Dr. Staffan Lindeberg's group has published a new paleolithic diet paper in the journal Nutrition and Metabolism, titled "A Paleolithic Diet is More Satiating per Calorie than a Mediterranean-like Diet in Individuals with Ischemic Heart Disease" (1).
The data in this paper are from the same intervention as his group's 2007 paper in Diabetologia (2). To review the results of this paper, 12 weeks of a Paleolithic-style diet caused impressive fat loss and improvement in glucose tolerance, compared to 12 weeks of a Mediterranean-style diet, in volunteers with pre-diabetes or diabetes and ischemic heart disease. Participants who started off with diabetes ended up without it. A Paleolithic diet excludes grains, dairy, legumes and any other category of food that was not a major human food source prior to agriculture. I commented on this study a while back (3, 4).
One of the most intriguing findings in his 2007 study was the low calorie intake of the Paleolithic group. Despite receiving no instruction to reduce calorie intake, the Paleolithic group only ate 1,388 calories per day, compared to 1,823 calories per day for the Mediterranean group*. That's a remarkably low ad libitum calorie intake in the former (and a fairly low intake in the latter as well).
With such a low calorie intake over 12 weeks, you might think the Paleolithic group was starving. Fortunately, the authors had the foresight to measure satiety, or fullness, in both groups during the intervention. They found that satiety was almost identical in the two groups, despite the 24% lower calorie intake of the Paleolithic group. In other words, the Paleolithic group was just as full as the Mediterranean group, despite a considerably lower intake of calories. This implies to me that the body fat "set point" decreased, allowing a reduced calorie intake while body fat stores were burned to make up the calorie deficit. I suspect it also decreased somewhat in the Mediterranean group, although we can't know for sure because we don't have baseline satiety data for comparison.
There are a few possible explanations for this result. The first is that the Paleolithic group was eating more protein, a highly satiating macronutrient. However, given the fact that absolute protein intake was scarcely different between groups, I think this is unlikely to explain the reduced calorie intake.
A second possibility is that certain potentially damaging Neolithic foods (e.g., wheat and refined sugar) interfere with leptin signaling**, and removing them lowers fat mass by allowing leptin to function correctly. Dr. Lindeberg and colleagues authored a hypothesis paper on this topic in 2005 (5).
A third possibility is that a major dietary change of any kind lowers the body fat setpoint and reduces calorie intake for a certain period of time. In support of this hypothesis, both low-carbohydrate and low-fat diet trials show that overweight people spontaneously eat fewer calories when instructed to modify their diets in either direction (6, 7). More extreme changes may cause a larger decrease in calorie intake and fat mass, as evidenced by the results of low-fat vegan diet trials (8, 9). Chris Voigt's potato diet also falls into this category (10, 11). I think there may be something about changing food-related sensory cues that alters the defended level of fat mass. A similar idea is the basis of Seth Roberts' book The Shangri-La Diet.
If I had to guess, I would think the second and third possibilities contributed to the finding that Paleolithic dieters lost more fat without feeling hungry over the 12 week diet period.
*Intakes were determined using 4-day weighed food records.
**Leptin is a hormone produced by body fat that reduces food intake and increases energy expenditure by acting in the brain. The more fat a person carries, the more leptin they produce, and hypothetically this should keep body fat in a narrow window by this form of "negative feedback". Clearly, that's not the whole story, otherwise obesity wouldn't exist. A leading hypothesis is that resistance to the hormone leptin causes this feedback loop to defend a higher level of fat mass.
Showing posts with label leptin. Show all posts
Showing posts with label leptin. Show all posts
Monday, January 3, 2011
Tuesday, November 9, 2010
The Twinkie Diet for Fat Loss
The Experiment
I've received several e-mails from readers about a recent experiment by nutrition professor Mark Haub at Kansas State university (thanks to Josh and others). He ate a calorie-restricted diet in which 2/3 of his calories came from junk food: Twinkies, Hostess and Little Debbie cakes, Dorito corn chips and sweetened cereals (1). On this calorie-restricted junk food diet (800 calorie/day deficit), he lost 27 pounds in two months.
