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. This is based on the observation that thin people fidget more than overweight people. Leptin also influences activity levels, so it's possible 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 industrial food.
Showing posts sorted by relevance for query leptin. Sort by date Show all posts
Showing posts sorted by relevance for query leptin. Sort by date Show all posts
Wednesday, August 20, 2008
Saturday, January 16, 2010
The Body Fat Setpoint, Part II: Mechanisms of Fat Gain
The Timeline of Fat Gain
Modern humans are unusual mammals in that fat mass varies greatly between individuals. Some animals carry a large amount of fat for a specific purpose, such as hibernation or migration. But all individuals of the same sex and social position will carry approximately the same amount of fat at any given time of year. Likewise, in hunter-gatherer societies worldwide, there isn't much variation in body weight-- nearly everyone is lean. Not necessarily lean like Usain Bolt, but not overweight.
Although overweight and obesity occurred forty years ago in the U.S. and U.K., they were much less common than today, particularly in children. Here are data from the U.S. Centers for Disease Control NHANES surveys (from this post):
Together, this shows that a) leanness is the most natural condition for the human body, and b) something about our changing environment, not our genes, has caused our body fat to grow.
Fat Mass is Regulated by a Feedback Circuit Between Fat Tissue and the Brain
In the last post, I described how the body regulates fat mass, attempting to keep it within a narrow window or "setpoint". Body fat produces a hormone called leptin, which signals to the brain and other organs to decrease appetite, increase the metabolic rate and increase physical activity. More fat means more leptin, which then causes the extra fat to be burned. The little glitch is that some people become resistant to leptin, so that their brain doesn't hear the fat tissue screaming that it's already full. Leptin resistance nearly always accompanies obesity, because it's a precondition of significant fat gain. If a person weren't leptin resistant, he wouldn't have the ability to gain more than a few pounds of fat without heroic overeating (which is very very unpleasant when your brain is telling you to stop). Animal models of leptin resistance develop something that resembles human metabolic syndrome (abdominal obesity, blood lipid abnormalities, insulin resistance, high blood pressure).
The Role of the Hypothalamus
The hypothalamus is on the underside of the brain connected to the pituitary gland. It's the main site of leptin action in the brain, and it controls the majority of leptin's effects on appetite, energy expenditure and insulin sensitivity. Most of the known gene variations that are associated with overweight in humans influence the function of the hypothalamus in some way (1). Not surprisingly, leptin resistance in the hypothalamus has been proposed as a cause of obesity. It's been shown in rats and mice that hypothalamic leptin resistance occurs in diet-induced obesity, and it's almost certainly the case in humans as well. What's causing leptin resistance in the hypothalamus?
There are three leading explanations at this point that are not mutually exclusive. One is cellular stress in the endoplasmic reticulum, a structure inside the cell that's used for protein synthesis and folding. I've read the most recent paper on this in detail, and I found it unconvincing (2). I'm open to the idea, but it needs more rigorous support.
A second explanation is inflammation in the hypothalamus. Inflammation inhibits leptin and insulin signaling in a variety of cell types. At least two studies have shown that diet-induced obesity in rodents leads to inflammation in the hypothalamus (3, 4)*. [2013 update: several studies have shown that preventing hypothalamic inflammation attenuates fat gain in obesity models]. If leptin is getting to the hypothalamus, but the hypothalamus is insensitive to it, it will require more leptin to get the same signal, and fat mass will creep up until it reaches a higher setpoint.
The other possibility is that leptin simply isn't reaching the hypothalamus. The brain is a unique organ. It's enclosed by the blood-brain barrier (BBB), which greatly restricts what can enter and leave it. Both insulin and leptin are actively transported across the BBB. It's been known for a decade that obesity in rodents is associated with a lower rate of leptin transport across the BBB (5, 6).
