Ancestral Health Symposium 2012

I recently returned from AHS12 and a little side trip to visit family. The conference was hosted at Harvard University through the Harvard Food Law Society. Many thanks to all the organizers who made it happen. By and large, it went smoothly.

The science as expected ranged from outstanding to mediocre, but I was really encouraged by the presence and enthusiastic participation of a number of quality researchers and clinicians. The basic concept of ancestral health is something almost anyone can get behind: many of our modern health problems are due to a mismatch between the modern environment and what our bodies "expect". The basic idea is really just common sense, but of course the devil is in the details when you start trying to figure out what exactly our bodies expect, and how best to give it to them. I think our perspective as a community is moving in the right direction.

Read more »

Read More

New Review Paper by Yours Truly: High-Fat Dairy, Obesity, Metabolic Health and Cardiovascular Disease

My colleagues Drs. Mario Kratz, Ton Baars, and I just published a paper in the European Journal of Nutrition titled "The Relationship Between High-Fat Dairy Consumption and Obesity, Cardiovascular, and Metabolic Disease". Mario is a nutrition researcher at the Fred Hutchinson Cancer Research Center here in Seattle, and friend of mine. He's doing some very interesting research on nutrition and health (with an interest in ancestral diets), and I'm confident that we'll be getting some major insights from his research group in the near future. Mario specializes in tightly controlled human feeding trials. Ton is an agricultural scientist at the University of Kassel in Germany, who specializes in the effect of animal husbandry practices (e.g., grass vs. grain feeding) on the nutritional composition of dairy. None of us have any connection to the dairy industry or any other conflicts of interest.

The paper is organized into three sections:

1. A comprehensive review of the observational studies that have examined the relationship between high-fat dairy and/or dairy fat consumption and obesity, metabolic health, diabetes, and cardiovascular disease.
2. A discussion of the possible mechanisms that could underlie the observational findings.
3. Differences between pasture-fed and conventional dairy, and the potential health implications of these differences.

Read more »

Read More

Is Sugar Fattening?

Buckle your seat belts, ladies and gentlemen-- we're going on a long ride through the scientific literature on sugar and body fatness. Some of the evidence will be surprising and challenging for many of you, as it was for me, but ultimately it paints a coherent and actionable picture.

Read more »

Read More

What Causes Insulin Resistance? Part VII

In previous posts, I outlined the factors I'm aware of that can contribute to insulin resistance. In this post, first I'll list the factors, then I'll provide my opinion of effective strategies for preventing and potentially reversing insulin resistance.

The factors

These are the factors I'm aware of that can contribute to insulin resistance, listed in approximate order of importance. I could be quite wrong about the order-- this is just my best guess. Many of these factors are intertwined with one another.
Read more »

Read More

The Brain Controls Insulin Action

Insulin regulates blood glucose primarily by two mechanisms:

1. Suppressing glucose production by the liver
2. Enhancing glucose uptake by other tissues, particularly muscle and liver

Since the cells contained in liver, muscle and other tissues respond directly to insulin stimulation, most people don't think about the role of the brain in this process. An interesting paper just published in Diabetes reminds us of the central role of the brain in glucose metabolism as well as body fat regulation (1). Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin's ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%. In other words, the majority of insulin's ability to cause muscle to take up glucose is mediated by its effect on the brain.

Read more »

Read More

Fast Food, Weight Gain and Insulin Resistance

CarbSane just posted an interesting new study that fits in nicely with what we're discussing here. It's part of the US Coronary Artery Risk Development in Young Adults (CARDIA) study, which is a long-term observational study that is publishing many interesting findings. The new study is titled "Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis" (1). The results speak for themselves, loud and clear (I've edited some numbers out of the quote for clarity):
Read more »

Read More

Food Reward: a Dominant Factor in Obesity, Part III

Low-Fat Diets

In 2000, the International Journal of Obesity published a nice review article of low-fat diet trials. It included data from 16 controlled trials lasting from 2-12 months and enrolling 1,910 participants (1). What sets this review apart is it only covered studies that did not include instructions to restrict calorie intake (ad libitum diets). On average, low-fat dieters reduced their fat intake from 37.7 to 27.5 percent of calories. Here's what they found:
Read more »

Read More

Oltipraz

Oltipraz is a drug that was originally used to treat intestinal worms. It was later found to prevent a broad variety of cancers (1). This was attributed to its ability to upregulate cellular detoxification and repair mechanisms.

