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 »
Showing posts with label metabolic syndrome. Show all posts
Showing posts with label metabolic syndrome. Show all posts
Sunday, May 22, 2011
Wednesday, May 18, 2011
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 »
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 »
Tuesday, March 1, 2011
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.
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.
Wednesday, April 9, 2008
Leptin and Lectins: Part III
Thanks to everyone for the great comments, this has been an interesting discussion.
I received a very kind e-mail response from Dr. Lindeberg, in which he told me that his group didn't measure leptin levels in his paleolithic pig study because it would have required special reagents. He also sent me two very interesting papers, both hot off the presses.
The first paper shows that glycosylation (bound sugars) of the leptin receptor is required for normal leptin binding. One of the molecules they use to probe the function of the leptin receptor is our good friend wheat germ agglutinin (WGA), a lectin found in wheat, barley and rye. They used WGA to specifically block leptin binding at the receptor.
This fits in very nicely with the hypothesis that grain lectins cause leptin resistance. If WGA gets into the bloodstream, which it appears to, it has the ability to bind leptin receptors and block leptin binding. It doesn't take much imagination to see how this could cause leptin resistance.
One caveat is that they used a high concentration of WGA in the study; 10 ug/mL was the lowest concentration they used. I can't imagine that concentration is possible in an actual human body. However, the paper doesn't explore the lower limit of WGA's ability to block leptin binding. At the lowest concentration used, it blocked 50% of the leptin from binding. It's possible that much smaller amounts could still have a significant effect.
The second paper Dr. Lindeberg sent me was on the soy isoflavone genistein. Here's the executive summary: it's bad. Unless you are a man who really wants to embrace his feminine side. It gets into all tissues and effectively activates the estrogen receptor in mice. It shrinks the prostate just like administering estrogen. It also passes into pups through the mothers' milk at levels high enough to activate their estrogen receptors. All this from the same amount of genistein you can get by eating a meal of soy.
The bad news doesn't stop there. Fermentation doesn't break it down. Miso, tempeh and natto actually have more genistein than non-fermented soy. Sigh...
I received a very kind e-mail response from Dr. Lindeberg, in which he told me that his group didn't measure leptin levels in his paleolithic pig study because it would have required special reagents. He also sent me two very interesting papers, both hot off the presses.
The first paper shows that glycosylation (bound sugars) of the leptin receptor is required for normal leptin binding. One of the molecules they use to probe the function of the leptin receptor is our good friend wheat germ agglutinin (WGA), a lectin found in wheat, barley and rye. They used WGA to specifically block leptin binding at the receptor.
This fits in very nicely with the hypothesis that grain lectins cause leptin resistance. If WGA gets into the bloodstream, which it appears to, it has the ability to bind leptin receptors and block leptin binding. It doesn't take much imagination to see how this could cause leptin resistance.
One caveat is that they used a high concentration of WGA in the study; 10 ug/mL was the lowest concentration they used. I can't imagine that concentration is possible in an actual human body. However, the paper doesn't explore the lower limit of WGA's ability to block leptin binding. At the lowest concentration used, it blocked 50% of the leptin from binding. It's possible that much smaller amounts could still have a significant effect.
The second paper Dr. Lindeberg sent me was on the soy isoflavone genistein. Here's the executive summary: it's bad. Unless you are a man who really wants to embrace his feminine side. It gets into all tissues and effectively activates the estrogen receptor in mice. It shrinks the prostate just like administering estrogen. It also passes into pups through the mothers' milk at levels high enough to activate their estrogen receptors. All this from the same amount of genistein you can get by eating a meal of soy.
The bad news doesn't stop there. Fermentation doesn't break it down. Miso, tempeh and natto actually have more genistein than non-fermented soy. Sigh...
Monday, April 7, 2008
Leptin and Lectins: Part II
Why do Americans become overweight and diseased on a high-carbohydrate diet while the carbohydrate-loving Kuna and Kitavans remain exceptionally free of chronic disease? Dr. Lindeberg proposes an answer- grains.
