Monday, November 21, 2011
Several types of mitochondrial defects have been observed. These are summarized by M.M. Rogge and by J.A. Houmard in their review articles. (The picture above comes from the Rogge article.) Both reviews cite a 2002 study by Kelley et al. that used electron microscopy to show a 35% decrease in skeletal muscle mitochondrial area in obese vs. lean subjects. In some obese subjects, but not lean subjects, there were also large vacuoles which appeared to be degenerated mitochondria. Obese subjects also tended to have mitochondria with less clearly defined inner structure and narrower cristae.
The reviews also cite a 2005 study by Ritov et al. showing lower mitochondrial DNA content (fewer mitochondria) in obese subjects and reduced electron transport chain activity of the mitochondria, even after adjustment for the reduced mitochondrial content. This is consistent with a number of studies that show an increase in activity of certain glycolytic enzymes and a decrease in activity of other enzymes related to oxidative function in obese vs. normal-weight subjects. (See the two review articles for lots of references.) One of the important enzymes that has a lower activity in obese subjects is carnitine palmitoyltransferase 1 (CPT1, the smallest green rectangle in the drawing above), the enzyme that regulates and facilitates the entry of long-chain fatty acids into the matrix of the mitochondria.
To summarize, there are several possible reasons that obese people may have a harder time oxidizing fatty acids than they should. (1) They have fewer mitochondria. (2) They have smaller mitochondria. (3) Their mitochondria have structural problems that are visible by electron microscopy, and some of their mitochondria may even have degenerated completely. (4) Their mitochondria have reduced oxidative activity.
So far, I have painted a fairly bleak picture. It’s even bleaker when you read the articles I’ve referenced and realize that while metabolic flexibility is poor in obese people, it’s even worse in people with type 2 diabetes. (I’ve cited only the lean vs. obese in this discussion, but many of my citations also include a type II diabetes group as well, and these typically perform worse than the obese subjects do.)
It’s possible that some people have a genetic predisposition against metabolic flexibility. However, because obesity and type 2 diabetes become more prevalent with increasing age, it’s also possible that we are gradually poisoning our mitochondria, so that our surviving mitochondria are the ones that prefer to metabolize carbohydrates. These survivors not only tend to shunt fatty acids into storage, but they also resist metabolizing the fatty acids that are mobilized out of storage between meals. Our low energy production (and the easy availability of food) encourages us to eat more carbohydrate to provide the ATP we need for daily life. We could propose various possible mechanisms for gradual mitochondrial poisoning but at this point it is only speculation. In any case, we can’t change our genetics, and we can only hope that what we currently call a healthy lifestyle is genuinely healthy for our mitochondria.
On the positive side, there do seem to be a few things we can do to improve our metabolic flexibility. The first of these is mild-to-moderate exercise. In 2007 Solomon et al. described a 12-week program of moderate aerobic exercise in older obese people that improved (decreased) their respiratory quotient by 0.04. In 2010 Meex et al. asked older male type 2 diabetics to exercise twice a week for 30 minutes on a cycling ergometer and to perform resistance exercise once a week. Before the training program, their metabolic flexibility was about 60% of that of a group of matched controls. After twelve weeks, their metabolic flexibility was the same as that of the control group, and the protein content of their electron transport chain proteins had increased by 275%.
It is possible that more vigorous exercise may not be as helpful as mild-to-moderate exercise for restoration of metabolic flexibility. When the body’s AMP to ATP ratio increases, it activates adenosine monophosphate (AMP) kinase. In order to restore high ATP levels, the AMP kinase does a number of things including downregulation of physical activity and upregulation of feeding behavior. Because of this, it may be necessary for a mitochondrially impaired individual to titrate their exercise so that there is just enough to promote mitochondrial flexibility but not so much that it would cause an AMP kinase-mediated drive to eat more and exercise less.
Once metabolic flexibility is somewhat restored, it is important to take advantage of it. Because carbohydrate will always be metabolized first, it makes sense to decrease the availability of this substrate to the mitochondria. Meals should be low in carbohydrate, moderate in protein and relatively high in fat, to keep the mitochondria in fat oxidation mode as much as possible. Snacks should be avoided because each time carbohydrate is consumed, it moves to the front of the line in the mitochondrial queue. (For an interesting discussion of the effect of exercise, high-fat meals and improvement of the respiratory quotient in healthy young men, see Smith et al.)
As mentioned earlier, carnitine palmitoyltransferase 1 (CPT1) is a major control point for the entry of long-chain fatty acids into the mitochondrion. A third strategy for improving fatty acid oxidation is to circumvent CPT1 by consuming medium-chain fats like coconut oil and butter, rather than fats that contain long-chain fatty acids. Medium-chain fatty acids are metabolized differently than long-chain fatty acids because they can diffuse across plasma membranes without the help of transporter proteins. Thus, they can find their way into the mitochondrial matrix and present themselves to the beta oxidation machinery, to the TCA cycle, and to the electron transport chain without the need to deal with gatekeeper CPT1 proteins that are either downregulated or present in insufficient amounts. According to Houmard, circumvention of the CPT1 chokepoint may be helpful in increasing fatty acid oxidation and decreasing insulin resistance. However, this line of reasoning involves a fair amount of handwaving and probably needs a clinical study or two to back it up.
There it is. Mitochondrial dysfunction may be a plausible explanation for some forms of obesity. If mitochondria fail to oxidize fatty acids, both ingested and de-novo synthesized fatty acids will be preferentially routed to and will tend to remain in storage. The fact that weight loss by itself does not improve fatty acid oxidation in mitochondria explains why it is so easy to regain weight on a diet that is fairly high in carbohydrate. The fact that mitochondrial defects can be accumulated over time explains why a person can eat all sorts of foods and remain a normal weight while he or she is young, but when middle-age approaches, as often as not, so will the middle-age spread.
There are lots of other explanations for obesity, and this may not be a definitive one. But if you suspect that it might apply in your own case, it may be worth it to try (1) a mild-to-moderate level of exercise, (2) a low-carb, moderate-protein, high-fat diet and (3) replacing some of the long chain fatty acids you've been eating with medium chain ones. Enjoy that exercise machine or walking program and bon appétit!
Tuesday, November 15, 2011
Mitochondria are granular organelles found in the cytoplasm of most eukaryotic cells. They have an outer membrane, and a multiply-folded inner membrane. Inside the second membrane is a viscous matrix containing a large number of proteins used to produce energy for the cell. The picture of a mitochondrion above comes from a 2009 review article by M.M. Rogge, The role of impaired mitochondrial lipid oxidation in obesity. If you click on the picture to open it in a new window, it will be easier to follow this discussion.
The brown elliptical line represents the outer membrane of the mitochondrion. The gray area is a somewhat schematic representation of the inner membrane. That membrane actually follows the folds (cristae) surrounding the white matrix, but this level of detail would make the picture confusing. Just say that the gray area is the inner membrane. The whole mitochondrion resides inside the cytosol of the cell, which, as you will recall, has a cell membrane of its own.