Researchers eventually discovered that oltipraz acts by activating Nrf2, the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4). Nrf2 activation mounts a broad cellular protective response that appears to reduce the risk of multiple health problems.

A recent paper in Diabetologia illustrates this (5). Investigators put mice on a long-term refined high-fat diet, with or without oltipraz. These carefully crafted diets are very unhealthy indeed, and when fed to rodents they rapidly induce fat gain and something that looks similar to human metabolic syndrome (insulin resistance, abdominal adiposity, blood lipid disturbances). Adding oltipraz to the diet prevented the fat gain, insulin resistance and inflammatory changes that occurred in the refined high-fat diet group.

The difference in fasting insulin was remarkable. The mice taking oltipraz had 1/7 the fasting insulin of the refined high-fat diet comparison group, and 1/3 the fasting insulin of the low-fat comparison group! Yet their glucose tolerance was normal, indicating that they were not low on insulin due to pancreatic damage. The low-fat diet they used in this study was also refined, which is why the two control groups (high-fat and low-fat) didn't diverge more in body fatness and other parameters. If they had used a group fed unrefined rodent chow as the comparator, the differences between groups would have been larger.

This shows that in addition to preventing cancer, Nrf2 activation can attenuate the metabolic damage caused by an unhealthy diet in rodents. Oltipraz illustrates the power of the cellular hormesis response. We can exploit this pathway naturally using polyphenols and other chemicals found in whole plant foods.

Read More

Intervew with Chris Kresser of The Healthy Skeptic

Last week, I did an audio interview with Chris Kresser of The Healthy Skeptic, on the topic of obesity. We put some preparation into it, and I think it's my best interview yet. Chris was a gracious host. We covered some interesting ground, including (list copied from Chris's post):

• The little known causes of the obesity epidemic
• Why the common weight loss advice to “eat less and exercise more” isn’t effective
• The long-term results of various weight loss diets (low-carb, low-fat, etc.)
• The body-fat setpoint and its relevance to weight regulation
• The importance of gut flora in weight regulation
• The role of industrial seed oils in the obesity epidemic
• Obesity as immunological and inflammatory disease
• Strategies for preventing weight gain and promoting weight loss

Some of the information we discussed is not yet available on my blog. You can listen to the interview through Chris's post here.

Read More

Saturated Fat and Insulin Sensitivity, Again

A new study was recently published exploring the effect of diet composition on insulin sensitivity and other factors in humans (1). 29 men with metabolic syndrome-- including abdominal obesity, low HDL, high blood pressure, high triglycerides, and high fasting glucose-- were fed one of four diets for 12 weeks:

1. A diet containing 38% fat: 16% saturated (SFA), 12% monounsaturated (MUFA) and 6% polyunsaturated (PUFA)
   
2. A diet containing 38% fat: 8% SFA, 20% MUFA and 6% PUFA
3. A diet high in unrefined carbohydrate, containing 28% fat (8% SFA, 11% MUFA and 6% PUFA)
4. A diet high in unrefined carbohydrate, containing 28% fat (8% SFA, 11% MUFA and 6% PUFA) and an omega-3 supplement (1.24 g/day EPA and DHA)
   

After 12 weeks, insulin sensitivity, fasting glucose, glucose tolerance, and blood pressure did not change significantly in any of the four groups. This is consistent with the majority of the studies that have examined this question, although somehow the idea persists that saturated fat impairs insulin sensitivity. I discussed this in more detail in a recent post (2).

The paper that's typically cited by people who wish to defend the idea that saturated fat impairs insulin sensitivity is the KANWU study (3). In this study, investigators found no significant difference in insulin sensitivity between volunteers fed primarily SFA or MUFA for 12 weeks. You wouldn't realize this from the abstract however; you have to look very closely at the p-values in table 4.