Dr. Lindeberg's hypothesis is that grains cause leptin resistance, which as we saw in the last post, has the potential to precipitate the metabolic syndrome and its various consorts. It's an attractive idea. The Kitavans (who he has studied personally), Kuna, and other cultures in Melanesia, Malaysia, Africa, the Arctic and South America, do not suffer from the diseases of civilization. These are all cultures that consume little or no grain, despite some having starchy diets. The Kitavans have low circulating leptin and remain lean and disease-free despite a high intake of carbohydrate.
Dr. Lindeberg says that grain-based cultures almost universally suffer from varying degrees of our illnesses, although his references to support that statement are unsatisfying. He did provide a reference showing that stroke occurs in affluent grain-based societies (whereas it seems not to in Kitavans), but I would really have liked to see a side-by-side comparison of cultures with similar lifestyles and differing grain intakes.
One thing that's certain is humans have not been eating grains for very long. Before the invention of agriculture in the fertile crescent, grains were a minor and seasonal crop for a small number of groups. Something we have been eating for a long time however is starchy tubers, bulbs and roots. Hunter-gatherers didn't generally go after wild grass seeds (grains) because they weren't a concentrated enough food source in most places. If you collect grass seeds all day, you might end up with a mouthful, after which you have to soak, grind, and cook them before chowing down. Dig up a few camas bulbs however, and you've got yourself a meal in 5 minutes.
The distinction between different sources of starch may lie in a class of molecules called lectins. Lectins were originally defined by their ability to aggregate red blood cells (erythrocytes). They do this by binding to the natural coating of carbohydrate on the cells' surface. A more current definition of a lectin is a molecule that specifically binds carbohydrate. Lectins are found throughout all kingdoms of life, and they serve a variety of useful functions. Many plants use lectins as a defense against hungry animals. Thus, an animal that is not adapted to the lectins in the plant it's eating may suffer damage or death.
Grains and legumes (beans, soy, peas, peanuts) are rich in some particularly nasty lectins. Especially wheat. Some can degrade the intestinal lining. Some have the ability to pass through the intestinal lining and show up in the bloodstream. Once in the bloodstream, they may bind all sorts of carbohydrate-containing proteins in the body, including the insulin receptor. They could theoretically bind the leptin receptor, which also contains carbohydrate (= it's glycosylated), potentially desensitizing it. This remains to be tested, and to my knowledge is pure speculation at this point. What is not so speculative is that once you're leptin-resistant, you become obese and insulin resistant, and at that point you are intolerant to any type of carbohydrate. This may explain the efficacy of carbohydrate restriction in weight loss and improving general health.
Another thing I have to mention about lectins is they can be broken down by certain food processing techniques. Remember all those old-fashioned things our grandparents used to do to grains and beans before eating them, like soaking beans overnight, sourdough-fermenting bread dough and nixtamalizing corn? All those things we've abandoned in favor of modern convenience foods? You guessed it, those reduce lectins dramatically, along with a long list of other toxins like phytic acid and protease inhibitors. Modern yeast-leavened breads, pastries, crackers, corn and soy products are no longer prepared according to these methods, and their lectin levels are typically much higher. One thing to keep in mind is that these processes reduce but generally do not eliminate lectins and other toxins.
The thing I really like about Dr. Lindeberg's idea is it explains a lot of what is happening in the world around us. The Kitavans eat yams, sweet potatoes, taro and tapioca as their staples. Incidentally, the long-lived Okinawans also eat sweet potatoes as a staple. The Kuna eat mostly plantains, yucca and kidney beans. These are three exceptionally healthy populations with a very low intake of grains. What happens when you feed these same people wheat? The Kuna have a well-documented rise in blood pressure, diabetes and cardiovascular disease mortality when they move to an urban, westernized setting. Okinawans became obese and unhealthy when American food was introduced. Wherever white flour and sugar go, the diseases of civilization follow. Weston Price documented this in the dental and skeletal health of 14 different cultures throughout the world.
It also explains what's going on under our very noses. Like I mentioned earlier, modern processed food is rich in lectins because it hasn't been treated by soaking, sprouting or bacterial fermentation. Soy has one of the highest lectin activities of any food, unless it's traditionally fermented into miso, tempeh, tamari or natto. As we've begun relying more and more on industrial food, our health has taken a major turn for the worse. Obesity is soaring in the US and diabetes is close on its heels.