At the top of the picture are three columns, representing the three macronutrients available to cells: Triglycerides (fats), Glucose (representative of carbohydrates) and Amino Acids (from proteins). These have already made their way inside the cell and are presenting themselves to the mitochondrion as potential sources of cellular energy.
(1) Triglycerides have to be broken down to free fatty acids and then converted to fatty acyl-CoA in order to cross the two membranes and enter the mitochondrial matrix. There they are converted to many two-carbon units of acetyl-CoA by beta oxidation and produce some energy. The two-carbon acetyl-CoA units are converted to more energy by feeding into the TCA/citric acid/Krebs cycle, illustrated at the center of the mitochondrion. High-energy molecules are produced (NADH and FADH2), and these go to the respiratory chain that resides in the inner mitochondrial membrane. This is represented by the yellow ovals labeled I, II, III and IV at the bottom of the drawing. The respiratory chain uses NADH and FADH2 to produce ATP, which in turn provides energy for the cell.
(2) Glucose is first broken down by glycolysis into two molecules of pyruvate in the cytosol. The pyruvate is transported across both of the mitochondrial membranes and is converted to two of the two-carbon acetyl-CoA units in the matrix. Just like the acetyl-CoAs from free fatty acids, the two acetyl-CoAs from a molecule of glucose feed into the TCA cycle and ultimately produce ATP through the respiratory chain.
(3) Amino acids are also converted into forms that can cross the mitochondrial membranes and feed into the TCA cycle. This is presented for completeness, but will not be discussed in detail.
When a meal of fats and carbohydrates is eaten, both substances are taken up into cells. Although both macronutrients are available to be converted into energy, typically the mitochondrion will use the carbohydrate first. The insulin that is secreted in response to carbohydrate ingestion inhibits fatty acyl-CoA oxidation and routes fatty acyl-CoA toward fat synthesis in the cytosol. Insulin enhances glucose oxidation by upregulating the enzyme that converts pyruvate to acetyl-CoA and feeds it into the TCA cycle. By a multistep feedback mechanism this also inhibits carnitine palmitoyltransferase 1 (CPT1, the smallest green rectangle in the drawing), the enzyme that mediates the transport of fatty acids into the mitochondrial matrix.
In normal cells after an hour or two, insulin will decline and less glucose will be available to the mitochondrion. Free fatty acids will still be present in the cytosol and will finally be allowed to transit as fatty acyl-CoA into the mitochondrion via carnitine palmitoyltransferase 1. Once inside the matrix, they will produce energy through beta oxidation, the TCA cycle and the respiratory chain. This is called metabolic flexibility. When carbohydrate is present, the mitochondrion will preferentially use carbohydrate. When free fatty acids are present but carbohydrates are in short supply, the mitochondrion will normally switch over to using fatty acids for fuel.
Mitochondria use different amounts of oxygen when they metabolize carbohydrates and fats. This is expressed as the Respiratory Quotient (RQ) or the Respiratory Exchange Ratio (RER). When carbohydrate is used as fuel, more CO2 is produced for a particular amount of oxygen consumed and the RQ is higher. The RQ number for pure carbohydrate is approximately 1.0. When fat is used for energy, less CO2 will be produced for a particular amount of oxygen and the RQ will be lower. The RQ for pure fat is about 0.7. The RQ for protein varies with the specific amino acid content but is about 0.8. Now we get to the meat (pun intended) of the matter.
Impaired metabolic flexibility
Since the early 1990’s, evidence has been accumulating that obese individuals have a depressed ability to oxidize free fatty acids in skeletal muscle. It further appears that defects in the mitochondria of skeletal muscle are responsible for this impaired lipid oxidation. Two review articles that discuss these phenomena are Intramuscular lipid oxidation and obesity by J.A. Houmard and The role of impaired mitochondrial lipid oxidation in obesity by M.M. Rogge.
It is possible to measure the relative use of carbohydrate or fat for fuel by the mitochondria by measuring the Respiratory Quotient. However, it is also possible to measure the ability of mitochondria to oxidize fatty acids by infusing radiolabeled palmitate (a free fatty acid or FFA) into a patient and subsequently measuring the appearance of radiolabeled CO2 as an indication that the palmitate has been oxidized.
Even pre-obese subjects may be destined for fatness because their mitochondria prefer to oxidize carbohydrates rather than fats. Rogge cites two longitudinal studies (Zurlo et al., 1990 and Seidel et al., 1992) that indicate that normal weight subjects who demonstrated preferential oxidation of carbohydrates rather than fatty acids were more likely to gain weight over time. However, these findings were not supported in a subsequent longitudinal study published by Katzmarzyk et al. in 2000. It is possible that some of us are doomed to become fat because we start our lives with mitochondria that prefer to oxidize carbohydrates and oxidize fatty acids relatively poorly. Or not. The data from the literature is not overwhelming on this.
To be continued…
That’s probably enough for this time. I have a bunch more to say, but there is a limit to how much science can be absorbed at one sitting. I do promise that it won’t be two months before I publish Part Two: How can defective mitochondria explain the difficulty some people have with the oxidation of fatty acids and what can be done about it?
Tuesday, September 6, 2011
The human brain evolved to deal with a certain range of rewarding experiences. It didn't evolve to constructively manage strong drugs of abuse such as heroin and crack cocaine, which overstimulate reward pathways, leading to the pathological drug seeking behaviors that characterize addiction. These drugs are "superstimuli" that exceed our reward system's normal operating parameters. Over the next few posts, I'll try to convince you that in a similar manner, industrially processed food, which has been professionally crafted to maximize its rewarding properties, is a superstimulus that exceeds the brain's normal operating parameters, leading to an increase in body fatness and other negative consequences.In other words, when the brain perceives that a food is highly palatable or provides excessive food reward, a superstimulative effect will cause overall caloric intake to increase and will raise the bodyweight setpoint.
After a considerable back and forth between Stephan and his readers, he finally put up a summary post, Roadmap to Obesity. He concluded, "The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat. Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role."
The blog you are currently reading subscribes to the carbohydrate hypothesis of obesity. Here it is as described by Gary Taubes:
This alternative hypothesis of obesity constitutes three distinct propositions. First, as I've said, is the basic proposition that obesity is caused by a regulatory defect in fat metabolism, and so a defect in the distribution of energy rather than an imbalance of energy intake and expenditure. The second is that insulin plays a primary role in this fattening process, and the compensatory behaviors of hunger and lethargy. The third is that carbohydrates, and particularly refined carbohydrates-- and perhaps the fructose content as well, and thus perhaps the amount of sugars consumed-- are the prime suspects in the chronic elevation of insulin; hence, they are the ultimate cause of common obesity.Briefly summarized, the low-food-reward diet consists of simple foods such as gently cooked tubers, meats and vegetables. It minimizes added fats, added sugars, and added flavorings including salt, herbs and spices. The macronutrient breakdown is high carb, adequate protein and low fat. The low-carb diet consists of foods that are low in carbohydrate, moderate in protein and fairly high in fat. The use of salt is permitted and the use of herbs and spices is encouraged. Whole foods and natural foods are preferred, but many low-carbers also include low-carb food products such as protein shakes, protein bars and diet soda.