One of the questions one could legitimately ask, however, is whether SFA have a different effect on people with metabolic syndrome. Maybe the inflammation and metabolic problems they already have make them more sensitive to the hypothetical damaging effects of SFA? That's the question the first study addressed, and it appears that SFA are not uniquely harmful to insulin signaling in those with metabolic syndrome on the timescale tested.

It also showed that the different diets did not alter the proportion of blood fats being burned in muscle, as opposed to being stored in fat tissue. The human body is a remarkably adaptable biological machine that can make the best of a variety of nutrient inputs, at least over the course of 12 weeks. Metabolic damage takes decades to accumulate, and in my opinion is more dependent on food quality than macronutrient composition. Once metabolic dysfunction is established, some people may benefit from carbohydrate restriction, however.

Read More

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!

Read More

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 is a marker of metabolic problems and may contribute to some of them as well.

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.

Read More

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.

Read More

Eicosanoids, Fatty Liver and Insulin Resistance

I have to take a brief intermission from the heart disease series to write about a very important paper I just read in the journal Obesity, "COX-2-mediated Inflammation in Fat is Crucial for Obesity-linked Insulin Resistance and Fatty Liver". It's actually related to cardiovascular disease, although indirectly.

First, some background. Polyunsaturated fatty acids (PUFA) come mostly from omega-6 and omega-3 sources. Omega-6 and omega-3 are precursors to eicosanoids, a large and poorly understood class of signaling molecules that play a role in basically everything. Eicosanoids are either omega-6-derived or omega-3-derived. Omega-6 and omega-3 compete for the enzymes that convert PUFA into eicosanoids. Therefore, the ratio of omega-6 to omega-3 in tissues (related to the ratio in the diet) determines the ratio of omega-6-derived eicosanoids to omega-3-derived eicosanoids.

Omega-6 eicosanoids are very potent and play a central role in inflammation. They aren't "bad", in fact they're essential, but an excess of them is probably not good. Omega-3 eicosanoids are generally less potent, less inflammatory, and tend to participate in long-term repair processes. So in sum, the ratio of omega-6 to omega-3 in the diet will determine the potency and quality of eicosanoid signaling, which will determine an animal's susceptibility to inflammation-mediated disorders.

One of the key enzymes in the pathway from PUFA to eicosanoids (specifically, a subset of them called prostanoids) is cyclooxygenase (COX). COX-1 is expressed all the time and serves a "housekeeping" function, while COX-2 is induced by cellular stressors and contributes to the the formation of inflammatory eicosanoids. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen inhibit COX enzymes, which is why they are effective against inflammatory problems like pain and fever. They are also used as a preventive measure against cardiovascular disease. Basically, they reduce the excessive inflammatory signaling promoted by a diet with a poor omega-6:3 balance. You wouldn't need to inhibit COX if it were producing the proper balance of eicosanoids to begin with.

Dr. Kuang-Chung Shih's group at the Department of Internal Medicine in Taipei placed rats on five different diets:

1. A control diet, eating normal low-fat rat chow.


2. A "high-fat diet", in which 45% of calories came from a combination of industrial lard and soybean oil, and 17% of calories came from sucrose*.


3. A "high-fat diet" (same as above), plus the COX-2 inhibitor celecoxib (Celebrex).


4. A "high-fat diet" (same as above), plus the COX-2 inhibitor mesulid.


5. An energy-restricted "high-fat diet".

The "high-fat diets", besides being high in sucrose (table sugar), also presumably had a poor omega-6:3 ratio, in the neighborhood of 10:1 or possibly higher. Weight and fat mass in rats and humans increases with increasing omega-6 in the diet, and also increases with a high 6:3 ratio. I wrote about that here. Rats eating the high-fat diets (groups 2- 4) gained weight as expected**.

Rats in group 2 not only gained weight, they also experienced increased fasting glucose, leptin, insulin, triglycerides, blood pressure and a massive decline in insulin sensitivity (seven-fold relative to group 1). Rats in groups 3 and 4 gained weight, but saw much less of a deterioration in insulin and leptin sensitivity, and blood pressure. Group 2 also developed fatty liver, which was attenuated in groups 3 and 4. If you're interested, group 5 (energy restricted high-fat) was similar to groups 3 and 4 on pretty much everything, including insulin sensitivity.