I think it's very likely that grains are one of the major culprits in the diseases of civilization. This could be due to lectins causing leptin resistance. It's a fantastic hypothesis that could explain the health problems we see in modern grain-based societies.
Dr. Lindeberg's hypothesis is that grains cause leptin resistance, which as we saw in the last post, has the potential to precipitate the metabolic syndrome and its various consorts. It's an attractive idea. The Kitavans (who he has studied personally), Kuna, and other cultures in Melanesia, Malaysia, Africa, the Arctic and South America, do not suffer from the diseases of civilization. These are all cultures that consume little or no grain, despite some having starchy diets. The Kitavans have low circulating leptin and remain lean and disease-free despite a high intake of carbohydrate.
Dr. Lindeberg says that grain-based cultures almost universally suffer from varying degrees of our illnesses, although his references to support that statement are unsatisfying. He did provide a reference showing that stroke occurs in affluent grain-based societies (whereas it seems not to in Kitavans), but I would really have liked to see a side-by-side comparison of cultures with similar lifestyles and differing grain intakes.
One thing that's certain is humans have not been eating grains for very long. Before the invention of agriculture in the fertile crescent, grains were a minor and seasonal crop for a small number of groups. Something we have been eating for a long time however is starchy tubers, bulbs and roots. Hunter-gatherers didn't generally go after wild grass seeds (grains) because they weren't a concentrated enough food source in most places. If you collect grass seeds all day, you might end up with a mouthful, after which you have to soak, grind, and cook them before chowing down. Dig up a few camas bulbs however, and you've got yourself a meal in 5 minutes.
The distinction between different sources of starch may lie in a class of molecules called lectins. Lectins were originally defined by their ability to aggregate red blood cells (erythrocytes). They do this by binding to the natural coating of carbohydrate on the cells' surface. A more current definition of a lectin is a molecule that specifically binds carbohydrate. Lectins are found throughout all kingdoms of life, and they serve a variety of useful functions. Many plants use lectins as a defense against hungry animals. Thus, an animal that is not adapted to the lectins in the plant it's eating may suffer damage or death.
Grains and legumes (beans, soy, peas, peanuts) are rich in some particularly nasty lectins. Especially wheat. Some can degrade the intestinal lining. Some have the ability to pass through the intestinal lining and show up in the bloodstream. Once in the bloodstream, they may bind all sorts of carbohydrate-containing proteins in the body, including the insulin receptor. They could theoretically bind the leptin receptor, which also contains carbohydrate (= it's glycosylated), potentially desensitizing it. This remains to be tested, and to my knowledge is pure speculation at this point. What is not so speculative is that once you're leptin-resistant, you become obese and insulin resistant, and at that point you are intolerant to any type of carbohydrate. This may explain the efficacy of carbohydrate restriction in weight loss and improving general health.
Another thing I have to mention about lectins is they can be broken down by certain food processing techniques. Remember all those old-fashioned things our grandparents used to do to grains and beans before eating them, like soaking beans overnight, sourdough-fermenting bread dough and nixtamalizing corn? All those things we've abandoned in favor of modern convenience foods? You guessed it, those reduce lectins dramatically, along with a long list of other toxins like phytic acid and protease inhibitors. Modern yeast-leavened breads, pastries, crackers, corn and soy products are no longer prepared according to these methods, and their lectin levels are typically much higher. One thing to keep in mind is that these processes reduce but generally do not eliminate lectins and other toxins.
The thing I really like about Dr. Lindeberg's idea is it explains a lot of what is happening in the world around us. The Kitavans eat yams, sweet potatoes, taro and tapioca as their staples. Incidentally, the long-lived Okinawans also eat sweet potatoes as a staple. The Kuna eat mostly plantains, yucca and kidney beans. These are three exceptionally healthy populations with a very low intake of grains. What happens when you feed these same people wheat? The Kuna have a well-documented rise in blood pressure, diabetes and cardiovascular disease mortality when they move to an urban, westernized setting. Okinawans became obese and unhealthy when American food was introduced. Wherever white flour and sugar go, the diseases of civilization follow. Weston Price documented this in the dental and skeletal health of 14 different cultures throughout the world.