What causes a decrease in leptin transport across the BBB? Triglycerides are a major factor. These are circulating fats going from the liver and the digestive tract to other tissues. They're one of the blood lipid measurements the doctor makes when he draws your blood. Several studies in rodents have shown that high triglycerides cause a reduction in leptin transport across the BBB, and reducing triglycerides allows greater leptin transport and fat loss (7, 8). In support of this theory, the triglyceride-reducing drug gemfibrozil also causes weight loss in humans (9)**. Low-carbohydrate diets, and avoiding sugar and refined carbohydrates in particular, reduce triglycerides and produce weight loss, although that doesn't necessarily mean one causes the other.
In the next post, I'll get more specific about what factors could be causing hypothalamic inflammation and/or reduced leptin transport across the BBB. I'll also discuss some ideas on how to reduce leptin resistance sustainably through diet and exercise.
* This is accomplished by feeding them sad little pellets that look like raw cookie dough. They're made up mostly of lard, soybean oil, casein, maltodextrin or cornstarch, sugar, vitamins and minerals (this is a link to the the most commonly used diet for inducing obesity in rodents). Food doesn't get any more refined than this stuff, and adding just about anything to it, from fiber to fruit extracts, makes it less damaging.
** Fibrates are PPAR agonists, so the weight loss could also be due to something besides the reduction in triglycerides.
Modern humans are unusual mammals in that fat mass varies greatly between individuals. Some animals carry a large amount of fat for a specific purpose, such as hibernation or migration. But all individuals of the same sex and social position will carry approximately the same amount of fat at any given time of year. Likewise, in hunter-gatherer societies worldwide, there isn't much variation in body weight-- nearly everyone is lean. Not necessarily lean like Usain Bolt, but not overweight.
Although overweight and obesity occurred forty years ago in the U.S. and U.K., they were much less common than today, particularly in children. Here are data from the U.S. Centers for Disease Control NHANES surveys (from this post):
Together, this shows that a) leanness is the most natural condition for the human body, and b) something about our changing environment, not our genes, has caused our body fat to grow.Fat Mass is Regulated by a Feedback Circuit Between Fat Tissue and the Brain
In the last post, I described how the body regulates fat mass, attempting to keep it within a narrow window or "setpoint". Body fat produces a hormone called leptin, which signals to the brain and other organs to decrease appetite, increase the metabolic rate and increase physical activity. More fat means more leptin, which then causes the extra fat to be burned. The little glitch is that some people become resistant to leptin, so that their brain doesn't hear the fat tissue screaming that it's already full. Leptin resistance nearly always accompanies obesity, because it's a precondition of significant fat gain. If a person weren't leptin resistant, he wouldn't have the ability to gain more than a few pounds of fat without heroic overeating (which is very very unpleasant when your brain is telling you to stop). Animal models of leptin resistance develop something that resembles human metabolic syndrome (abdominal obesity, blood lipid abnormalities, insulin resistance, high blood pressure).
The Role of the Hypothalamus
The hypothalamus is on the underside of the brain connected to the pituitary gland. It's the main site of leptin action in the brain, and it controls the majority of leptin's effects on appetite, energy expenditure and insulin sensitivity. Most of the known gene variations that are associated with overweight in humans influence the function of the hypothalamus in some way (1). Not surprisingly, leptin resistance in the hypothalamus has been proposed as a cause of obesity. It's been shown in rats and mice that hypothalamic leptin resistance occurs in diet-induced obesity, and it's almost certainly the case in humans as well. What's causing leptin resistance in the hypothalamus?
There are three leading explanations at this point that are not mutually exclusive. One is cellular stress in the endoplasmic reticulum, a structure inside the cell that's used for protein synthesis and folding. I've read the most recent paper on this in detail, and I found it unconvincing (2). I'm open to the idea, but it needs more rigorous support.
A second explanation is inflammation in the hypothalamus. Inflammation inhibits leptin and insulin signaling in a variety of cell types. At least two studies have shown that diet-induced obesity in rodents leads to inflammation in the hypothalamus (3, 4)*. [2013 update: several studies have shown that preventing hypothalamic inflammation attenuates fat gain in obesity models]. If leptin is getting to the hypothalamus, but the hypothalamus is insensitive to it, it will require more leptin to get the same signal, and fat mass will creep up until it reaches a higher setpoint.