So there you have it folks: direct evidence that insulin resistance, leptin resistance, high blood pressure and fatty liver are mediated by excessive inflammatory eicosanoid signaling. I wrote about something similar before when I reviewed a paper showing that fish oil reverses many of the consequences of a high-vegetable oil, high-sugar diet in rats. I also reviewed two papers showing that in pigs and rats, a high omega-6:3 ratio promotes inflammation (mediated by COX-2) and lipid peroxidation in the heart. Are you going to quench the fire by taking drugs, or by reducing your intake of omega-6 and ensuring an adequate intake of omega-3?

*Of course, they didn't mention the sucrose in the methods section. I had to go digging around for the diet's composition. This is typical of papers on "high-fat diets". They load them up with sugar, and blame everything on the fat.

**Rats gain fat mass when fed a high-fat diet (even if it's not loaded with sugar). But humans don't necessarily gain weight on a high-fat diet (i.e. low-carb weight loss diet). What's the difference? Low-carbohydrate diet trials indicate that humans spontaneously reduce their caloric intake when eating low carbohydrate, high-fat food.

Read More

Fructose vs. Glucose Showdown

As you've probably noticed, I believe sugar is one of the primary players in the diseases of civilization. It's one of the "big three" that I focus on: sugar, industrial vegetable oil and white flour. It's becoming increasingly clear that fructose, which constitutes half of table sugar and typically 55% of high-fructose corn syrup, is the problem. A reader pointed me to a brand new study (free full text!), published in the Journal of Clinical Investigation, comparing the effect of ingesting glucose vs. fructose.

The investigators divided 32 overweight men and women into two groups, and instructed each group to drink a sweetened beverage three times per day. They were told not to eat any other sugar. The drinks were designed to provide 25% of the participants' caloric intake. That might sound like a lot, but the average American actually gets about 25% of her calories from sugar! That's the average, so there are people who get a third or more of their calories from sugar. In one group, the drinks were sweetened with glucose, while in the other group they were sweetened with fructose.

After ten weeks, both groups had gained about three pounds. But they didn't gain it in the same place. The fructose group gained a disproportionate amount of visceral fat, which increased by 14%! Visceral fat is the most dangerous type; it's associated with and contributes to chronic disease, particularly metabolic syndrome, the quintessential modern metabolic disorder (see the end of the post for more information and references). You can bet their livers were fattening up too.

The good news doesn't end there. The fructose group saw a worsening of blood glucose control and insulin sensitivity. They also saw an increase in small, dense LDL particles and oxidized LDL, both factors that associate strongly with the risk of heart attack and may in fact contribute to it. Liver synthesis of fat after meals increased by 75%. If you look at table 4, it's clear that the fructose group experienced a major metabolic shift, and the glucose group didn't. Practically every parameter they measured in the fructose group changed significantly over the course of the 9 weeks. It's incredible.

25% of calories from fructose is a lot. The average American gets about 13%. But plenty of people exceed that, perhaps going up to 20% or more. Furthermore, the intervention was only 10 weeks. What would a lower intake of fructose, say 10% of calories, do to a person over a lifetime? Nothing good, in my opinion. Avoiding refined sugar is one of the best things you can do for your health.

U.S. Fructose Consumption Trends
Peripheral vs. Ectopic Fat
Visceral Fat
Visceral Fat and Dementia
How to Give a Rat Metabolic Syndrome
How to Fatten Your Liver

Read More

Leptin Resistance and Sugar

Leptin is a major hormone regulator of fat mass in vertebrates. It's a frequent topic on this blog because I believe it's central to overweight and modern metabolic disorders. Here's how it works. Leptin is secreted by fat tissue, and its blood levels are proportional to fat mass. The more fat tissue, the more leptin. Leptin reduces appetite, increases fat release from fat tissue and increases the metabolic rate. Normally, this creates a "feedback loop" that keeps fat mass within a fairly narrow range. Any increase in fat tissue causes an increase in leptin, which burns fat tissue at an accelerated rate. This continues until fat mass has decreased enough to return leptin to its original level.