Okay, that's enough with the background. Superficially, if people are eating healthy whole foods, they should be healthy, right? So what's the problem? There are several of them.
Problem One--Cause and Effect
The low-food-reward diet assumes that food is similar to a drug. When palatable food is eaten, dopamine D2 receptors are stimulated and down-regulated in a manner similar to that seen in drug addiction. According to Johnson and Kenny in a 2010 rat study, "overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating."
While this may be true in rats, it seems a bit extreme in humans. One does not see addicted fatties mugging people or robbing houses to support a Twinkie habit. Indeed, a person who has just gorged on Twinkies does not present with the symptoms of, say a cocaine user. For 15-60 minutes after the ingestion of cocaine, a person will experience alertness, confidence, euphoria and high energy. A person who has overdosed on Twinkies will tend to experience quiet contentment and lethargy. While both drug-addicted people and people with obesity are observed to have lower than normal levels of the dopamine D2 receptor, it is possible that the causes of this condition are different. The real-world behaviors seen in drug addicts with low dopamine D2 receptors are certainly different from those in food-rewarded people with low dopamine D2 receptors.
The low-carb diet assumes that carbohydrate ingestion prompts a release of insulin by the pancreas in order to maximize storage and utilization of the glucose that will shortly be entering the circulation. Insulin is a hormone that acts through a transmembrane receptor on the surface of most cells. When insulin is present in high concentration and/or for long periods of time, insulin receptors are downregulated. This produces a condition called insulin resistance, meaning that a higher concentration of insulin will be required to effect insulin signaling in a particular cell. In the short term, insulin resistance is reversible. Just lower the blood insulin for several hours or days and eventually the usual number of insulin receptors will return to the cell surface. However, when insulin has been kept chronically high for years, the resilience of the system goes away. Eventually, insulin resistance becomes a constant feature. The liver resists turning off gluconeogenesis. Muscles resist taking up glucose. In most people, fat cells remain insulin responsive, but eventually they too bcome resistant to fat storage and will release free fatty acids from fat depots.
It is not certain that chronic high insulin alone produces insulin resistance. For instance, genetic susceptibility and inflammatory processes may also play a role. However, once the symptoms of insulin resistance are observed clinically, taking steps to reduce chronic high insulin will permit at least a partial recovery of insulin sensititivity. Not coincidentally, these actions will also cause the loss of fat while sparing the loss of lean muscle mass.
Problem Two--Scientific Training
In general, people with PhDs come to science in a way that differs from MDs. They are taught to break down large questions into small pieces and to look at differences between carefully controlled groups. They use dishes of cells, strains of rodents, and matched groups of human subjects. This makes it easier to see significant changes between groups that differ only (one hopes) because of the treatment variable. However, PhDs must always be careful to remember that their conclusions may not be valid outside the tissue type/rodent strain/particular human subjects they have studied. Scientific studies of this type are useful because they provide guidance about what might work to treat a particular condition or disease. They do not provide absolute truth about what must work to treat a particular condition or disease.
Unlike PhDs, MDs tend to be found in a clinical rather than an academic setting. While MDs are interested in scientific studies, they must also be aware that what works on paper may not be particularly successful when treating patients. The body has lots of counterregulatory systems, and what takes place in an isolated dish of cells may be prevented from happening the context of an entire organism. What is true for a particular type of rat may not follow the physiology of a human being. What happens in the short term in a controlled environment for a selected group of people may not be the case for a large number of free-range humans. MDs in active practice will tend to gravitate toward approaches that are successful for their patients, particularly if they are treating patients with similar conditions. Examples of this in the low-carb community are Robert Atkins in the treatment of obesity, the Drs. Eades in the treatment of obesity, Richard Bernstein in the treatment of diabetes and William Davis in the treatment of coronary heart disease.
Problem Three--Practical Experience
The idea of a low-food-reward diet has apparently been around at least since 1965 when Hashim and Van Itallie used a feeding machine that dispensed bland liquid food through a straw. They noted that morbidly obese volunteers lost a great deal of weight on that regimen. However, no follow-on studies were published. Many other diets have come and gone in the interim, including the standard low-fat diet promoted by much of the medical community, and none of these has been particulary successful.
A possible exception to this rule has been the low-carb diet. Starting with the publication of Dr. Atkins' Diet Revolution in 1972, the low-carb diet in one form or another has been found to be useful in weight loss and in the promotion of various aspects of good health such as decreased blood pressure, decreased blood glucose and improvement in other metabolic markers. (See here for a summary of three articles in top-tier scientific journals.) Judging by comments in health-related blogs, this has been the anedotal experience of many ordinary people who have tried the low-carb lifestyle. Nearly 40 years after Dr. Atkins wrote his book, there appears to be good evidence that low-carb eating provides lasting benefits with regard to weight loss and health.
Several commenters say that they have tried the low-food-reward approach to eating and have been successful with it. This may be true in the short term. In the long term, it remains to be seen whether following a low-food-reward diet will be of benefit in people who have eaten the standard American diet for 20 to 50 years, in people with type 2 diabetes, in people who have heart disease and/or in people who lose weight and then attempt to maintain the weight loss over many years. It might work in theory. We will need to wait several decades to see if it works in practice.
An excellent comparison of the food reward and the carbohydrate hypotheses of obesity can be found at Peter's Hyperlipid blog. Peter has much more training and experience in physiology than I do, and he presents several very important refutations of journal citations that seem to discredit the carbohydrate hypothesis. It may take a couple of readings to absorb his point-by-point analyses, but it will be very much worth the time invested.
Monday, May 30, 2011
On May 31 hubby and I leave for a 14-day vacation in Northern Europe. I will have limited access to the internet, so go ahead and leave comments if you wish, but they may end up in comment limbo for a fairly long time. I probably won't be able to respond to questions very well, and you may have to wait until I return to get a detailed answer.
While I'm gone, I'll give you something to think about. During the last few days I've been having fun over at Stephan Guyenet's Whole Health Source blog. Commenters have been discussing his post on Food Reward: a Dominant Factor in Obesity, Part IV and have started thinking about the effect of leptin on the prevention of weight regain following a significant weight loss. Commenter ItsTheWooo2 has lost over 160 pounds but is now faced with the lifelong challenge of maintaining that weight loss. She noticed that when she began taking injectable synthetic leptin as an experimental treatment for hypothalamic amenorrhea, the leptin made it much easier for her to stay at her goal weight. Wooo has some rather strong opinions, but she also explains herself well, and the comments are worth reading if you have the time.