Therefore, junk food doesn't cause fat gain and the only thing that determines body fatness is how much you eat and exercise. Right?
Discussion
Let's start with a few things most people can agree on. If you don't eat any food at all, you will lose fat mass. If you voluntarily force-feed yourself with a large excess of food, you will gain fat mass, whether the excess comes from carbohydrate or fat (2). So calories obviously have something to do with fat mass.
But of course, the situation is much more subtle in real life. Since a pound of body fat contains roughly 3,500 calories, eating an excess of 80 calories per day (1 piece of toast) should lead to a weight gain of 8 lbs of fat per year. Conversely, if you're distracted and forget to eat your toast, you should lose 8 lbs of fat per year, which would eventually be dangerous for a lean person. That's why we all record every crumb of food we eat, determine its exact calorie content, and match that intake precisely with our energy expenditure to maintain a stable weight.
Oh wait, we don't do that? Then how do so many people maintain a stable weight over years and decades? And how do wild animals maintain a stable body fat percentage (except when preparing for hibernation) even in the face of food surpluses? How do lab rats and mice fed a whole food diet maintain a stable body fat percentage in the face of literally unlimited food, when they're in a small cage with practically nothing to do but eat?
The answer is that the body isn't stupid. Over hundreds of millions of years, we've evolved sophisticated systems that maintain "energy homeostasis". In other words, these systems act to regulate fat mass and keep it within the optimal range. The evolutionary pressures operating here are obvious: too little fat mass, and an organism will be susceptible to starvation; too much, and an organism will be less agile and less efficient at locomotion and reproduction. Energy homeostasis is such a basic part of survival that even the simplest organisms regulate it.
Not only is it clear that we have an energy homeostasis system, we even know a thing or two about how it works. Early studies showed that lesioning a part of the brain called the ventromedial hypothalamus causes massive obesity (3; this is also true in humans, when a disruption results from cancer). Investigators also discovered several genetic mutations in rats and mice that result in massive obesity*. Decades-long research eventually demonstrated that these models have something in common: they all interfere with an energy homeostasis circuit that passes information about fat mass to the hypothalamus via the hormone leptin.
The leptin system is a classic negative feedback loop: the more fat mass accumulates, the more leptin is produced. The more leptin is produced, the more the hypothalamus activates programs to reduce hunger and increase energy expenditure, which continues until fat mass is back in the optimal range. Conversely, low fat mass and low leptin lead to increased hunger and energy conservation by this same pathway**.
So if genetic mutants can become massively obese, I guess that argues against the idea that voluntary food intake and energy expenditure are the only determinants of fat mass. But a skeptic might point out that these are extreme cases, and such mutations are so rare in humans that the analogy is irrelevant.
Let's dig deeper. There are many studies in which rodents are made obese using industrial high-fat diets made from refined ingredients. The rats eat more calories (at least in the beginning), and gain fat rapidly. No big surprise there. But what may come as a surprise to the calorie counters is that rodents on these diets gain body fat even if their calorie intake is matched precisely to lean rodents eating a whole food diet (4, 5, 6). In fact, they sometimes gain almost as much fat as rodents who are allowed to eat all the industrial food they want. This has been demonstrated repeatedly.
How is this possible? The answer is that the calorie-matched rats reduce their energy expenditure to a greater degree than those that are allowed free access to food. The most logical explanation for this behavior is that the "set point" of the energy homeostasis system has changed. The industrial diet causes the rodents' bodies to "want" to accumulate more fat, therefore they will accomplish that by any means necessary, whether it means eating more, or if that's not possible, expending less energy. This shows that a poor diet can, in principle, dysregulate the system that controls energy homeostasis.
Well, then why did Dr. Haub's diet allow him to lose weight? The body can only maintain body composition in the face of a calorie deficit up to a certain point. After that, it has no choice but to lower fat mass. It will do so reluctantly, at the same time increasing hunger, and reducing lean mass***, muscular strength and energy dedicated to tissue repair and immune function. However, I hope everyone can agree that a sufficient calorie deficit can lead to fat loss regardless of what kind of food is eaten. Dr. Haub's 800 calorie deficit qualifies. I think only a very small percentage of people are capable of maintaining that kind of calorie deficit for more than a few months, because it is mentally and physically difficult to fight against what the hypothalamus has decided is in your best interest.