Leptin was first identified through research on the "obese" mutant mouse. The obese strain arose by a spontaneous mutation, and is extremely fat. The mutation turned out to be in a protein investigators dubbed leptin. When researchers first discovered leptin, they speculated that it could be the "obesity gene", and supplemental leptin a potential treatment for obesity. They later discovered (to their great chagrin) that obese people produce much more leptin than thin people, so a defeciency of leptin was clearly not the problem, as it was in the obese mouse. They subsequently found that obese people scarcely respond to injected leptin by reducing their food intake, as thin people do. They are leptin resistant. This makes sense if you think about it. The only way a person can gain significant fat mass is if the leptin feedback loop isn't working correctly.

Another rodent model of leptin resistance arose later, the "Zucker fatty" rat. Zucker rats have a mutation in the leptin receptor gene. They secrete leptin just fine, but they don't respond to it because they have no functional receptor. This makes them an excellent model of complete leptin resistance. What happens to Zucker rats? They become obese, hypometabolic, hyperphagic, hypertensive, insulin resistant, and they develop blood lipid disturbances. It should sound familiar; it's the metabolic syndrome and it affects 24% of Americans (CDC NHANES III). Guess what's the first symptom of impending metabolic syndrome in humans, even before insulin resistance and obesity? Leptin resistance. This makes leptin an excellent contender for the keystone position in overweight and other metabolic disorders.

I've mentioned before that the two most commonly used animal models of the metabolic syndrome are both sugar-fed rats. Fructose, which accounts for 50% of table sugar and 55% of high-fructose corn syrup, is probably the culprit. Glucose, which is the remainder of table sugar and high-fructose corn syrup, and the product of starch digestion, does not have the same effects. I think it's also relevant that refined sugar contains no vitamins or minerals whatsoever. Sweetener consumption in the U.S. has increased from virtually nothing in 1850, to 84 pounds per year in 1909, to 119 pounds in 1970, to 142 pounds in 2005 (source).

In a recent paper, Dr. Philip Scarpace's group (in collaboration with Dr. Richard Johnson), showed that a high-fructose diet causes leptin resistance in rats. The diet was 60% fructose, which is extreme by any standards, but it caused a complete resistance to the effect of leptin on food intake. Normally, leptin binds receptors in a brain region called the hypothalamus, which is responsible for food intake behaviors (including in humans). This accounts for leptin's ability to reduce food consumption. Fructose-fed rats did not reduce their food intake at all when injected with leptin, while rats on a normal diet did. When subsequently put on a high-fat diet (60% lard), rats that started off on the fructose diet gained more weight.

I think it's worth mentionong that rodents don't respond to high-fat diets in the same way as humans, as judged by the efficacy of low-carbohydrate diets for weight loss. Industrial lard also has a very poor ratio of omega-6 to omega-3 fats (especially if it's hydrogenated), which may also contribute to the observed weight gain.

Fructose-fed rats had higher cholesterol and twice the triglycerides of control-fed rats. Fructose increases triglycerides because it goes straight to the liver, which makes it into fat that's subsequently exported into the bloodstream. Elevated triglycerides impair leptin transport from the blood to the hypothalamus across the blood-brain barrier, which separates the central nervous system from the rest of the body. Fructose also impaired the response of the hypothalamus to the leptin that did reach it. Both effects may contribute to the leptin resistance Dr. Scarpace's group observed.

Just four weeks of fructose feeding in humans (1.5g per kg body weight) increased leptin levels by 48%. Body weight did not change during the study, indicating that more leptin was required to maintain the same level of fat mass. This may be the beginning of leptin resistance.

Read More

Peripheral vs. Ectopic Fat

I went to an interesting presentation the other day by Dr. George Ioannou of the University of Washington, on obesity and liver disease. He made an interesting distinction between the health effects of two types of body fat. The first is called subcutaneous fat (or peripheral fat). It accumulates right under the skin and is evenly distributed over the body's surface area, including extremities. The second is called ectopic fat. Ectopic means "not where it's supposed to be". It accumulates in the abdominal region (beer belly), the liver, muscle tissue including the heart, the pancreas, and perhaps in lipid-rich deposits in the arteries. Subcutaneous fat can be measured by taking skinfold thickness in different places on the body, or sometimes by measuring arm or leg circumference. Ectopic fat can be measured by taking waist circumference.