The other possibility is that leptin simply isn't reaching the hypothalamus. The brain is a unique organ. It's enclosed by the blood-brain barrier (BBB), which greatly restricts what can enter and leave it. Both insulin and leptin are actively transported across the BBB. It's been known for a decade that obesity in rodents is associated with a lower rate of leptin transport across the BBB (5, 6).
What causes a decrease in leptin transport across the BBB? Triglycerides are a major factor. These are circulating fats going from the liver and the digestive tract to other tissues. They're one of the blood lipid measurements the doctor makes when he draws your blood. Several studies in rodents have shown that high triglycerides cause a reduction in leptin transport across the BBB, and reducing triglycerides allows greater leptin transport and fat loss (7, 8). In support of this theory, the triglyceride-reducing drug gemfibrozil also causes weight loss in humans (9)**. Low-carbohydrate diets, and avoiding sugar and refined carbohydrates in particular, reduce triglycerides and produce weight loss, although that doesn't necessarily mean one causes the other.
In the next post, I'll get more specific about what factors could be causing hypothalamic inflammation and/or reduced leptin transport across the BBB. I'll also discuss some ideas on how to reduce leptin resistance sustainably through diet and exercise.
* This is accomplished by feeding them sad little pellets that look like raw cookie dough. They're made up mostly of lard, soybean oil, casein, maltodextrin or cornstarch, sugar, vitamins and minerals (this is a link to the the most commonly used diet for inducing obesity in rodents). Food doesn't get any more refined than this stuff, and adding just about anything to it, from fiber to fruit extracts, makes it less damaging.
** Fibrates are PPAR agonists, so the weight loss could also be due to something besides the reduction in triglycerides.
Sunday, April 6, 2008
Leptin
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 may come 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?
Tuesday, July 2, 2013
The Genetics of Obesity, Part II
Rodents Lead the Way
The study of obesity genetics dates back more than half a century. In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene. They named this the "obese" (ob/ob) mouse. Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.
At the time of discovery, no one knew where the mutations resided in the genome. All they knew is that the mutations were in single genes, and they resulted in extreme obesity. Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way. Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned. Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.
At the time of discovery, no one knew where the mutations resided in the genome. All they knew is that the mutations were in single genes, and they resulted in extreme obesity. Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way. Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned. Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.
Thursday, March 22, 2012
Food Reward: Approaching a Scientific Consensus
Review papers provide a bird's-eye view of a field from the perspective of experts. Recent review papers show that many obesity researchers are converging on a model for the development of obesity that includes excessive food reward*, in addition to other factors such as physical inactivity, behavioral traits, and alterations in the function of the hypothalamus (a key brain region for the regulation of body fatness). Take for example the four new review papers I posted recently by obesity and reward researchers:
Saturday, January 23, 2010
The Body Fat Setpoint, Part III: Dietary Causes of Obesity
[2013 update: I've edited this post to remove elements that I feel were poorly supported. I now think that changes in the setpoint are at least partially secondary to passive overconsumption of calories, particularly low quality calories]
What Caused the Setpoint to Change?
We have two criteria to narrow our search for the cause of modern fat gain:
In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:
The Role of Digestive Health
What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.
Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.
Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).
A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.
Overall, I think gut dysfunction could play a role in obesity and other modern metabolic problems.
Exiting the Niche
I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.
In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.
* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.
What Caused the Setpoint to Change?
We have two criteria to narrow our search for the cause of modern fat gain:
- It has to be new to the human environment
- At some point, it has to cause leptin resistance or otherwise disturb the setpoint
In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:
- Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
- Low-carbohydrate diets are somewhat effective for fat loss and lower triglycerides
- Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
- Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
The Role of Digestive Health
What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.
Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.
Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).
A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.
Overall, I think gut dysfunction could play a role in obesity and other modern metabolic problems.
Exiting the Niche
I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.
In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.
* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.