My hypothesis is that, in many people, industrial food and an unnatural lifestyle lead to gradual fat gain by dysregulating the energy homeostasis system. This "breaks" the system that's designed to automatically keep our fat mass in the optimal range by regulating energy intake, energy expenditure and the relative partitioning of energy resources between lean and fat tissue. This system is not under our conscious control, and it has nothing to do with willpower.
I suspect that if you put a group of children on this junk food diet for many years, and compared them to a group of children on a healthy diet, the junk food group would end up fatter as adults. This would be true if neither group paid any attention to calories, and perhaps even if calorie intake were identical in the two groups (as in the rodent example). The result of Dr. Haub's experiment does not contradict that hypothesis.
So do calories matter? Yes, but in a healthy person, all the math is done automatically by the hypothalamus and energy balance requires no conscious effort. In 2010, many people have already accumulated excess fat mass. How that may be sustainably lost is another question entirely, and a more challenging one in my opinion. As they say, an ounce of prevention is worth a pound of cure. There are many possible strategies, with varying degrees of efficacy that depend highly on individual differences, but I think overall the question is still open. I discussed some of my thoughts in a recent series on body fat regulation (7, 8, 9, 10, 11).
* ob/ob and db/db mice. Zucker and Koletsky rats. Equivalent mutations in humans also result in obesity.
** Via an increase in muscular efficiency and perhaps a decrease in basal metabolism. Thyroid hormone activity drops.
*** Loss of muscle, bone and connective tissue can be compensated for by strength training during calorie restriction. Presumed loss of other non-adipose tissues (liver, kidney, brain, etc.) is probably not affected by strength training.
I've received several e-mails from readers about a recent experiment by nutrition professor Mark Haub at Kansas State university (thanks to Josh and others). He ate a calorie-restricted diet in which 2/3 of his calories came from junk food: Twinkies, Hostess and Little Debbie cakes, Dorito corn chips and sweetened cereals (1). On this calorie-restricted junk food diet (800 calorie/day deficit), he lost 27 pounds in two months.
Therefore, junk food doesn't cause fat gain and the only thing that determines body fatness is how much you eat and exercise. Right?
Discussion
Let's start with a few things most people can agree on. If you don't eat any food at all, you will lose fat mass. If you voluntarily force-feed yourself with a large excess of food, you will gain fat mass, whether the excess comes from carbohydrate or fat (2). So calories obviously have something to do with fat mass.
But of course, the situation is much more subtle in real life. Since a pound of body fat contains roughly 3,500 calories, eating an excess of 80 calories per day (1 piece of toast) should lead to a weight gain of 8 lbs of fat per year. Conversely, if you're distracted and forget to eat your toast, you should lose 8 lbs of fat per year, which would eventually be dangerous for a lean person. That's why we all record every crumb of food we eat, determine its exact calorie content, and match that intake precisely with our energy expenditure to maintain a stable weight.
Oh wait, we don't do that? Then how do so many people maintain a stable weight over years and decades? And how do wild animals maintain a stable body fat percentage (except when preparing for hibernation) even in the face of food surpluses? How do lab rats and mice fed a whole food diet maintain a stable body fat percentage in the face of literally unlimited food, when they're in a small cage with practically nothing to do but eat?
The answer is that the body isn't stupid. Over hundreds of millions of years, we've evolved sophisticated systems that maintain "energy homeostasis". In other words, these systems act to regulate fat mass and keep it within the optimal range. The evolutionary pressures operating here are obvious: too little fat mass, and an organism will be susceptible to starvation; too much, and an organism will be less agile and less efficient at locomotion and reproduction. Energy homeostasis is such a basic part of survival that even the simplest organisms regulate it.
Not only is it clear that we have an energy homeostasis system, we even know a thing or two about how it works. Early studies showed that lesioning a part of the brain called the ventromedial hypothalamus causes massive obesity (3; this is also true in humans, when a disruption results from cancer). Investigators also discovered several genetic mutations in rats and mice that result in massive obesity*. Decades-long research eventually demonstrated that these models have something in common: they all interfere with an energy homeostasis circuit that passes information about fat mass to the hypothalamus via the hormone leptin.