It's an absolutely critical distinction, because ectopic fat associates with poor health outcomes while subcutaneous fat does not. In this recent study, waist circumference was associated with increased risk of death while arm and leg circumference were associated with a reduced risk of death. I think the limb circumference association in this particular study is probably confounded by muscle mass, but other studies have also shown a strong, consistent association between ectopic fat and risk of death, but not subcutaneous fat. The same goes for dementia and a number of other diseases. I think it's more than an epidemiological asssociation. Surgically removing the abdominal fat from mice prevents insulin resistance and prolongs their lifespan.

People with excess visceral fat are also much more likely to have fatty liver and cirrhosis. It makes sense if you think of them both as manifestations of ectopic fat. There's a spectrum of disorders that goes along with excess visceral fat and fatty liver: it's called the metabolic syndrome, and it affects a quarter of Americans (NHANES III). We already have a pretty good idea of what causes fatty liver, at least in lab animals: industrial vegetable oils and sugar. What's the most widely used animal model of metabolic syndrome? The sugar-fed rat. What are two of the main foods whose consumption has increased in recent decades? Vegetable oil and sugar. Hmm... Fatty liver is capable of causing insulin resistance and diabetes, according to a transgenic mouse that expresses a hepatitis C protein in its liver.

You want to keep your liver happy. All those blood tests they do in the doctor's office to see if you're healthy-- cholesterol levels, triglycerides, insulin, glucose-- reflect liver function to varying degrees.

Abdominal fat is a sign of ectopic fat distribution throughout the body, and its associated metabolic consequences. I think we know it's unhealthy on a subconscious level, because belly fat is not attractive whereas nicely distributed subcutaneous fat can be. If you have excess visceral fat, take it as a sign that your body does not like your current lifestyle. It might be time to think about changing your diet and exercise regime. Here are some ideas.

Read More

Health is Multi-Factorial

Thanks to commenter Brock for pointing me to this very interesting paper, "Effects of fish oil on hypertension, plasma lipids, and tumor necrosis factor-alpha in rats with sucrose-induced metabolic syndrome". As we know, sugar gives rats metabolic syndrome when it's added to regular rat chow, probably the same thing it does to humans when added to a processed food diet.

One thing has always puzzled me about sugar. It doesn't appear to cause major metabolic problems when added to an otherwise healthy diet, yet it wreaks havoc in other contexts. One example of the former situation is the Kuna, who are part hunter-gatherer, part agricultural. They eat a lot of refined sugar, but in the context of chocolate, coconut, fish, plantains, root vegetables and limited grains and beans, they are relatively healthy. Perhaps not quite on the same level as hunter-gatherer groups, but healthier than the average modernized person from the point of view of the diseases of civilization.

This paper really sheds light on the matter. The researchers gave a large group of rats access to drinking water containing 30% sucrose, in addition to their normal rat chow, for 21 weeks. The rats drank 4/5 of their calories in the form of sugar water. There's no doubt that this is an extreme treatment. They subsequently developed metabolic syndrome, including abdominal obesity, elevated blood pressure, elevated fasting insulin, elevated triglycerides, elevated total cholesterol and LDL, lowered HDL, greatly increased serum uric acid, greatly elevated liver enzymes suggestive of liver damage, and increased tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a hormone secreted by visceral (abdominal) fat tissue that may play a role in promoting insulin resistance.

After this initial 12-week treatment, they divided the metabolic syndrome rats into two groups:

• One that continued the sugar treatment, along with a diet enriched in corn and canola oil (increased omega-6).
• A second that continued the sugar treatment, along with a diet enriched in fish oil (increased omega-3).

The two diets contained the same total amount of polyunsaturated fat (PUFA), but had very different omega-6 : omega-3 ratios. The first had a ratio of 9.3 (still better than the average American), while the second had a ratio of 0.02, with most of the omega-3 in the second group coming from EPA and DHA (long-chain, animal omega-3s). The second diet also contained four times as much saturated fat as the first, mostly in the form of palmitic acid.