Sunday, March 24, 2013
Neuronal Control of Appetite, Metabolism and Weight
Last week, I attended a Keystone conference, "Neuronal Control of Appetite, Metabolism and Weight", in Banff. Keystone conferences are small, focused meetings that tend to attract high quality science. This particular conference centered around my own professional research interests, and it was incredibly informative. This post is a summary of some of the most salient points.
Rapid Pace of Scientific Progress
Rapid Pace of Scientific Progress
Sunday, July 1, 2012
Why Did Energy Expenditure Differ Between Diets in the Recent Study by Dr. Ludwig's Group?
As discussed in the previous post, a recent study by Dr. David Ludwig's group suggested that during weight maintenance following fat loss, eating a very low carbohydrate (VLC) diet led to a higher metabolic rate (energy expenditure) than eating a low-fat (LF) diet, with a low glycemic index (LGI) diet falling in between the two (1). The VLC diet was 30 percent protein, while the other two were 20 percent. It's important to note that these were three dietary patterns that differed in many ways, and contrary to claims that are being made in the popular media, the study was not designed to isolate the specific influence of protein, carbohydrate or fat on energy expenditure in this context.
Not only did the VLC diet lead to a higher total energy expenditure than the LF and LGI diets, the most remarkable finding is that it led to a higher resting energy expenditure. Basically, people on the VLC diet woke up in the morning burning more energy than people on the LGI diet, and people on the LGI diet woke up burning more than people on the LF diet. The VLC dieters burned 326 more calories than the LF dieters, and 200 more than the LGI dieters.
It's always tempting to view each new study in isolation, without considering the numerous studies that came before it, but in this case it's essential to see this study through a skeptical lens that places it into the proper scientific context. Previous studies have suggested that:
With that, let's see what could have accounted for the differences observed in Dr. Ludwig's study.
Not only did the VLC diet lead to a higher total energy expenditure than the LF and LGI diets, the most remarkable finding is that it led to a higher resting energy expenditure. Basically, people on the VLC diet woke up in the morning burning more energy than people on the LGI diet, and people on the LGI diet woke up burning more than people on the LF diet. The VLC dieters burned 326 more calories than the LF dieters, and 200 more than the LGI dieters.
It's always tempting to view each new study in isolation, without considering the numerous studies that came before it, but in this case it's essential to see this study through a skeptical lens that places it into the proper scientific context. Previous studies have suggested that:
- The carbohydrate:fat ratio of the diet has little or no detectable impact on energy expenditure in people who are not trying to lose weight (2, 3).
- The carbohydrate:fat ratio of the diet has little or no detectable impact on energy expenditure in people who are being experimentally overfed, and if anything carbohydrate increases energy expenditure more than fat (4, 5).
- The carbohydrate:fat ratio of the diet has little or no detectable impact on energy expenditure during weight loss (6, 7, 8), and does not influence the rate of fat loss when calories are precisely controlled.
With that, let's see what could have accounted for the differences observed in Dr. Ludwig's study.
Friday, October 16, 2015
Why Do Girls and Boys Reach Puberty Younger Than They Used To?
Girls, and probably boys, are reaching puberty years younger than they did in our great-grandparents' generation. Why? There's no shortage of explanations, but the primary reason is probably quite simple.
Thursday, January 31, 2013
Why Do We Eat? A Neurobiological Perspective. Part III
In the first post, I explained that all voluntary actions are driven by a central action selection system in the mesolimbic area (the reward system). This is the part of you that makes the decision to act, or not to act. This system determines your overall motivation to obtain food, based on a variety of internal and external factors, for example hunger, the effort required to obtain food, and the sensory qualities of food/drink. These factors are recognized and processed by a number of specialized 'modules' in the brain, and forwarded to the reward system where the decision to eat, or not to eat, is made. Researchers divide food intake into two categories: 1) eating from a true energy need by the body (homeostatic eating), e.g. hunger, and 2) eating for other reasons (non-homeostatic eating), e.g. eating for social reasons or because the food tastes really good.