The leptin system is a classic negative feedback loop: the more fat mass accumulates, the more leptin is produced. The more leptin is produced, the more the hypothalamus activates programs to reduce hunger and increase energy expenditure, which continues until fat mass is back in the optimal range. Conversely, low fat mass and low leptin lead to increased hunger and energy conservation by this same pathway**.
So if genetic mutants can become massively obese, I guess that argues against the idea that voluntary food intake and energy expenditure are the only determinants of fat mass. But a skeptic might point out that these are extreme cases, and such mutations are so rare in humans that the analogy is irrelevant.
Let's dig deeper. There are many studies in which rodents are made obese using industrial high-fat diets made from refined ingredients. The rats eat more calories (at least in the beginning), and gain fat rapidly. No big surprise there. But what may come as a surprise to the calorie counters is that rodents on these diets gain body fat even if their calorie intake is matched precisely to lean rodents eating a whole food diet (4, 5, 6). In fact, they sometimes gain almost as much fat as rodents who are allowed to eat all the industrial food they want. This has been demonstrated repeatedly.
How is this possible? The answer is that the calorie-matched rats reduce their energy expenditure to a greater degree than those that are allowed free access to food. The most logical explanation for this behavior is that the "set point" of the energy homeostasis system has changed. The industrial diet causes the rodents' bodies to "want" to accumulate more fat, therefore they will accomplish that by any means necessary, whether it means eating more, or if that's not possible, expending less energy. This shows that a poor diet can, in principle, dysregulate the system that controls energy homeostasis.
Well, then why did Dr. Haub's diet allow him to lose weight? The body can only maintain body composition in the face of a calorie deficit up to a certain point. After that, it has no choice but to lower fat mass. It will do so reluctantly, at the same time increasing hunger, and reducing lean mass***, muscular strength and energy dedicated to tissue repair and immune function. However, I hope everyone can agree that a sufficient calorie deficit can lead to fat loss regardless of what kind of food is eaten. Dr. Haub's 800 calorie deficit qualifies. I think only a very small percentage of people are capable of maintaining that kind of calorie deficit for more than a few months, because it is mentally and physically difficult to fight against what the hypothalamus has decided is in your best interest.
My hypothesis is that, in many people, industrial food and an unnatural lifestyle lead to gradual fat gain by dysregulating the energy homeostasis system. This "breaks" the system that's designed to automatically keep our fat mass in the optimal range by regulating energy intake, energy expenditure and the relative partitioning of energy resources between lean and fat tissue. This system is not under our conscious control, and it has nothing to do with willpower.
I suspect that if you put a group of children on this junk food diet for many years, and compared them to a group of children on a healthy diet, the junk food group would end up fatter as adults. This would be true if neither group paid any attention to calories, and perhaps even if calorie intake were identical in the two groups (as in the rodent example). The result of Dr. Haub's experiment does not contradict that hypothesis.
So do calories matter? Yes, but in a healthy person, all the math is done automatically by the hypothalamus and energy balance requires no conscious effort. In 2010, many people have already accumulated excess fat mass. How that may be sustainably lost is another question entirely, and a more challenging one in my opinion. As they say, an ounce of prevention is worth a pound of cure. There are many possible strategies, with varying degrees of efficacy that depend highly on individual differences, but I think overall the question is still open. I discussed some of my thoughts in a recent series on body fat regulation (7, 8, 9, 10, 11).
* ob/ob and db/db mice. Zucker and Koletsky rats. Equivalent mutations in humans also result in obesity.
** Via an increase in muscular efficiency and perhaps a decrease in basal metabolism. Thyroid hormone activity drops.
*** Loss of muscle, bone and connective tissue can be compensated for by strength training during calorie restriction. Presumed loss of other non-adipose tissues (liver, kidney, brain, etc.) is probably not affected by strength training.
Wednesday, August 20, 2008
Cardiovascular Risk Factors on Kitava, Part IV: Leptin
Leptin is a hormone that is a central player in the process of weight gain and chronic disease. Its existence had been predicted for decades, but it was not identified until 1994. Although less well known than insulin, its effects on nutrient disposal, metabolic rate and feeding behaviors place it on the same level of importance.