During the discussion, Stephan mentioned the work of Rudolph L. Leibel at Columbia University. Conveniently, one of the commenters gave a link to a blogpost summarizing Dr. Leibel's work on lepin, Why is it so Hard to Maintain a Reduced Body Weight? The blogger, Arya M. Sharma, M.D., has a couple of followup posts entitled Why Hyperleptinemia is Not Leptin Resistance and Using Leptin to Treat Obesity.
If you would like to look at some of the primary literature on the topic, here are several articles: Low Dose Leptin Administration Reverses Effects of Sustained Weight-Reduction on Energy Expenditure and Circulating Concentrations of Thyroid Hormones
, Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight , and Leptin reverses weight loss–induced changes in regional neural activity responses to visual food stimuli .
It has been nearly ten years since the first of these studies was published. One wonders why such an efficatious drug is not being prescribed far and wide for the maintenace of weight loss. According to Dr. Sharma, this has to do with a peculiarity in the regulations of the FDA. Drugs can be licensed for weight loss, but except in extremely rare cases, leptin does not work for weight loss. However, the FDA does not recognize a need for drugs to preserve weight loss once it has happened. Leptin is a drug that works for a condition that the FDA does not believe exists. The FDA does not understand that, while weight loss is hard, weight maintenance is even harder. If you think that synthetic leptin might help you hold on to your hard-won weight loss, it might be time to send the FDA a letter.
Tuesday, May 17, 2011
If you have done much reading about the low-carb lifestyle, you have heard about insulin. Insulin is a hormone secreted by the pancreas after we eat carbohydrate or to a lesser extent when we eat protein. Insulin is important because it binds to the insulin receptor, which is found on the surface of most of the cells in the body. The figure above shows the surface of a cell with a molecule of insulin bound to its receptor.
The insulin receptor is made of four protein subunits. The two beta subunits pass from the exterior through the cell wall and into the interior of the cell. When insulin binds to its receptor, the receptor auto-activates and begins to affect a large number of signaling proteins that reside within the cell. As illustrated on the left side of the drawing, some of these proteins propagate growth signals to the nucleus of the cell. We’ll deal with those later. The proteins shown on the right side of the drawing transmit metabolic signals into the cell. Depending on the type of cell, this signaling cascade can cause the uptake of glucose and amino acids into the cell, the synthesis of glycogen in the cell, the synthesis of protein in the cell, the cessation of lipolysis in the cell and the inhibition of de novo glucose synthesis in the cell.
So far so good. Insulin is such a powerful hormone and it has so many effects that its absence is incompatible with life. However, an excess of insulin is not particularly good either. When too much insulin is present, the metabolic signaling cascade becomes too strong. The cells defend against excessive signaling by degrading some of their insulin receptors and by making fewer receptors to replace the ones that have been destroyed. Some of the intermediate signaling proteins are also downregulated in various ways. The cell is said to have become “insulin resistant.”
Normally insulin resistance is not a problem. As insulin levels fall, the synthesis and/or activation of signaling intermediates resumes and the cell becomes ready for the next onset of insulin release. In native cultures like the Inuit, where carbohydrate intake is low, the levels of blood insulin only rise a modest amount in response to ingested protein. In non-Westernized cultures like the Kitavans of Papua New Guinea, a large amount of carbohydrate is consumed, but it comes in the form of sweet potatoes, cassava, taro and yams. These people have a low fasting insulin that decreases with age.  Kitavans also have low obesity, low diastolic blood pressure, and low-to-no incidence of stroke or ischemic heart disease. If Kitavans can maintain insulin sensitivity and good health while eating a high carbohydrate diet, why should we even consider the challenges of attempting a low-carb diet?
What kinds of carbs?
The answer probably involves the types of carbohydrates we consume rather than the absolute percentage of carbohydrates in our diet. Post-800 AD, the Aztec consumed maize as their most important staple. They were known to suffer from dental problems, obesity and heart disease.[4, Comments] The ancient Egyptians ate bread and porridge made from wheat and used barley to make beer. They suffered from periodontal disease, and atherosclerosis was found in 60% of those who lived past age 40. In Good Calories Bad Calories (pp 89-97), Gary Taubes gives numerous examples of native peoples (Gabonese, South Africans, Native Americans, Melanesians) who did not experience chronic diseases such as obesity, diabetes and heart disease until after well-meaning explorers and settlers, beginning in about the middle of the nineteenth century, brought them large quantities of white flour and sugar.
Permanent insulin resistance
Although the proof is only inferential, it appears that carbohydrates such as refined grains, beer and sugar may have the ability to cause permanent insulin resistance in susceptible individuals who consume them. The effect is not immediate. For some reason, after years of eating these types of food, some people progressively lose the ability to reset their metabolic insulin response system. Muscle cells require more insulin to take up glucose. Liver cells require more insulin before they will stop making glucose through gluconeogenesis. It becomes harder to shut down lipolysis and it becomes more difficult to maintain muscle mass. On the other hand, the action of insulin as a growth signal is not impaired (see the left side of the figure above). A steady, high level of insulin produces proliferation and migration of vascular smooth muscle cells, and these in turn play an important role in diseases such as hypertension, atherosclerosis and cardiovascular disease.
It appears that once the metabolic insulin signaling system is broken, it cannot be repaired. It can be treated with drugs, or it can be managed by eating foods that minimize the release of insulin. For those who spend their lives eating the types of carbohydrates that indigenous peoples do, insulin is a good and faithful servant. It helps them metabolize and store their food for later use and performs a myriad of functions without causing insulin resistance. But for those who have spent too many years indulging in sugar, high-fructose corn syrup, refined grains, beer and other easily digestible carbohydrates, it may be necessary to switch to a diet that keeps insulin secretion at a minimum, i.e., a diet low in all kinds of carbs, in order to achieve and maintain a healthy lifestyle.
Sunday, April 3, 2011
Coconut oil is the stuff that used to make movie popcorn taste like movie popcorn. When somebody realized that coconut oil is 90% saturated fat, things changed in a hurry. Movie popcorn began to taste more like the cardboard tub it comes in, and coconut oil became hard to find. Recently coconut oil has come back into favor in the low-carb world, and it can be purchased in health food stores and even in grocery stores.
I began using coconut oil several years ago and noticed that when I did so, I was better able to control my weight. I didn't mind the taste too much, but I was no particular fan of it either. (Nutiva seems to me to be the best-tasting brand so that's what I buy, but there are many other extra virgin organic coconut oils on the market.)
About two months ago, as a sort of personal experiment, I began eating two tablespoons of coconut oil for breakfast. Just 250 calories of coconut oil, plus my supplements, seemed to hold me until lunch, which was a surprise. Not only that, I didn't seem to be quite as hungry during the rest of the day. Not only that, I seemed to do much better at weight maintenance than I have for many years. I was curious about why it worked, but didn't have the time to puzzle it out.