In the second post of the series, we explored how the brain regulates food intake on a meal-to meal basis based on feedback from the digestive system, and how food properties can influence this process. The integrated gut-brain system that accomplishes this can be called the satiety system.
In this post, we'll explore the energy homeostasis system, which regulates energy balance (energy in vs. energy out) and body fatness on a long term basis.
The Energy Homeostasis System
In the second post of the series, we explored how the brain regulates food intake on a meal-to meal basis based on feedback from the digestive system, and how food properties can influence this process. The integrated gut-brain system that accomplishes this can be called the satiety system.
In this post, we'll explore the energy homeostasis system, which regulates energy balance (energy in vs. energy out) and body fatness on a long term basis.
The Energy Homeostasis System
Tuesday, August 5, 2014
Can Hypothalamic Inflammation and Leptin Resistance be Reversed?
A new study by yours truly begins to address the key question: can hypothalamic inflammation and leptin resistance be reversed?
Leptin is the primary hormonal regulator of body fatness in the human body (1). Secreted by fat tissue, it acts in many places in the body, but its most important effects on body weight occur via the brain, and particularly a brain region called the hypothalamus. The hypothalamus is responsible for keeping certain physiological variables within the optimal range, including blood pressure, body temperature, and body fatness.
In obesity, the brain loses its sensitivity to leptin, and this causes the body to begin 'defending' a higher level of body fatness, analogous to how a person with a fever 'defends' a higher body temperature (1). Once a person has become obese, it's difficult to return to true leanness because this system vigorously opposes major fat loss. Leptin resistance makes fat loss more difficult.
In rodent models, leptin resistance is caused at least in part by inflammatory signaling in the hypothalamus. We can observe this in multiple ways, but one common way is to look at the appearance of specific cells in the brain that change number, size, and shape when inflammation is present (2). These cells are called microglia and astrocytes. In addition to the work in rodents, we've published preliminary evidence that these same inflammatory changes occur in the hypothalamus of obese humans (2).
A key question is whether or not these inflammatory changes can be reversed. Is a person with leptin resistance doomed to have it forever, undermining fat loss efforts for the rest of his or her life? Or can it be corrected, possibly allowing easier and more sustainable fat loss? We just published a study in Endocrinology that begins to answer this question, using a mouse model of dietary obesity (3). I'm co-first author of this study along with my colleague Kathryn Berkseth, MD. My former mentor Mike Schwartz, MD is senior author.
The Study
Leptin is the primary hormonal regulator of body fatness in the human body (1). Secreted by fat tissue, it acts in many places in the body, but its most important effects on body weight occur via the brain, and particularly a brain region called the hypothalamus. The hypothalamus is responsible for keeping certain physiological variables within the optimal range, including blood pressure, body temperature, and body fatness.
In obesity, the brain loses its sensitivity to leptin, and this causes the body to begin 'defending' a higher level of body fatness, analogous to how a person with a fever 'defends' a higher body temperature (1). Once a person has become obese, it's difficult to return to true leanness because this system vigorously opposes major fat loss. Leptin resistance makes fat loss more difficult.
In rodent models, leptin resistance is caused at least in part by inflammatory signaling in the hypothalamus. We can observe this in multiple ways, but one common way is to look at the appearance of specific cells in the brain that change number, size, and shape when inflammation is present (2). These cells are called microglia and astrocytes. In addition to the work in rodents, we've published preliminary evidence that these same inflammatory changes occur in the hypothalamus of obese humans (2).
A key question is whether or not these inflammatory changes can be reversed. Is a person with leptin resistance doomed to have it forever, undermining fat loss efforts for the rest of his or her life? Or can it be corrected, possibly allowing easier and more sustainable fat loss? We just published a study in Endocrinology that begins to answer this question, using a mouse model of dietary obesity (3). I'm co-first author of this study along with my colleague Kathryn Berkseth, MD. My former mentor Mike Schwartz, MD is senior author.
