this oil in conjunction with high-vitamin cod liver oil to heal tooth decay and a number of other ailments in his patients. The method he used to produce it would have concentrated fats with a low melting temperature, including butyrate, in addition to vitamin K2*****. Thus, the combination of high-vitamin cod liver oil and butter oil would have provided a potent cocktail of fat-soluble vitamins (A, D3, K2), omega-3 fatty acids and butyrate. It's no wonder it was so effective in his patients.


* According to insulin tolerance test.

** Acetate (acetic acid, the main acid in vinegar), propionate and butyrate are the primary three fatty acids produced by intestinal fermentation.

*** The lowest concentration used in this study, 30 micromolar, is probably higher than the concentration in peripheral serum under normal circumstances. Human serum butyrate is in the range of 4 micromolar in British adults, and 29 micromolar in the hepatic portal vein which brings fats from the digestive tract to the liver (ref). This would likely be at least two-fold higher in populations eating high-fiber diets.

**** Due to higher mitochondrial density in brown fat and more mitochondrial uncoupling.

***** Slow crystallization, which selectively concentrates triglycerides with a low melting point.

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Dr. Rosedale Replies

A few months ago, I posted link to an article by Dr. Ron Rosedale and made a few comments about it. Dr. Rosedale has sent a reply to my comments, which I have agreed to publish as a new post because they may be of interest to readers. In the following exchange, my numbered comments are in quotes and Dr. Rosedale's replies follow them.

Dr. Rosedale's Comments

1. Dr. Rosedale says that insulin's ability to regulate blood sugar is a minor role, and that other hormones do the same thing. Tell that to a type 1 diabetic. Excessive blood glucose is Not Good, and that's what you get if there isn't enough insulin around.

What I have said was that insulin does not control glucose levels in the blood, and that insulin's biological purpose (not ability) plays only a minor role in BS control... and that is a correct statement. Insulin reduces blood glucose by storing it for a rainy day as glycogen and fat, but not for the purpose of regulating blood sugar levels. The control of BS is in an upward direction, not a downward direction. The problem in our evolutionary history was to have enough BS for emergency anaerobic respiration and for those tissues that require it such as red blood cells. Lowering blood sugar was never a priority in our history. For one, it didn't rise much very often. There wasn't much glucose around. Uncooked rice and potatoes, etc., are mostly indigestible. The sugar that was around, such as in fruit, required considerable effort to obtain therefore lowered the sugar prior to obtaining it. Also, the sugar that is in fruit is largely fructose which doesn't convert that much into glucose but rather into fat in the liver. Even if it did raise blood sugar levels, even if it did cause diabetes in evolutionary time, nature would consider that irrelevant as it wouldn't have killed people prior to the reproductive years, only post-reproductively when nature doesn't give a damn.

Furthermore, insulin's major purpose goes way beyond sugar. At the very least, it is a nutrient storage hormone being relevant not only in glucose storage, but also in fat and protein (amino acid) storage. It also plays a significant role in micronutrient storage and conversions. However, overwhelmingly more important, is insulin's role as a nutrient sensor greatly influencing genetic expression and modifying the rate of aging by up or down regulating maintenance and repair.

2. I'm not convinced by the theory that organisms balance reproduction and repair, emphasizing one at the expense of the other. The amount of energy it takes to fuel cellular repair processes is negligible compared to the amount it takes to maintain body temperature, fuel the brain and contract skeletal muscles. Why not just have the organism eat an extra half-teaspoon of mashed potatoes to fuel the heat-shock proteins and make a little extra catalase? I think the true reasons behind lifespan extension upon caloric restriction will turn out to be more complex than a balance between reproduction and repair.

Stephan does not have to be convinced. Almost everybody who studies the biology of aging is convinced that there is a dichotomy between reproduction and maintenance and repair and that biologically a cell can spend the majority of available resources towards one or the other, but not both. This can actually be shown genetically as the up or down regulation of the expression of genes regulating heat shock proteins, intracellular antioxidant systems, DNA repair enzymes, "garbage collection", etc versus the up or down regulation of genes which regulate reproductive behavior. It should also be noted that excessive reproductive behavior is, in individual cells of multicellular organisms, a strong predisposition to cancer. Furthermore, Stephan’s statement that it takes negligible energy for maintenance and repair is very wrong. In fact one could make the argument that almost all of the energy spent by both individual cells and by the cell societies of multi-celled organisms when not reproducing is towards maintenance and repair.

3. I disagree with the idea that carbohydrate itself is behind elevated fasting insulin and leptin. Just look at the Kitavans. They get 69% of their calories from high-glycemic-load carbohydrates, with not much fat (21%) or protein (10%) to slow digestion. Yet, they have low fasting insulin and remarkably low fasting leptin. I believe the fasting levels of these hormones are more responsive to macronutrient quality than quantity. In other words, what matters most is not how much carbohydrate is in the diet, but where the carbohydrate comes from. The modern Western combination of carelessly processed wheat, sugar and linoleic acid-rich vegetable oil seems to be particularly harmful.

It is not where the carbohydrates come from, but where the carbohydrates go. In other words, what carbohydrates are digested into, i.e what the cells are being fed. Feeding them glucose, fructose, galactose and amino acids as energy (as opposed to using the amino acids whole as structural components) is bad.

Stephan himself could answer this one. It's not the percent of calories from carbohydrates that is relevant; it is the absolute amount of non-fiber carbohydrates that is relevant as the glycemic load.