Then one day as I was reading an article over at the Heart Scan Blog, I happened upon a comment by Might-o'chondri-AL (#23 in the list). He explained that coconut contains a 12-carbon saturated fat called lauric acid, and that lauric acid upregulates the secretion of glucagon-like peptide (GLP-1). GLP-1 in turn increases satiety by slowing stomach emptying.
I checked out the fatty acid profile of coconut oil and found that, sure enough, it contains about 50% lauric acid. Next I did a Google search and found a journal article that backed up the rest of Might-o'chondri-AL's statements: Effects of intraduodenal fatty acids on appetite, antropyloroduodenal motility and plasma CCK and GLP-1 in humans vary with their chain length.
The article reported that in 2004 a group of investigators did a 90-minute duodenal infusion of water (control), capric acid (a saturated fatty acid with 10 carbon atoms) or lauric acid (a saturated fatty acid with 12 carbon atoms) into twelve healthy, normal-weight, male volunteers. They administered only 0.375 kcal/min in the treatment groups, but the contrast between the capric acid (C10) group and the lauric acid (C12) group was quite large.
By 45 minutes of infusion, plasma GLP-1 increased significantly and stayed high in subjects who received C12, while plasma GLP-1 in the C10 group was no different from control. (Remember, GLP-1 slows gastric emptying.) Cholecystokinin (CCK) is a peptide hormone that also produces satiety by decreasing the rate of gastric emptying. By 30 minutes, both C10 and C12 had increased CCK over control, but C12 did so to a greater extent. Gastro-duodenal motility was measured directly using a manometric catheter. Consistent with the GLP-1 and CCK levels, C12 suppressed both antral and duodenal pressure waves while C10 did not. Finally, at the conclusion of the infusion, subjects were offered a buffet meal. Subjects who had received C12 ate significantly less than those who had received C10 or water. In other words, intraduodenal infusion of lauric acid (C12) decreased gastric motility and suppressed the appetites of subjects who received it.
A 2010 review article by Little and Feinle-Bisset confirmed these findings and added a few more. The presence of fatty acids like lauric acid in the intestine (and possibly even in the mouth) stimulates the secretion of hormones that suppress gastric emptying (GLP-1, CCK, and peptide YY) as well as down-regulating the hunger hormone ghrelin. A lauric acid infusion also appears to be able to signal the brainstem and hypothalamus directly via the vagus nerve and a CCK receptor mediated pathway. In addition to all of that, lauric acid is classified as a medium chain fatty acid. Unlike longer-chain fatty acids, it can be absorbed directly from the gut, transported to the liver, and there be readily converted into ketone bodies and used for energy rather than for fat storage. Both in suppressing energy intake and in improving energy utilization, the lauric acid found in abundance in coconut oil looks like a good candidate to help with weight loss and weight maintenance.
To be fair, the Little and Feinle-Bisset review article goes on to state that some studies have shown that a high-fat diet or the presence of obesity may attenuate the effects of fat intake on slowing gastric emptying and decreasing energy intake. However, none of the studies they cite were done in the context of a low carbohydrate intake.
In any case, after reading these articles, I now understand why coconut oil seems to be such a help to me in weight maintenance. Whether that will hold true in the long term or whether it will work for other people is not certain, but for now personal experience seems to be backed by a fair amount of science.
Saturday, February 12, 2011
(This blogpost is mostly about me and not about science. For those who come here for the science, please feel free to skip it.)
As time passes, it becomes more and more obvious that the low-carb lifestyle offers many metabolic benefits. It reduces blood sugar and blood insulin, lowers blood pressure, decreases triglycerides and raises HDL cholesterol. For a summary of these effects, check out my blogpost reviewing three low-carb studies published in three well-respected journals.
Nevertheless, the reason most of us started doing low-carb was not for its health benefits but for weight loss. And unsurprisingly the three studies also showed that low-carbing works as well or better than other forms of dieting for weight loss and weight maintenance.
Nearly eight years ago I read Dr. Atkins' New Diet Revolution (DANDR)and was struck by the fact that his approach to dieting was based on solid science and was presented in a way that was easy to understand. Before long, I knew the book inside out and followed it to the letter. I did indeed make my goal weight and have (almost) maintained it since then. (For those who like to see if I practice what I preach, I report my weight weekly on the Maintain Lane at Low Carb Friends.) Recently I began re-reading DANDR and had a couple of thoughts that I'll share with those of you who are using the low-carb lifestyle to lose weight. You can decide if they're deep thoughts or not.
1. Low-carb is good for weight loss, but it's not perfect.
The low-carb boards on the internet are populated with hundreds of people who have lost some weight doing low-carb, but have not managed to make it to goal. It goes without saying that if you lose weight on low-carb, you have to keep doing low-carb or the weight will come right back. But why is it so hard for us to get all the way down to our goal weight even if we keep our carbs strictly below 20 or even very close to zero?
In DANDR, Dr. Atkins says to count carbs not calories. One of the reasons this works is that low-carbing produces what Dr. Atkins called a "metabolic advantage." As we change over from metabolizing carbs for energy to metabolizing fat for energy, our bodies perform somewhat inefficiently. If we use Ketostix, we'll see that we excrete a large amount of unused energy in the form of urinary ketones. We also tend to experience an increase in body temperature. However, after a year or so of low-carbing, we become fully keto-adapted and our bodies are able to utilize nearly every scrap of the energy we consume. The Ketostix no longer change color.
One of the things that doesn't change over time is that low-carbing keeps our insulin levels lower than they would be on a high-carb diet. This means that our bodies are better able to mobilize our stored fat, and we don't experience the constant hunger that results when we can't properly access our fat stores. In addition, foods that are high in fat and protein tend to satitate us much more quickly than do carb-rich foods. Finally, the ketosis produced by low-carbing has the wonderful side effect of decreasing our appetite.
So by counting carbs we can lose some weight, and we may even lose a large amount of weight. However, the sad truth is, Calories Count. In the long run, the number of calories we take in must be less than the number of calories we expend. Granted, when we low-carb we may be able to burn more calories than our peers thanks to a faster metabolism, a greater willingness to exercise, and the loss of ketone calories by excretion. But we can't fool Mother Nature. In order to lose weight, the calories in must be less than the calories out.
I had suspected this before, but just this week I've proven it to myself by using Dr. Atkins' Fat Fast. I have done low-carb and I've done zero-carb, but the most weight I could get off was a fraction of a pound a week. By doing the Fat Fast, I've stayed at 1000 calories per day and the weight has fallen off. Yes, it's nearly zero carbs, but as I said, I've done zero-carb and have lost weight at a snail's pace, if at all. What I haven't done before is intentionally cut my calories. To be sure, the Fat Fast is not a healthy long-term weight loss plan, but it does show that if carb counting alone isn't producing a weight loss, carb counting plus calorie counting is the next necessary step.