It also explains what's going on under our very noses. Like I mentioned earlier, modern processed food is rich in lectins because it hasn't been treated by soaking, sprouting or bacterial fermentation. Soy has one of the highest lectin activities of any food, unless it's traditionally fermented into miso, tempeh, tamari or natto. As we've begun relying more and more on industrial food, our health has taken a major turn for the worse. Obesity is soaring in the US and diabetes is close on its heels.
I think it's very likely that grains are one of the major culprits in the diseases of civilization. This could be due to lectins causing leptin resistance. It's a fantastic hypothesis that could explain the health problems we see in modern grain-based societies.
Sunday, April 6, 2008
Leptin and Lectins
I've been puzzled by an interesting question lately. Why is it that certain cultures are able to eat large amounts of carbohydrate and remain healthy, while others suffer from overweight and disease? How do the pre-industrial Kuna and Kitavans maintain their insulin sensitivity while their bodies are being bombarded by an amount of carbohydrate that makes the average American look like a bowling ball?I read a very interesting post on the Modern Forager yesterday that sent me on a nerd safari through the scientific literature. The paper that inspired the Modern Forager post is a review by Dr. Staffan Lindeberg. In it, he attempts to draw a link between compounds called lectins, found in grains (among other things), and resistance to the hormone leptin. Let's take a step back and go over some background.
One of the most-studied animal models of obesity is called the "Zucker" rat. This rat has a missense mutation in its leptin receptor gene, causing it to be nonfunctional. Leptin is a hormone that signals satiety, or fullness. It's secreted by fat tissue. The more fat tissue an animal has, the more leptin it secretes. Normally, this creates negative feedback that causes it to eat less when fat begins to accumulate, keeping its weight within a narrow range.
Zucker rats secrete leptin just fine, but they lack leptin receptors in their brain. Their blood leptin is high but their brain isn't listening. Thus, the signal to stop eating never gets through and they eat themselves to morbid obesity. Cardiovascular disease and diabetes follow shortly thereafter, unless you remove their visceral fat surgically.
The reason Zucker rats are so interesting is they faithfully reproduce so many features of the disease of civilization in humans. They become obese, hypometabolic, develop insulin resistance, impaired glucose tolerance, dyslipidemia, diabetes, and cardiovascular disease. Basically, severe metabolic syndrome. So here's a rat that shows that leptin resistance can cause something that looks a whole heck of a lot like the disease of civilization in humans.
For this model to be relevant to us, we'd expect that humans with metabolic syndrome should be leptin-resistant. Well what do you know, administering leptin to obese people doesn't cause satiety like it does in thin people. Furthermore, elevated leptin predicts the onset of obesity and metabolic syndrome. It also predicts insulin resistance. Yes, you read that right, leptin resistance comes before insulin resistance.
Interestingly enough, the carbohydrate-loving Kitavans don't get elevated leptin like europeans do, and they don't become overweight, develop insulin dysfunction or the metabolic syndrome either. This all suggests that leptin may be the keystone in the whole disease process, but what accounts for the differences in leptin levels between populations?
I'll talk about a possible explanation in my next post.
Monday, March 31, 2008
Body Composition
I don't want to leave you with those last two posts without giving you some practical ways to improve body composition. Body composition is the ratio of lean tissue to fat. The ideal ratio differs depending on gender and individual differences. In general, 10% and 20% bodyfat are good targets for men and women, respectively. There's no need to measure however, as the eye is a pretty good judge.
The most dangerous fat is visceral fat, or the "beer belly". Fortunately, it's also the most responsive to lifestyle changes.
The strategies I recommend all have one thing in common: they work to restore insulin sensitivity. This will not only improve body composition, it will normalize your metabolism on a fundamental level, reducing the risk of all the common chronic diseases. I may cover these topics again in more detail at another time.