A few further comments on the Kitavans, though I really am not an expert on their diet:

I find that indigenous diets are only partially helpful as there are so many variables that can go unaccounted for. I prefer the more elementary sciences to form opinions. However, it sounds like there really isn't that much non-fiber carbohydrate in the diet and there is considerable fiber, fish and coconut oil, and moderate to low protein, all of which are quite fine for health. If it is known, the total gram quantities of macronutrients would be good to know. Another important point; what is their lifespan? It sounds like it might be long, but it would be nice to know a more accurate figure. It is not weight loss that we should be after, it is health as indicated by a long and youthful lifespan. Another point; though they (the Kitavans) may be doing well if one defines well as better than most human counterparts, it isn't really saying much. The majority of society eats so badly that it really is not difficult to eat a diet that is better. What I am after is not just better, but best. Perhaps one could take the Kitavan diet and improve upon it by reducing the non-fiber carbohydrate content and perhaps adding more beneficial fats and oils. It is quite possible, in fact probable, that there have been no human societies that have eaten an ideal diet. We can only use what modern science is telling us to come up with this.

My Reply to Dr. Rosedale

Thank you for your comments.

1. I agree with you that control of blood sugar is not insulin's only purpose, and that there are other mechanisms of blood glucose control. There were several papers published recently showing that type 1 diabetic rats (lacking insulin) can be restored to a normal blood glucose level and near-normal glucose tolerance by infusing leptin into the lateral or the third cerebral ventricles (1, 2). This was totally independent of insulin, because the rats weren't producing any. And yes, insulin signaling influences lifespan in a number of animal models.

However, insulin is still the primary controller of blood sugar under normal circumstances, as shown in type 1 diabetes where the primary defect is in insulin production. Furthermore, excessively elevated glucose is damaging per se, due to protein glycation, competition with vitamin C, etc. Therefore, the glucose-controlling function of insulin is important.

I do not agree that glucose from starch and fruit played an insignificant role in human evolution. A number of modern hunter-gatherers eat a significant amount of starch, and our ancestors probably did as well, as soon as they could cook. The timeline of cooking is debated, but we've probably been doing it for at least half a million years, or as long as Homo sapiens has existed. Fruit sugar is roughly 50% glucose, as is honey.

2. As someone who spent two years in the field of aging research, I don't see a scientific consensus on the idea that reproduction and aging are in balance with one another. The two correlate with one another in some, but not all models. I was at a seminar just the other day by Dr. Linda Partridge, from the Max Planck institute, and she was talking about her lifespan experiments in fruit flies. She was able to independently modify lifespan and fecundity using amino acid restriction, leading her to the conclusion that there is no link between the two in her model. She published these data recently in the journal Nature (reference).

Regarding the energy required for cellular maintenance, a little math is instructive here. I eat maybe 3,200 calories a day, which is normal for an active male of my weight. My basal metabolic rate is roughly 1,700 kcal per day. So 1,500 of my calories have already gone to moving my skeletal muscles. Of the basal metabolic rate, the vast majority comes from maintaining body temperature. Thermogenesis is why cold-blooded animals only need to eat a fraction of the calories mammals do. Then there's cardiac function, and smooth muscle activity, which eat up more calories. Then there are the energy-intensive cellular processes of maintaining ionic gradients across cell membranes (which is why the brain eats up 20% of our calories) and protein synthesis.

After you subtract out all those functions, only a small fraction of total caloric intake is left for other cellular processes. So the caloric needs for processes that combat cellular aging (DNA repair, etc.) are quite low, compared to overall energy requirements. This is consistent with the fact that naked mole rats, which live ten times longer than Rattus norvegicus, have a similar basal metabolic rate to one another. Keeping cells from being damaged is not a particularly energy-intensive process, and so we have to look elsewhere for the reason why it hasn't been prioritized by evolution.

3. The Kitavan diet is high in digestible starch. The foods they eat have been characterized for starch content, glycemic index, and fiber content. Their diet overall has a high glycemic load, is 69% carbohydrate by calories, and is similar in calories to the American diet. They have a low BMI, a low fasting insulin and low fasting glucose. I agree that there are many factors at play here, and the example of the Kitavans doesn't necessarily give carbohydrate a free pass in all situations. But it does show that a high carbohydrate intake, at least under certain circumstances, is compatible with low fasting insulin, high insulin sensitivity, leanness, and apparent good health.

I also agree that the Kitavans are not really a good model of longevity. Although they live a long time relative to other non-industrial cultures, and have individuals exceeding 95 years old, they don't have a longer average lifespan than people in affluent nations. One can guess that it's due to a lack of modern medical care to treat infectious diseases, and I think that's likely to play a role, but ultimately it's speculation. It's an open question whether you could improve their lifespan by reducing the non-fiber carbohydrate content of their diet, but I'm skeptical.

In the end, it's also an open question whether or not you can extend life by restricting carbohydrate. For the typical overweight American who responds well to carbohydrate restriction, it's reasonable to speculate that it might. For an insulin-sensitive, lean American, it's not clear that it would have much benefit, outside of reducing potentially harmful foods such as gluten and sugar. Although insulin signaling is probably tied up with lifespan in humans, as in many other species, no one has shown that post-meal insulin spikes caused by carbohydrate, as opposed to chronically elevated insulin and insulin resistance, is harmful. The story is not as simple as "more serum insulin = shorter lifespan".

Is there any evidence that carbohydrate restriction extends lifespan in a non-carnivorous mammal such as a rodent or monkey? I'm open to the possibility, but I haven't seen any studies. I'll look forward to them.

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