Caloric intake and expenditure vary from day to day and week to week in humans, yet most people maintain a relatively stable weight without consciously adjusting food intake. For example, I become hungry after a long fast, whereas I won't be very hungry if I've stuffed myself for two meals in a row. This suggests a homeostatic mechanism, or feedback loop, which keeps weight in the body's preferred range. Leptin is the major feedback signal.
Here's how it works. Leptin is secreted by adipose (fat) tissue, and its blood levels are proportional to fat mass. The more fat, the more leptin. It acts in the brain to increase the metabolic rate, decrease eating behaviors, and inhibit the deposition of fat. Thus, if fat mass increases, hunger diminishes and the body tries to burn calories to regain its preferred equilibrium.
The next logical question is "how could anyone become obese if this feedback loop inhibits energy storage in response to fat gain?" The answer is a problem called leptin resistance. In people who are obese, the brain no longer responds to the leptin signal. In fact, the brain believes leptin levels are low, implying stored energy is low, so it thinks it's starving. This explains the low metabolic rate, increased tendency for fat storage and hyperphagia (increased eating) seen in many obese people. Leptin resistance has reset the body's preferred weight 'set-point' to a higher level.
Incidentally, some reaserchers have claimed that obese people gain fat because they don't fidget as much as others (a variation on the "obesity is caused by sloth" theory). This is based on the observation that thin people fidget more than overweight people. Leptin also influences activity levels, so I would argue that obese people fidget less than thin people due to their leptin resistance. In other words, they fidget less because they're fat, rather than the other way around.
The problem of leptin resistance is well illustrated by a rat model called the Zucker fatty strain. The Zucker rat has a mutation in the leptin receptor gene, making its brain unresponsive to leptin signals. The rat's fat tissue pumps out leptin, but its brain is deaf to it. This is basically a model of severe leptin resistance, the same thing we see in obese humans. What happens to these rats? They become hyperphagic, hypometabolic, obese, develop insulin resistance, impaired glucose tolerance, dyslipidemia, diabetes, and cardiovascular disease. Basically, severe metabolic syndrome.
This shows that leptin resistance is sufficient to cause many of the common metabolic problems that plague modern societies. In humans, it's a little known fact that leptin resistance precedes the development of obesity, insulin resistance, and impaired glucose tolerance! Furthermore, humans with leptin receptor mutations or impaired leptin production become hyperphagic and severely obese. This puts leptin at the top of my list of suspects.
So here we have the Kitavans, who are thin and healthy. How's their leptin? Incredibly low. Even in young individuals, Kitavan leptin levels average less than half of Swedish levels. Beyond age 60, Kitavans have 1/4 the leptin level of Swedish people. The difference is so great, the standard deviations don't even overlap.
This isn't surprising, since leptin levels track with fat mass and the Kitavans are very lean (average male BMI = 20, female BMI = 18). Now we are faced with a chicken and egg question. Are Kitavans thin because they're leptin-sensitive, or are they leptin-sensitive because they're thin?
There's no way to answer this question conclusively using the data I'm familiar with. However, in mice and humans, leptin resistance by itself can initiate a spectrum of metabolic problems very reminiscent of what we see so frequently in modern societies. This leads me to believe that there's something about the modern lifestyle that causes leptin resistance. As usual, my microscope is pointed directly at wheat. Its lectins are capable of binding to and desensitizing the leptin and insulin receptors in vitro, as I wrote about before. Staffan Lindeberg proposed that grain lectins could be responsible for leptin resistance here. This is one of many possible mechanisms by which wheat could wreak metabolic damage, particularly in its industrially processed form.
Caloric intake and expenditure vary from day to day and week to week in humans, yet most people maintain a relatively stable weight without consciously adjusting food intake. For example, I become hungry after a long fast, whereas I won't be very hungry if I've stuffed myself for two meals in a row. This suggests a homeostatic mechanism, or feedback loop, which keeps weight in the body's preferred range. Leptin is the major feedback signal.