2. Too much protein can act like too many carbs.
While Dr. Atkins had lots to say about controlling our carb intake, for some reason he didn't warn his readers that eating too much protein can mimic the effect of eating too many carbs. People who have type 1 diabetes, or people who have type 2 diabetes and are using insulin, know something that most of the rest of us don't know. Eating excess protein raises your blood sugar.
Back in the summer of 2009 I wrote three blogposts on this topic: Protein Intake and Blood Glucose Levels, Observations on Protein Intake in Low-Carbers and How Can Eating Excess Protein Raise Blood Glucose? My readers participated in gathering data for these posts, and what we discovered was that when excess protein is consumed, it is converted to glucose. In younger people this did not show up on the blood glucose meter. In most cases they were able to secrete enough extra insulin to maintain a postprandial blood sugar in the vicinity of 85 mg/dl. However, in both low-carbers and zero-carbers over 50, it was not unusual to have a 30-40 mg/dl rise in blood glucose after consuming a large amount of protein.
Dr. Atkins did say that eating lots of protein has never been shown to cause kidney damage. And consuming good quality protein is essential to maintain our bones, muscles and organs. But for those of us who watch our carbs religiously, it's also important to watch our protein intake. A large excess of protein acts like carbs and can have a similar effect, especially in people who are prone to diabetes.
In closing, most of what Dr. Atkins said in his books has stood the test of time. But from my personal experience, a couple of points seemed to go missing. For those who are having a hard time making it to their goal weight, it might be helpful to consider (1) the importance of counting calories and (2) the carb-like effects that can be caused by excess protein intake.
Saturday, February 5, 2011
Thanks to the work of TV doctors, the American Heart Association and the American Diabetes Association, most Americans are convinced that a high fat intake is bad and exercise is good. As a result, knowledgeable Americans try to avoid fat and get at least some exercise. They eat meat that is as lean as possible, they use butter substitutes on their toast, and they do their best to emphasize high-fiber, low-cholesterol foods. They try to walk or jog regularly, and some even manage to buy memberships at a gym. How's that working out for us?
Not very well, according to a recent study in the British journal Lancet. The article carries the rather long title National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. The authors measured worldwide obesity in terms of BMI or body mass index, which compares a person's weight to his or her height. A BMI between 25 and 30 is considered overweight, and a BMI over 30 is considered obese.
Worldwide vs. U.S. obesity
The bottom line of the study was that, between 1980 and 2008, worldwide obesity has approximately doubled. For adult men, the percentage has gone from 4.8% to 9.8%. For adult women, the percentage went from 7.9% to 13.8%. And that wasn't all. Obesity-wise, America has left the average world citizen in the dust. In 2008, the number of obese American adults was not just one in ten. It was one in three.
Not only that, during nearly thirty years, the U.S. saw the fastest rise in BMI, about 1 full BMI point per decade, to an average BMI of 28 in 2008. In an interview, one of the lead authors of the study, Majid Ezzati of the Imperial College in London, suggested that remedies might include taxing sugar-containing foods and encouraging transportation by bicycle.
Some good news
Dr. Ezzati noted that, despite their increasing BMIs, the richer countries of the world had reduced average systolic blood pressure and average total cholesterol during the years of the study. This is surprising because, according to the National Health and Nutrition Examination Survey (NHANES), overweight and obesity raises the risk of hypertension and high LDL cholesterol. Dr. Ezzati suggested that improved screening and treatment, using less salt and eating unsaturated fats may have contributed to the decline in average blood pressure and cholesterol in the face of steadily increasing BMI. He did not give a relative value to each of these variables and did not note that the richest countries of the world tend to rely heavily on prescription drugs for the treatment of both hypertension and high cholesterol.
Even worse than the U.S.
Do you remember my first blogpost of 2011, suggesting that my readers observe the food choices of the people around them and the health status of the same individuals? The South Pacific island nation of Nauru provides some interesting data in that regard. The Lancet study noted that the people of Nauru have an average BMI of about 34, the highest in the world. Traditionally Nauruans ate ibija fish, coconuts (a very high-fat food) and the fruit of the pandanus tree. After phosphate was discovered on the island, they started selling it and using their income to buy Western foods. Today their most popular dish is chicken marinated in cola, fried, and accompanied by lots of Coke to wash it down. In 1991 the World Health Organization reported that half of Nauruan adults aged 30-64 had diabetes. Although Nauru has free health care, the life expectancy at birth is 59 for men and 64 for women.
Food for thought
One wonders if the rapid rise in obesity in the U.S. might be related to the media-promoted drive to shun fats and embrace carbohydrates, beginning in about 1970. Or if the amazing obesity rate of the Nauruan people may have something to do, not with fat alone, but with the addition of copious quantities of sugar to a fat-rich diet. Just observations, not proof. But it's something to think about.
Sunday, January 2, 2011
For the remainder of 2011, make mental notes of what your friends, relatives and acquaintances are eating.
You don't need to write anything down, but you can if you wish. Without staring or making comments, just start paying attention to what the people around you are eating and what they talk about eating. Do they tend to eat lots of foods that contain wheat flour? Do their preferred foods contain sugar or high fructose corn syrup? Or do they stick primarily to meat, cheese, eggs, nuts and vegetables? (Be sure to keep in mind that the purpose of this exercise is to gather data, not to confront people with their dietary sins.)
After you have a fairly good idea of everybody's dietary lifestyle, start to make notes about their health status.
This is the second stage of your data-gathering project. It will be fairly easy to see if people are a normal weight or if they are fat and getting fatter. Other information often comes out in conversation. Are they having trouble with high blood pressure? Do they complain of painful joints? Are they beginning to discuss issues that relate to the control of blood sugar? Or are they generally healthier than other people of their age?
As 2011 progresses, start to compare your two sets of data and see if you can detect any correlations.
Although I come to the discussion with preconceived ideas, this is your life and these are your data. We get messages from the TV, from our doctors and from the people around us about what food is good for us and what food isn't. Some of those messages spring from the profit motive and others come from dogma that we hold without knowing exactly why we hold it. This time you will be collecting your own data based on what you see, not on what somebody else tells you to see.
Seeing is believing
There it is -- a pain-free three-part resolution that could change your life. In 2011 simply begin to observe dietary choices and note which ones seem to correlate with good health and which ones don't. Correlation is not causation of course, but my guess is that 2011 will not be over before you start to make some long-term modifications in the way you eat. In so doing, you may well find that 2011 brings positive changes that you weren't even expecting.
Sunday, November 7, 2010
AIDS, the common cold, and measles are examples of diseases that are known to be contagious. A recent article in PLoS Computational Biology describes another medical condition that is contagious--obesity.
Obviously, obesity is not commonly thought of as a transmissible condition. Perhaps if you believe that you should feed a cold and starve a fever, there might be a contagious element to obesity, but that's stretching it. However, one of the authors of the PLoS article, Nicholas A. Christakis, had observed in an earlier article in the New England Journal of Medicine that members of the Offspring Cohort of the Framingham Heart Study were 57% more likely to become obese if they had a friend who became obese during a certain interval.