Compared to the vegetable oil group, the fish oil group had lower fasting insulin, lower blood pressure, lower triglycerides, lower cholesterol, and lower LDL. As a matter of fact, the fish oil group looked as good or better on all these parameters than a non-sugar fed control group receiving the extra vegetable oil alone (although the control group isn't perfect because it inevitably ate more vegetable oil-containing chow to make up for the calories it wasn't consuming in sugar). The only things reducing vegetable oil and increasing fish oil didn't fix were the weight and the elevated TNF-alpha, although they didn't report the level of liver enzymes in these groups. The TNF-alpha finding is not surprising, since it's secreted by visceral fat, which did not decrease in the fish oil group.

I think this is a powerful result. It may have been done in rats, but the evidence is there for a similar mechanism in humans. The Kuna have a very favorable omega-6 : omega-3 ratio, with most of their fat coming from highly saturated coconut and cocoa. This may protect them from their high sugar intake. The Kitavans also have a very favorable omega-6 : omega-3 ratio, with most of their fat coming from coconuts and fish. They don't eat refined sugar, but they do eat a tremendous amount of starch and a generous amount of fruit.

The paper also suggests that the metabolic syndrome is largely reversible.

I believe that both excessive sugar and excessive omega-6 from modern vegetable oils are a problem individually. But if you want to have a much bigger problem, try combining them!

Read More

The Fructose Index is the New Glycemic Index

I stumbled upon an interesting editorial recently in the American Journal of Clinical Nutrition from Dr. Richard Johnson's group, entitled "How Safe is Fructose for Persons With or Without Diabetes?" It was a response to a meta-analysis in the same journal pronouncing fructose safe up to 90 grams per day. That's the amount in eight apples or four cans of soda. Not quite what our hunter-gatherer ancestors were eating! The editorial outlined the case against excessive fructose, which I feel is quite strong. That led me to another, more comprehensive paper from Dr. Johnson's group, which argues that the amount of fructose found in a food, which they call the "fructose index", is more relevant to health than the food's glycemic index.

The glycemic index is a measure of the blood sugar response to a fixed amount of carbohydrate from a particular food. For example, white bread has a high glycemic index because it raises blood sugar more than another food containing the same amount of carbohydrate, say, lentils. Since chronically elevated blood sugar and its natural partner, insulin resistance, are part of the metabolic syndrome, it made sense that the glycemic index would be a good predictor of the metabolic effect of a food. I believed this myself for a long time.

My faith in the concept began to erode when I learned more about the diets of healthy traditional cultures. For example, the Kitavans get 69% of their calories from high-glycemic index carbohydrates (mostly starchy root vegetables), with little added fat-- that's a lot of fast-digesting carbohydrate! Overweight, elevated insulin and other symptoms of the metabolic syndrome are essentially nonexistent. Throughout Africa, healthy cultures make dishes from grains or starchy tubers that are soaked, pounded, fermented and then cooked. The result is a pile of mush that is very easily absorbed by the digestive tract, which is exactly the point of going through all the trouble.

The more I thought about the glycemic index and its relationship to insulin resistance and the metabolic syndrome, the more I realized there is a disconnect in the logic: elevated post-meal glucose and insulin do not necessarily lead to chronically elevated glucose and insulin. Here's what Dr. Mark Segal from Dr. Johnson's group had to say:

We suggest that the [glycemic index] is better aimed at identifying foods that stimulate insulin secretion rather than foods that stimulate insulin resistance. The underlying concept is based on the principle that it is the ingestion of foods that induce insulin resistance that carries the increased risk for obesity and cardiovascular disease and not eating foods that stimulate insulin secretion.

Well said! I decided to take a look through the literature to see if there had been any trials on the relationship between a diet's glycemic index and its ability to cause satiety (fullness) and affect weight. I found a meta-analysis from 2007. Two things are clear from the paper: 1) in the short term, given an equal amount of carbohydrate, a diet with a low glycemic index is more satiating (filling) than one with a high glycemic index, leading to a lower intake of calories. 2) this effect disappears in the long-term, and the three trials (1, 2, 3) lasting 10 weeks or longer found no consistent effect on caloric intake or weight*. As a matter of fact, the only statistically significant (p less than 0.001) weight difference was a greater weight loss in one of the high-glycemic index groups!