Here's how it works. Leptin is secreted by adipose (fat) tissue, and its blood levels are proportional to fat mass. The more fat, the more leptin. It acts in the brain to increase the metabolic rate, decrease eating behaviors, and inhibit the deposition of fat. Thus, if fat mass increases, hunger diminishes and the body tries to burn calories to regain its preferred equilibrium.
The next logical question is "how could anyone become obese if this feedback loop inhibits energy storage in response to fat gain?" The answer is a problem called leptin resistance. In people who are obese, the brain no longer responds to the leptin signal. In fact, the brain believes leptin levels are low, implying stored energy is low, so it thinks it's starving. This explains the low metabolic rate, increased tendency for fat storage and hyperphagia (increased eating) seen in many obese people. Leptin resistance has reset the body's preferred weight 'set-point' to a higher level.
Incidentally, some reaserchers have claimed that obese people gain fat because they don't fidget as much as others (a variation on the "obesity is caused by sloth" theory). This is based on the observation that thin people fidget more than overweight people. Leptin also influences activity levels, so I would argue that obese people fidget less than thin people due to their leptin resistance. In other words, they fidget less because they're fat, rather than the other way around.
The problem of leptin resistance is well illustrated by a rat model called the Zucker fatty strain. The Zucker rat has a mutation in the leptin receptor gene, making its brain unresponsive to leptin signals. The rat's fat tissue pumps out leptin, but its brain is deaf to it. This is basically a model of severe leptin resistance, the same thing we see in obese humans. What happens to these rats? They become hyperphagic, hypometabolic, obese, develop insulin resistance, impaired glucose tolerance, dyslipidemia, diabetes, and cardiovascular disease. Basically, severe metabolic syndrome.
This shows that leptin resistance is sufficient to cause many of the common metabolic problems that plague modern societies. In humans, it's a little known fact that leptin resistance precedes the development of obesity, insulin resistance, and impaired glucose tolerance! Furthermore, humans with leptin receptor mutations or impaired leptin production become hyperphagic and severely obese. This puts leptin at the top of my list of suspects.
So here we have the Kitavans, who are thin and healthy. How's their leptin? Incredibly low. Even in young individuals, Kitavan leptin levels average less than half of Swedish levels. Beyond age 60, Kitavans have 1/4 the leptin level of Swedish people. The difference is so great, the standard deviations don't even overlap.
This isn't surprising, since leptin levels track with fat mass and the Kitavans are very lean (average male BMI = 20, female BMI = 18). Now we are faced with a chicken and egg question. Are Kitavans thin because they're leptin-sensitive, or are they leptin-sensitive because they're thin?
There's no way to answer this question conclusively using the data I'm familiar with. However, in mice and humans, leptin resistance by itself can initiate a spectrum of metabolic problems very reminiscent of what we see so frequently in modern societies. This leads me to believe that there's something about the modern lifestyle that causes leptin resistance. As usual, my microscope is pointed directly at wheat. Its lectins are capable of binding to and desensitizing the leptin and insulin receptors in vitro, as I wrote about before. Staffan Lindeberg proposed that grain lectins could be responsible for leptin resistance here. This is one of many possible mechanisms by which wheat could wreak metabolic damage, particularly in its industrially processed form.
Saturday, August 9, 2008
Hyperphagia
One of the things I didn't mention in the last post is that Americans are eating more calories than ever before. According to Centers for Disease Control NHANES data, in 2000, men ate about 160 more calories per day, and women ate about 340 more than in 1971. That's a change of 7% and 22%, respectively. The extra calories come almost exclusively from refined grains, with the largest single contribution coming from white wheat flour (correction: the largest single contribution comes from corn sweeteners, followed by white wheat flour).
Some people will see those data and decide the increase in calories is the explanation for the expanding American waistline. I don't think that's incorrect, but I do think it misses the point. The relevant question is "why are we eating more calories now than we were in 1971?"
We weren't exactly starving in 1971. And average energy expenditure, if anything, has actually increased. So why are we eating more? I believe that our increased food intake, or hyperphagia, is the result of metabolic disturbances, rather than the cause of them.