Obesity and social networks
Christakis and his colleagues showed the phenomenon of the person-to-person spread of obesity in a graphic that can be viewed here. While the obesity of siblings and the obesity of spouses had an effect on the obesity of participants in the Offspring Cohort, the most important social network tie for transmission of obesity was mutual friendship. Interestingly, geographic separation did not diminish this phenomenon.
An infectious model for obesity
In 1971, the obesity of the Offspring Cohort of the Framingham Heart Study was 14%. By the year 2001 it was 29% and was continuing to increase. (Obesity was defined as a BMI of 30 or more.) In 2010, in the PLoS article Infectious Disease Modeling of Social Contagion in Networks, Hill et al. took the information from the 7500 members of the Offspring Cohort and used it to formulate an infectious disease model of obesity that they called SISa.
As described in the SISa model, the infectious equation for obesity includes a spontaneous appearance factor. Some percentage of people will spontaneously or automatically become obese in a particular year. In the Offspring Cohort, the rate of spontaneous obesity began at 0.8% in 1971 and has increased to 1.9% in 2001.
The infectious disease model of obesity also includes a remission factor that describes percentage of people who transition from obesity to a BMI below 30. The remission factor was unchanged over 30 years and was about 4% per year.
Finally the model includes an interpersonal transmission rate. That rate has increased over the years, from 0.12% for each obese friend in 1971 to 0.5% per obese friend in 2001. In other words, if a member of the Offspring Cohort had more than four obese friends, he or she would have an increased likelihood of being obese in the next year.
Transmission of obesity
In a news story in Science Daily, Dr. Hill speculated that the non-social transmission of obesity may result from unhealthy foods or increasingly sedentary lifestyles. (She did not rule out possible dietary causes such as consumption of HFCS, industrial oils or grains.) For the Offspring Cohort, the non-social transmission rate seems to have leveled off at about 2%. However, the social-network transmission of obesity continues to increase and has several interesting aspects.
It appears that the more obese friends a person has, the more likely that person is to become obese. It is the absolute number of obese friends that matters, not the percentage of friends who are obese. Conversely, the number of normal-weight friends seems to have no effect on a person's ability to avoid obesity or to recover from obesity once it occurs.
The authors speculate that the increasing prevalence of obesity provides a positive feedback mechanism. People will have more friends who are obese and will become inclined to think that obesity is "normal." When they themselves start gaining weight, they may see no reason to avoid the weight gain because several people they know and respect carry an increased amount of weight.
If we live in a society that is becoming increasingly obese, and we want to remain at or attain a normal weight, do we want to avoid making friends who are obese? Obviously not. Perhaps it will be enough to know that having obese friends can subtly influence us to believe that obesity is normal or even necessary for us to fit in with our peers. With a certain amount of effort, perhaps we can learn to accept friends who are obese without compromising our own pursuit of a journey to good health.
Tuesday, October 26, 2010
Admit it. Low-carbing is hard. You have to keep a constant eye on what you're eating. And you have to cope with the fact that the people around you are keeping a constant eye on you--trying to figure out why you eat in such a nonconventional way. Wouldn't it be easier just to take a pill to lose weight? Unfortunately, promising weight-loss drugs have a history of regulatory approval followed by withdrawal because of serious side effects.
In 1973 fenfluramine, a mixture of two isomers, dexfenfluramine and levofenfluramine, was approved for weight loss by the FDA. In 1996 the dexfenfluramine isomer was approved for long-term weight loss. These compounds produced a small but measurable amount decrease in weight for the patients who took them. When Dr. Michael Weintraub combined fenfluramine with another mildly-effective product called phentermine in a combination popularly called "fen-phen," it produced as much as a 16% weight loss in a four-year clinical trial. Word spread, and thousands of patients began to request prescriptions.
Nonetheless, by 1997 a large number of adverse events had occurred, and the FDA decided to remove both fenfluramine and dexfenfluramine from the market. Up to twenty five percent of users had experienced heart valve hypertrophy, with the degree of pathology tending to correlate with the length of time the product had been taken. Pulmonary arterial hypertension was reported as well. A 1997 article from the New York Times describes the reactions of physicians who had known that the drugs might pose a small risk but felt that it was more than counterbalanced by the public health problem of rising obesity rates.
Serotonin receptor specificity
Because fenfluramine was able to produce anorexia, researchers began to investigate its properties. It was found to work nonselectively on receptors for serotonin, one of the body's most important signaling molecules. Serotonin (also known as 5-HT) has at least seventeen receptor genes that mediate everything from moods to gut motility. As discussed in a review article by Keith J. Miller, the 5-HT1B and 5-HT2C serotonin receptors are known to suppress appetite, and fenfluramine or its metabolite norfenfluramine appear to exert their anorectic effects through these receptors.
Unfortunately, norfenfluramine also acts nonselectively on 5-HT2A and 5-HT2B serotonin receptors which are located in human heart valves. In this location it acts as a growth factor and causes hypertrophy of the valves.
In recent years, investigators have attempted to formulate drugs that activate 5-HT2C serotonin receptor but have little or no effect on the 5-HT2A and 5-HT2B serotonin receptors. Lorcaserin was designed to work in this way, and after a year in one trial, patients taking lorcaserin had lost about 4 kg more than those in the placebo group. After two years they had lost an additional two kg and reported reduction in almost all measures of diabetes and cardiovascular risk.
Although lorcaserin did not increase the risk of valvular hypertrophy or pulmonary hypertension, in October 2010, the FDA rejected the new drug application because lorcaserin had increased the incidence of tumors in rats, specifically adenocarcinoma in mammary glands and astrocytoma in the brain. It is possible that growth of these tumors is mediated through one or more of the other 5-HT receptor subtypes, and that lorcaserin nonspecifically stimulates them.
Silbutramine (Meridia) is not a 5-HT receptor agonist, but it exerts a satiety effect by blocking the reuptake of serotonin by presynaptic nerve terminals. Unlike selective serotonin reuptake inhibitors (SSRIs), silbutramine does not act as an antidepressant. Unlike fenfluramine, it does not produce valvular hypertrophy or pulmonary hypertension. It does have measurable but minimal efficacy for weight loss and was approved for use by the FDA in 1997 for the management of obesity, including weight loss and maintenance of weight loss. Thirteen years later a six-year clinical trial (SCOUT) with approximately 10,000 patients was completed. In the silbutramine group, there was a 16% increase in the risk of a set of serious events, including non-fatal heart attack and stroke, compared with the placebo group. On October 8, 2010, the FDA asked Abbott Laboratories to voluntarily withdraw silbutramine from the U.S. market.
No magic bullets
Orlistat (Xenical/Alli) is still available as a pharmacologic treatment for weight loss. It does have side effects with social significance, particularly for those who are trying to live a low-carb lifestyle. On the positive side, as of this writing it does not appear to increase morbidity or mortality when used as directed. Unfortunately that doesn't seem to be the case for anti-obesity drugs that have serotonergic actions.