1. Carbohydrate restriction. This is by far the most effective way to improve body composition. It will even benefit people who are already profoundly insulin resistant. Eliminating grains, legumes, potatoes and sugar is the simplest and best way to do this. That includes wheat, corn, rice, beans, oats, honorary grains like buckwheat and quinoa, and especially their derivatives. Carbohydrate is not the devil, but restricting intake to moderate amounts from vegetables and fruit is ideal for someone trying to lose weight. I think starchy root vegetables, soaked or sprouted legumes and soaked, sprouted or fermented non-gluten grains are OK for people who already have a healthy body composition.
2. Exercise. Our hunter-gatherer ancestors had a word for exercise: "life". Exercise helps improve insulin sensitivity by increasing the muscles' demand for fuel. It also builds muscle mass. Any exercise is great, but the best kind is brief and intense (anaerobic). This includes sprinting and brisk weight training. It's more effective than jogging at improving muscle mass, decreasing fat mass, decreasing insulin and improving other markers of metabolic health. Chris at Conditioning Research covers this topic regularly. Traditional sports like soccer and basketball are effective because they have anaerobic and aerobic components. Even walking up stairs or down the street have measurable health benefits, however.
3. Intermittent fasting. This is very effective at improving insulin sensitivity and body composition. IF isn't starvation; it simply postpones calorie intake. Nor is it unhealthy. In fact, it's probably closely in line with the variable energy intake to which we are fundamentally adapted. My method is one 24-hour, water-only fast per week. No juice; that defeats the purpose. If you have elevated insulin like most people, it's best to get into IF gradually. Try skipping breakfast first. If you can skip breakfast and lunch, you've completed a 23-hour fast.
4. Lose the soda! Soda and other sweet foods are the enemy of body composition and general health. Fructose, found abundantly in high-fructose corn syrup, table sugar and agave nectar, seems to have a particular talent for causing insulin resistance. It's rapidly converted to fat in the liver, which is partially stored on the spot, and partially exported into the bloodstream as triglycerides. Diet soda isn't much better. It's been associated with weight gain in humans, and actually causes weight gain in rats. Normalizing insulin through carbohydrate restriction and fasting reduces cravings for sweet foods. A moderate amount of fruit is probably fine.
The most dangerous fat is visceral fat, or the "beer belly". Fortunately, it's also the most responsive to lifestyle changes.
The strategies I recommend all have one thing in common: they work to restore insulin sensitivity. This will not only improve body composition, it will normalize your metabolism on a fundamental level, reducing the risk of all the common chronic diseases. I may cover these topics again in more detail at another time.
1. Carbohydrate restriction. This is by far the most effective way to improve body composition. It will even benefit people who are already profoundly insulin resistant. Eliminating grains, legumes, potatoes and sugar is the simplest and best way to do this. That includes wheat, corn, rice, beans, oats, honorary grains like buckwheat and quinoa, and especially their derivatives. Carbohydrate is not the devil, but restricting intake to moderate amounts from vegetables and fruit is ideal for someone trying to lose weight. I think starchy root vegetables, soaked or sprouted legumes and soaked, sprouted or fermented non-gluten grains are OK for people who already have a healthy body composition.
2. Exercise. Our hunter-gatherer ancestors had a word for exercise: "life". Exercise helps improve insulin sensitivity by increasing the muscles' demand for fuel. It also builds muscle mass. Any exercise is great, but the best kind is brief and intense (anaerobic). This includes sprinting and brisk weight training. It's more effective than jogging at improving muscle mass, decreasing fat mass, decreasing insulin and improving other markers of metabolic health. Chris at Conditioning Research covers this topic regularly. Traditional sports like soccer and basketball are effective because they have anaerobic and aerobic components. Even walking up stairs or down the street have measurable health benefits, however.
3. Intermittent fasting. This is very effective at improving insulin sensitivity and body composition. IF isn't starvation; it simply postpones calorie intake. Nor is it unhealthy. In fact, it's probably closely in line with the variable energy intake to which we are fundamentally adapted. My method is one 24-hour, water-only fast per week. No juice; that defeats the purpose. If you have elevated insulin like most people, it's best to get into IF gradually. Try skipping breakfast first. If you can skip breakfast and lunch, you've completed a 23-hour fast.