As I've said many times, the body has mechanisms for maintaining weight and caloric intake where they should be in the long term. As long as those mechanisms are working properly, weight and caloric intake will be appropriate. The big question is, how does the modern lifestyle derail those mechanisms?

Dr. Johnson believes fructose is a major contributor. Table sugar, fruit, high-fructose corn syrup and honey are all roughly 50% fructose by calories. Total fructose consumption has increased about 19% in the U.S. since 1970, currently accounting for almost one eighth of our total calorie intake (total sugars account for one quarter!). That's the average, so many people actually consume more.

Fructose, but not starch or its component sugar glucose, causes insulin resistance, elevated serum uric acid (think gout and kidney stones), poorer blood glucose control, increased triglycerides and LDL cholesterol in animal studies and controlled human trials. All of these effects relate to the liver, which clearly does not like excessive fructose (or omega-6 oils). Some of these trials were conducted using doses that are near the average U.S. intake. The effect seems to compound over time both in humans and animals. The overweight, the elderly and the physically unfit are particularly vulnerable. I find this pretty damning.

Drs. Johnson and Segal recommend limiting fructose to 15-40 grams per day, which is the equivalent of about two apples or one soda (choose the apples!). They also recommend temporarily eliminating fructose for two weeks, to allow the body to recover from the negative long-term metabolic adaptation that can persist even when intake is low. I think this makes good sense.

The glycemic index may still be a useful tool for people with poor glucose control, like type II diabetics, but I'm not sure how much it adds to simply restricting carbohydrate. Reducing fructose may be a more effective way to address insulin resistance than eating a low glycemic index diet.


*Here was the author's way of putting it in the abstract: "Because of the increasing number of confounding variables in the available long-term studies, it is not possible to conclude that low-glycaemic diets mediate a health benefit based on body weight regulation. The difficulty of demonstrating the long-term health benefit of a satietogenic food or diet may constitute an obstacle to the recognition of associated claims." In other words, the data not supporting our favorite hypothesis is an obstacle to its recognition. You don't say?

Read More

How to Give a Rat Metabolic Syndrome

I was doing my usual journal rounds today when I came across an article in the American Journal of Hypertension that caught my eye. It's called "Metabolic Syndrome: Comparison of the Two Commonly Used Animal Models." Metabolic syndrome is a cluster of symptoms including large waist circumference, elevated triglycerides, elevated blood pressure, and insulin resistance. It's the quintissential modern metabolic disorder, and it affects 24% of Americans (NHANES III). So what are the two most commonly used animal models of metabolic syndrome?

• A strain called the spontaneously hypertensive rat (SHR), fed a high-sucrose (table sugar, 50% fructose) diet.
• Sprague-Dawley (generic lab strain) rats fed a high-fructose diet.

When fed sugar, these rats develop insulin resistance, impaired glucose tolerance, elevated triglycerides and hypertension. Fructose causes leptin resistance in rats. Leptin resistance causes metabolic syndrome in rats. These studies trace a line directly from sugar to the metabolic syndrome.

On to humans. Total sugar and fructose consumption have been increasing in the U.S. in recent decades, along with metabolic syndrome. I think the average numbers may hide some important information, because there is a fraction of the population that consumes far more than the average amount of sugar through soda. Leptin resistance seems to be central to the metabolic syndrome, and typically precedes the other symptoms. The evidence suggests that the rat research on metabolic syndrome is applicable to humans.

I don't think sugar acts alone in causing the metabolic syndrome in humans. I believe the liver is a central player in the disorder, as many of the markers used to diagnose it are measures of processes that occur in the liver (triglyceride synthesis, glucose and insulin disposal). Insulin resistance in the liver is sufficient to cause many of the hallmarks of the metabolic syndrome in mice. The fructose portion of sugar and high-linoleic (omega-6) vegetable oils act synergistically to cause liver dysfunction in rats and probably humans.

I also believe wheat contributes to the process, perhaps through its ability to cause hyperphagia (overeating) or intestinal damage. So we're back to the three big killers in the modern diet:

• Refined vegetable oils
• Sugar
• Wheat
  

Read More