The Study
Friday, May 13, 2011
Healthy Skeptic Podcast and Reader Questions
Chris Kresser, Danny Roddy and I just finished recording the podcast that will be released on May 24th. It went really well, and we think you'll find it informative and maybe even practical!
Unfortunately, we only got around to answering three of the questions I had selected:
Unfortunately, we only got around to answering three of the questions I had selected:
- How does one lose fat?
- What do I (Stephan) eat?
- Why do many people gain fat with age, especially postmenopausal women?
Thursday, July 10, 2014
Upcoming Talks
I have two talks planned over the next two months. Hope to see you there!
Ancestral Health Symposium 2014: UC Berkeley, August 7-9
If you want to understand the most rigorous science available on leptin resistance-- a key mechanism of obesity and a major barrier to fat loss-- this talk is for you. This is my primary area of professional expertise; I have years of firsthand research experience on the subject and I've published a number of related papers in peer-reviewed journals. The talk will be accessible to nearly all levels of expertise. AHS14 tickets are available here. I've pasted the talk's abstract below.
What Causes Leptin Resistance?
Leptin is the primary hormonal regulator of body fatness. Obese people exhibit a resistance to leptin’s effects in the brain, causing the brain to oppose fat loss by multiple mechanisms. Research in animal models suggests that leptin resistance may be required for obesity to develop. How does leptin resistance occur, and what causes it? Research has not yet provided us with definitive answers, but several plausible possibilities have emerged. This talk will review what is known about leptin resistance and its causes.
McDougall Advanced Study Weekend: Santa Rosa, CA, September 5-7
Dr. John McDougall invited me to speak at his yearly symposium after viewing my TEDx talk "The American Diet: a Historical Perspective". I look forward to sharing my thoughts and interacting with a different audience than I'm used to. The talk will be an expanded version of the one I presented at AHS13. Tickets are available here. I've pasted a modified version of my AHS13 abstract below.
Insulin and Obesity: Reconciling Conflicting Evidence
The pancreatic hormone insulin regulates the trafficking and metabolism of carbohydrate and fat, and its secretion is particularly stimulated by carbohydrate and protein. Since circulating insulin is elevated in common obesity, and insulin influences fatty acid flux into and out of fat tissue, this has raised the possibility that elevated insulin causes common obesity, and that dietary carbohydrate is particularly fattening. A large amount of evidence appears to support the hypothesis that insulin causes obesity, and a large amount of evidence appears to falsify it. This presentation will outline a framework capable of reconciling this seemingly conflicting evidence.
Ancestral Health Symposium 2014: UC Berkeley, August 7-9
If you want to understand the most rigorous science available on leptin resistance-- a key mechanism of obesity and a major barrier to fat loss-- this talk is for you. This is my primary area of professional expertise; I have years of firsthand research experience on the subject and I've published a number of related papers in peer-reviewed journals. The talk will be accessible to nearly all levels of expertise. AHS14 tickets are available here. I've pasted the talk's abstract below.
What Causes Leptin Resistance?
Leptin is the primary hormonal regulator of body fatness. Obese people exhibit a resistance to leptin’s effects in the brain, causing the brain to oppose fat loss by multiple mechanisms. Research in animal models suggests that leptin resistance may be required for obesity to develop. How does leptin resistance occur, and what causes it? Research has not yet provided us with definitive answers, but several plausible possibilities have emerged. This talk will review what is known about leptin resistance and its causes.
McDougall Advanced Study Weekend: Santa Rosa, CA, September 5-7
Dr. John McDougall invited me to speak at his yearly symposium after viewing my TEDx talk "The American Diet: a Historical Perspective". I look forward to sharing my thoughts and interacting with a different audience than I'm used to. The talk will be an expanded version of the one I presented at AHS13. Tickets are available here. I've pasted a modified version of my AHS13 abstract below.