4. Lose the soda! Soda and other sweet foods are the enemy of body composition and general health. Fructose, found abundantly in high-fructose corn syrup, table sugar and agave nectar, seems to have a particular talent for causing insulin resistance. It's rapidly converted to fat in the liver, which is partially stored on the spot, and partially exported into the bloodstream as triglycerides. Diet soda isn't much better. It's been associated with weight gain in humans, and actually causes weight gain in rats. Normalizing insulin through carbohydrate restriction and fasting reduces cravings for sweet foods. A moderate amount of fruit is probably fine.
Wednesday, March 26, 2008
Visceral Fat
This week, I stumbled upon a very interesting series of articles from the lab of Dr. Nir Barzilai.
The first article I came across showed that surgical removal of the visceral fat deposit of rats increased their lifespan. Visceral fat (VF) is the "beer belly", and consists of the perinephratic fat around the kidneys and the omental fat in front of the intestines. It doesn't include subcutaneous fat, the fat layer under the skin.
VF is tightly associated with the metabolic syndrome, the quintessential "disease of civilization" that affects 24% of Americans (NHANES III). It's defined by three or more of the following criteria: high blood pressure, large waist circumference, low HDL cholesterol, high triglycerides, and high fasting glucose. The metabolic syndrome is associated with a 3-4-fold increase in the risk of death from cardiovascular disease, and a 6-fold increase in the risk of developing type II diabetes. From a review on the metabolic syndrome (parentheses mine):
This is all well and good, but who cares? What's to say VF plays any role other than as a simple marker for overweight?
The longevity paper led me to Dr. Barzilai's previous papers, which answered this question rather thoroughly. Rats raised on standard rat chow, which is a sad little compressed pellet made of grains and added nutrients, develop elevated insulin and insulin resistance with age, just like humans. Unless they don't have VF. Rats that had their VF surgically removed did not develop insulin resistance or elevated insulin with age, despite rebounding to their original total fat mass rather quickly (VF accounts for ~18% of total fat in these rats). These parameters are unaffected by removing an equal amount of subcutaneous fat, which has been shown in human liposuction patients as well.
Removing VF also improved diabetes-prone Zucker rats, which are profoundly insulin-resistant (leptin receptor loss-of-function). It kept wild-type rats just as insulin-sensitive as calorically restricted controls, which had a small amount of VF. This shows that VF isn't just a passive player; it's essential for the development of insulin resistance. It also shows, along with human studies, that insulin resistance is not an inevitable consequence of aging.
Adipose (fat) tissue is being increasingly recognized as an important endocrine (hormone-secreting) organ. It produces many different hormones that affect insulin sensitivity and appetite regulation, among other things. These hormones are collectively known as fat-derived peptides (FDPs). At least one of these FDPs, TNF-alpha, promotes insulin resistance.
Dr. Barzilai's group went on to explore the mechanism of VF contributing to insulin resistance. They increased the rate of glucose flux into the fat tissue of rats by infusing either glucose or insulin into the bloodstream. These treatments both cause increased glucose uptake by fat cells. What they saw when they dissected the rats was striking. The VF had ramped up its production of FDPs from 2- to 15-fold, while the subcutaneous fat had barely changed. Incidentally, insulin increased glucose uptake by VF twice as much as subcutaneous fat.
I'll say this again, because it's important. They forced glucose into VF cells, and those cells dramatically upregulated FDP production. And again, no visceral fat, no FDPs.
In earlier papers, he also showed that the removal of VF dramatically reduces the expression of TNF-alpha and leptin (two FDPs) in subcutaneous fat on a longer timescale, showing that VF and subcutaneous fat communicate to alter the metabolism. Again, TNF-alpha promotes insulin resistance, making it a possible link between the fat tissue and peripheral effects. VF removal had no effect on triglycerides, suggesting that they're only a marker of insulin dysfunction rather than a cause.
Now to take this research to its logical conclusion. Here's a plausible sequence of events leading up to the metabolic syndrome:
The first article I came across showed that surgical removal of the visceral fat deposit of rats increased their lifespan. Visceral fat (VF) is the "beer belly", and consists of the perinephratic fat around the kidneys and the omental fat in front of the intestines. It doesn't include subcutaneous fat, the fat layer under the skin.