Humans, like all animals, have a sophisticated system of hormones and brain regions whose function is to maintain a proper energy balance. Part of the system's job is to keep fat mass at an appropriate level. With a properly functioning system, feedback loops inhibit hunger once fat mass has reached a certain level, and also increase resting metabolic rate to burn excess calories. If the system is working properly, it's very difficult to gain weight. There have been a number of overfeeding studies in which subjects have consumed huge amounts of excess calories. Some people gain weight, many don't.
The fact that fat mass is hormonally regulated can be easily seen in other mammals. When was the last time you saw a fat squirrel in the springtime? When was the last time you saw a thin squirrel in the fall? These events are regulated by hormones. A squirrel in captivity will put on weight in the fall, even if its daily food intake is not changed.
A key hormone in this process is leptin. Leptin levels are proportional to fat mass, and serve to inhibit hunger and eating behaviors. Under normal conditions, the more fat tissue a person has, the more leptin they will produce, and the less they will eat until the fat mass has reached the body's preferred 'set-point'. The problem is that overweight Westerners are almost invariably leptin-resistant, meaning their body doesn't respond to the signal to stop eating!
Leptin resistance leads to hyperphagia, overweight and the metabolic syndrome (a common cluster of symptoms that implies profound metabolic disturbance). It typically precedes insulin resistance during the downward slide towards metabolic syndrome.
I suspect that wheat, sugar and perhaps other processed foods cause hyperphagia. It's the same thing you see when wheat is first introduced to a culture, even if it's replacing another refined carbohydrate. I believe hyperphagia is secondary to a disturbed metabolism. There's something about the combination of refined wheat, sugar, processed vegetable oils and other industrial foods that reached a critical mass in the mid-70s. The shift in diet composition disturbed our normal hormonal profile (even more than it was already disturbed), and sent us into a tailspin of excessive eating and unprecedented weight gain.
Some people will see those data and decide the increase in calories is the explanation for the expanding American waistline. I don't think that's incorrect, but I do think it misses the point. The relevant question is "why are we eating more calories now than we were in 1971?"
We weren't exactly starving in 1971. And average energy expenditure, if anything, has actually increased. So why are we eating more? I believe that our increased food intake, or hyperphagia, is the result of metabolic disturbances, rather than the cause of them.
Humans, like all animals, have a sophisticated system of hormones and brain regions whose function is to maintain a proper energy balance. Part of the system's job is to keep fat mass at an appropriate level. With a properly functioning system, feedback loops inhibit hunger once fat mass has reached a certain level, and also increase resting metabolic rate to burn excess calories. If the system is working properly, it's very difficult to gain weight. There have been a number of overfeeding studies in which subjects have consumed huge amounts of excess calories. Some people gain weight, many don't.
The fact that fat mass is hormonally regulated can be easily seen in other mammals. When was the last time you saw a fat squirrel in the springtime? When was the last time you saw a thin squirrel in the fall? These events are regulated by hormones. A squirrel in captivity will put on weight in the fall, even if its daily food intake is not changed.
A key hormone in this process is leptin. Leptin levels are proportional to fat mass, and serve to inhibit hunger and eating behaviors. Under normal conditions, the more fat tissue a person has, the more leptin they will produce, and the less they will eat until the fat mass has reached the body's preferred 'set-point'. The problem is that overweight Westerners are almost invariably leptin-resistant, meaning their body doesn't respond to the signal to stop eating!
Leptin resistance leads to hyperphagia, overweight and the metabolic syndrome (a common cluster of symptoms that implies profound metabolic disturbance). It typically precedes insulin resistance during the downward slide towards metabolic syndrome.
I suspect that wheat, sugar and perhaps other processed foods cause hyperphagia. It's the same thing you see when wheat is first introduced to a culture, even if it's replacing another refined carbohydrate. I believe hyperphagia is secondary to a disturbed metabolism. There's something about the combination of refined wheat, sugar, processed vegetable oils and other industrial foods that reached a critical mass in the mid-70s. The shift in diet composition disturbed our normal hormonal profile (even more than it was already disturbed), and sent us into a tailspin of excessive eating and unprecedented weight gain.