Insulin and Obesity: Reconciling Conflicting Evidence
The pancreatic hormone insulin regulates the trafficking and metabolism of carbohydrate and fat, and its secretion is particularly stimulated by carbohydrate and protein. Since circulating insulin is elevated in common obesity, and insulin influences fatty acid flux into and out of fat tissue, this has raised the possibility that elevated insulin causes common obesity, and that dietary carbohydrate is particularly fattening. A large amount of evidence appears to support the hypothesis that insulin causes obesity, and a large amount of evidence appears to falsify it. This presentation will outline a framework capable of reconciling this seemingly conflicting evidence.
Saturday, January 30, 2016
Testing the Insulin Model: A Response to Dr. Ludwig
Dr. David Ludwig, MD, recently published a response to my critique of the carbohydrate-insulin-obesity hypothesis. This is good because he defends the idea in more detail than I've encountered in other written works. In fact, his piece is the most scientifically persuasive defense of the idea I can recall.
Before we dig in, I want to emphasize that this is science, not tribal warfare. The goal is to arrive at the best answer, rather than to win an argument. I'm proceeding in good faith, based on my belief that Ludwig and I are both serious people who care about science and human health, and I hope my audience will do the same. That said, let's get to it.
Before we dig in, I want to emphasize that this is science, not tribal warfare. The goal is to arrive at the best answer, rather than to win an argument. I'm proceeding in good faith, based on my belief that Ludwig and I are both serious people who care about science and human health, and I hope my audience will do the same. That said, let's get to it.
Tuesday, May 10, 2016
Why some dogs (and humans) are born hungry
The brain is the central regulator of appetite and body fatness, and genetic variation that affects body fatness tends to act in the brain. One important site of variation is the POMC gene, which codes for a signaling molecule that suppresses food intake. A new study shows that Labrador retrievers often carry an inactive version of the POMC gene, causing them to be highly food motivated, obesity-prone-- and perhaps more easily trainable.
Friday, October 28, 2011
The Brain Controls Insulin Action
Insulin regulates blood glucose primarily by two mechanisms:
- Suppressing glucose production by the liver
- Enhancing glucose uptake by other tissues, particularly muscle and liver
Thursday, August 25, 2011
A Roadmap to Obesity
In this post, I'll explain my current understanding of the factors that promote obesity in humans.
Heritability
To a large degree, obesity is a heritable condition. Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1). However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2). How do we reconcile these two facts? By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors. In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain. As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment. This idea received experimental support from an interesting recent study (3).
Heritability
To a large degree, obesity is a heritable condition. Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1). However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2). How do we reconcile these two facts? By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors. In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain. As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment. This idea received experimental support from an interesting recent study (3).
Monday, January 3, 2011
Paleolithic Diet Clinical Trials, Part V
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.
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.
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.
Thursday, January 24, 2013
Comment Published in Nature
I recently read an opinion piece by Gary Taubes in the scientific journal Nature, titled "Treat Obesity as Physiology, not Physics", in which he promoted NuSI and repeated the statement that obesity research is a "house of cards" because it focuses on calories in/out, at the expense of studying the "hormonal regulatory disorders" underlying obesity (1). I wrote a letter to the editor in response to Taubes's commentary, which has been published in Nature (2).
I'm used to seeing these kinds of claims in the popular press at this point, but to see it published in a scientific journal is galling (even if it's in the opinion section). This is the equivalent of a person who has never held an ax telling a group of lumberjacks they need to focus on cutting trees. It's part of a disturbing trend of popular writers in the low-carb and Paleo world attacking researchers, and even entire fields of research, they have little understanding of. Of course this only applies to a minority of the community, but this argumentation style smells of desperation and reflects poorly on the community as a whole.
I'm used to seeing these kinds of claims in the popular press at this point, but to see it published in a scientific journal is galling (even if it's in the opinion section). This is the equivalent of a person who has never held an ax telling a group of lumberjacks they need to focus on cutting trees. It's part of a disturbing trend of popular writers in the low-carb and Paleo world attacking researchers, and even entire fields of research, they have little understanding of. Of course this only applies to a minority of the community, but this argumentation style smells of desperation and reflects poorly on the community as a whole.
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