VF is tightly associated with the metabolic syndrome, the quintessential "disease of civilization" that affects 24% of Americans (NHANES III). It's defined by three or more of the following criteria: high blood pressure, large waist circumference, low HDL cholesterol, high triglycerides, and high fasting glucose. The metabolic syndrome is associated with a 3-4-fold increase in the risk of death from cardiovascular disease, and a 6-fold increase in the risk of developing type II diabetes. From a review on the metabolic syndrome (parentheses mine):
The most common alteration related to the impaired glucose metabolism with aging is the progressively increased fasting and postprandial [post-meal] plasma insulin levels, suggesting an insulin-resistant state.
This is all well and good, but who cares? What's to say VF plays any role other than as a simple marker for overweight?
The longevity paper led me to Dr. Barzilai's previous papers, which answered this question rather thoroughly. Rats raised on standard rat chow, which is a sad little compressed pellet made of grains and added nutrients, develop elevated insulin and insulin resistance with age, just like humans. Unless they don't have VF. Rats that had their VF surgically removed did not develop insulin resistance or elevated insulin with age, despite rebounding to their original total fat mass rather quickly (VF accounts for ~18% of total fat in these rats). These parameters are unaffected by removing an equal amount of subcutaneous fat, which has been shown in human liposuction patients as well.
Removing VF also improved diabetes-prone Zucker rats, which are profoundly insulin-resistant (leptin receptor loss-of-function). It kept wild-type rats just as insulin-sensitive as calorically restricted controls, which had a small amount of VF. This shows that VF isn't just a passive player; it's essential for the development of insulin resistance. It also shows, along with human studies, that insulin resistance is not an inevitable consequence of aging.
Adipose (fat) tissue is being increasingly recognized as an important endocrine (hormone-secreting) organ. It produces many different hormones that affect insulin sensitivity and appetite regulation, among other things. These hormones are collectively known as fat-derived peptides (FDPs). At least one of these FDPs, TNF-alpha, promotes insulin resistance.
Dr. Barzilai's group went on to explore the mechanism of VF contributing to insulin resistance. They increased the rate of glucose flux into the fat tissue of rats by infusing either glucose or insulin into the bloodstream. These treatments both cause increased glucose uptake by fat cells. What they saw when they dissected the rats was striking. The VF had ramped up its production of FDPs from 2- to 15-fold, while the subcutaneous fat had barely changed. Incidentally, insulin increased glucose uptake by VF twice as much as subcutaneous fat.
I'll say this again, because it's important. They forced glucose into VF cells, and those cells dramatically upregulated FDP production. And again, no visceral fat, no FDPs.
In earlier papers, he also showed that the removal of VF dramatically reduces the expression of TNF-alpha and leptin (two FDPs) in subcutaneous fat on a longer timescale, showing that VF and subcutaneous fat communicate to alter the metabolism. Again, TNF-alpha promotes insulin resistance, making it a possible link between the fat tissue and peripheral effects. VF removal had no effect on triglycerides, suggesting that they're only a marker of insulin dysfunction rather than a cause.
Now to take this research to its logical conclusion. Here's a plausible sequence of events leading up to the metabolic syndrome:
- A meal high in quickly digested carbohydrate elevates blood glucose. OR, excessive fructose causes insulin resistance in the liver which leads to high fasting glucose.
- Visceral fat responds by increasing production of FDPs.
- FDPs, directly and/or indirectly, cause insulin resistance in the liver, muscle and other tissue. Liver insulin resistance causes alterations in lipoprotein ("cholesterol") profile (more on this in another post). Fat tissue remains insulin-sensitive.
- Fat tissue (including VF) grows in size, because due to its insulin sensitivity it's taking up more than its share of glucose.
- The vicious cycle continues, with increased visceral fat size and glucose uptake increasing FDP production, which makes the liver more insulin resistant, which increases glucose production by the liver, etc.
- In the absence of lifestyle changes, the cycle only stops when the fat tissue becomes insulin-resistant, at which point you lose control over blood sugar and become diabetic.
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