Friday, June 27, 2008
Two Things that Get on My Nerves, Part I
The "Thrifty Gene" Hypothesis
The thrifty gene hypothesis is the darling of many obesity researchers. It was proposed in 1962 by the geneticist James V. Neel to explain the high rates of obesity in modern populations, particularly modernizing American Indians. It states that our species evolved under conditions of frequent starvation, so we're designed to store every available calorie. In today's world of food abundance, our bodies continue to be thrifty and that's why we're fat.
Obesity researchers love it because it dovetails nicely with the equally dim "calories-in, calories-out hypothesis", whereby calories alone determine body composition. You practically can't read a paper on overweight without seeing an obligatory nod to the thrifty gene hypothesis. The only problem is, it's wrong.
The assumption that hunter-gatherers and non-industrial agriculturalists lived under chronic calorie deprivation has been proven false. The anthropological evidence indicates that most hunter-gatherers had abundant food, most of the time. They did have fluctuations in energy balance, but the majority of the time they had access to more calories than they needed, just like us. Yet they were not fat.
The Kitavans are a good example. They are an agricultural society that eats virtually no grains or processed food. In Dr. Staffan Lindeberg's studies, he has determined that overweight is virtually nonexistent among them, despite an abundant food supply.
The cause of obesity is not the availability of excess calories, it's the deregulation of the bodyweight homeostasis system. We have a very sophisticated set of feedback loops that "try" to maintain a healthy weight. It's composed of hormones (insulin, leptin, etc.), certain brain regions, and many other elements, known and unknown. These feedback loops influence what the body does with calories, as well as feeding behaviors. When you throw a wrench in the gears with a lifestyle that is unnatural to the human metabolism, you deregulate the system so that it no longer maintains an appropriate "set-point".
Here's what Neel had to say about his own theory in 1982 (excerpts from Good Calories, Bad Calories):
For more information on bodyweight regulation, see:
Insulin Controls Your Fat
Leptin and Lectins
Thoughts on Obesity Part I
Thoughts on Obesity Part II
Body Composition
The thrifty gene hypothesis is the darling of many obesity researchers. It was proposed in 1962 by the geneticist James V. Neel to explain the high rates of obesity in modern populations, particularly modernizing American Indians. It states that our species evolved under conditions of frequent starvation, so we're designed to store every available calorie. In today's world of food abundance, our bodies continue to be thrifty and that's why we're fat.
Obesity researchers love it because it dovetails nicely with the equally dim "calories-in, calories-out hypothesis", whereby calories alone determine body composition. You practically can't read a paper on overweight without seeing an obligatory nod to the thrifty gene hypothesis. The only problem is, it's wrong.
The assumption that hunter-gatherers and non-industrial agriculturalists lived under chronic calorie deprivation has been proven false. The anthropological evidence indicates that most hunter-gatherers had abundant food, most of the time. They did have fluctuations in energy balance, but the majority of the time they had access to more calories than they needed, just like us. Yet they were not fat.
The Kitavans are a good example. They are an agricultural society that eats virtually no grains or processed food. In Dr. Staffan Lindeberg's studies, he has determined that overweight is virtually nonexistent among them, despite an abundant food supply.
The cause of obesity is not the availability of excess calories, it's the deregulation of the bodyweight homeostasis system. We have a very sophisticated set of feedback loops that "try" to maintain a healthy weight. It's composed of hormones (insulin, leptin, etc.), certain brain regions, and many other elements, known and unknown. These feedback loops influence what the body does with calories, as well as feeding behaviors. When you throw a wrench in the gears with a lifestyle that is unnatural to the human metabolism, you deregulate the system so that it no longer maintains an appropriate "set-point".
Here's what Neel had to say about his own theory in 1982 (excerpts from Good Calories, Bad Calories):
The data on which that (rather soft) hypothesis was based has now largely collapsed.And what does he think causes overweight in American Indians now?
The composition of the diet, and more specifically the use of highly refined carbohydrates.RIP, thrifty gene.
For more information on bodyweight regulation, see:
Insulin Controls Your Fat
Leptin and Lectins
Thoughts on Obesity Part I
Thoughts on Obesity Part II
Body Composition
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.
Subscribe to:
Posts (Atom)