Pharmaceutical companies have a powerful motivation to develop drugs that will help with weight loss. However, if history is any guide, there is a high probability that drugs with initial promise will turn out to have serious adverse effects in the long run. In the meantime, there is growing evidence that the low-carb lifestyle offers us a non-drug way to lose weight and to maintain that loss. People have been doing low-carb safely since Dr. Atkins came out with his Diet Revolution in 1972. For those who prefer a non-anecdotal approach, more and more articles are being published that show an actual health advantage for the low-carb lifestyle.
Low-carb is not easy. But it isn't impossible either. Until scientists come out with a magic pill for weight loss, we can rejoice that we have found a way to cope with our own personal version of the obesity epidemic.
Tuesday, October 19, 2010
The short answer is yes, you can be fat and and not realize that you're fat.
A recent article in the Archives of Internal Medicine used data from the 2000-2002 Dallas Heart Study to describe this phenomenon. The full article (Body Size Misperception: A Novel Determinant in the Obesity Epidemic) is not yet available, but news descriptions of it are here, here and here. The authors have presented the data in powerpoint form here.
Misperception of body size
Researchers asked 2056 obese men and women to look at line drawings like those pictured above. The study participants were asked to choose the figure that looked the most like them. Although all of the participants met criteria for obesity, eight percent of them (14% of blacks, 11% of Hispanics and 2% of whites) did not consider themselves to be obese.
Let's take a moment to define our terms. Study patients did not have the benefit of the BMI values that are printed underneath each series of pictures. I've added those because I suspected that readers would like to take the test themselves and see (1) which figure they would choose and (2) which figure actually corresponds to their body size. (You can click on the pictures to enlarge them, if necessary.) If you don't know your BMI, it can be calculated here.
As obesity grows more common, it also becomes harder to pick out which figures are thin, normal and fat. Here are the definitions according to BMI:
- Underweight = BMI less than 18.5
- Normal weight = 18.5–24.9
- Overweight = 25–29.9
- Obese = BMI of 30 or greater
In the figures above, the only underweight figure is women's drawing 1. The overweight figures are drawings 5 & 6 of both sexes. The obese figures are drawings 7, 8 & 9 of both sexes. (Note that, in this context, "overweight" and "obese" have very specific definitions.)
Back to the Dallas Heart Study. Among the eight percent of obese study participants who misperceived their body size, 66% believed they were at low risk for obesity, even though they were already obese. Although those with and without body size misperception had equal probabilities of developing diabetes, heart disease and high blood pressure, those with body size misperception were significantly less aware of their risks for these conditions.
In practical terms, this meant that fifty six percent of obese subjects with body size misperception had seen a doctor in the past year. Of those, only 38-45% had discussed diet/habits, exercise or weight loss with their physician. By contrast, among the obese patients with accurate body size perception, 74% had seen a doctor in the past year and 64-68% had discussed such lifestyle issues with their physician. This suggests that obese people who do not realize their condition will get poorer medical care as a result of their misperceptions.
BMI and health risks
Not all causes of mortality can be related to obesity. A 2007 article in JAMA did an extensive analysis of the association of BMI with particular causes of death for the year 2004 in the United States. Researchers found that obesity was not related to increased deaths from cancer, respiratory disease or injuries. However, obesity was associated with increased mortality from cardiovascular disease and from diabetes and kidney disease. When all causes of mortality are considered, the graphs look like this (source article here):
Interestingly, these graphs show that a BMI of about 25 (between normal weight and overweight) seems to be the healthiest for long-term survival, and being underweight is actually unhealthy. However, the graphs do show that as obesity (BMI=30.0 or more) increases, all-cause mortality risk increases. For that reason, it pays to have an accurate idea of our body size, and to be willing to recognize that dealing with obesity could have a beneficial effect on our personal lifespan.
Monday, October 11, 2010
Winter is on its way. Leaves are changing color; daylight is diminishing. Another sign of impending winter is the temperature change, with coats and sweaters coming out of storage to accommodate the colder weather. But have you noticed that some people need sweaters in chilly weather while others don't?
Besides adding layers of clothing, people respond to cold by decreasing internal body temperature (hypothermia), by decreasing peripheral body temperature (insulation) and by increasing energy expenditure (adaptive thermogenesis). Thanks to modern conveniences, exposure to extreme cold is uncommon. However, people still have many opportunities to experience mild cold exposure, as can happen when they move from a heated house to a cooler situation outdoors, or from a hot outdoor environment into an over-air-conditioned building. In the context of weight loss, it is interesting to note that these temperature transitions may be made more easily by those who are lean than by those who are overweight.
Heat Production Higher in Lean Subjects
A 2006 article by Claessens-van Ooijen et al. compared the effect of mild cooling and rewarming on healthy men who were lean (average BMI=21) and overweight (average BMI=29). The men wore standardized clothing and spent an hour sitting in 59°F air while covered by a duvet. Under baseline conditions there was no significant difference in energy expenditure between the two groups. In order to produce cooling, the duvets were removed for an hour. During this time both groups showed an increase in heat production, but the increase in the lean group was significantly greater. (Possible shivering was monitored and did not occur.) When the duvets were replaced, after an hour heat production returned to baseline in the overweight group but remained significantly higher than baseline in the lean group. In other words, the overweight men showed less adaptive thermogenesis in response to a mild exposure to cold.
Thermogenesis by Mitochondrial Uncoupling
One mechanism for adaptive thermogenesis was proposed by Wijers et al. in 2008. Eleven lean male subjects spent 34 hours in a respiration chamber at a baseline of 72°F and subsequently spent 82 hours in the respiration chamber without shivering under mild cold conditions of 61°F. Although the activity of the subjects decreased about 20% under mild cold conditions, their total daily energy expenditure increased by 2.8%. Muscle biopsies were taken at the end of the baseline and mild cold conditions. Analysis of the tissue showed that the cold-induced increase in total daily energy expenditure of each subject was significantly related to the amount of mitochondrial uncoupling that had occurred in his skeletal muscle. It is possible that during cold conditions, adaptive thermogenesis occurs when muscle mitochondria bypass some of their ATP synthesis in favor of dissipating energy as heat.
Brown Fat Activity Higher in Lean Subjects
Another possible mechanism for adaptive thermogenesis is the action of brown fat, also called brown adipose tissue. Unlike white adipose tissue, brown adipose tissue has small lipid droplets and many more iron-containing mitochondria, which makes it brown. Normally it functions to provide body heat to newborn humans and to hibernating animals. However, it is still present to some extent in adult humans.
In a 2009 article in the New England Journal of Medicine, van Marken Lichtenbelt et al. studied 24 healthy men, 10 lean (average BMI=22) and 14 overweight (average BMI=30). They rested in a supine position for one hour at 72°F and then for two hours at 61°F. The activity of their brown adipose tissue was assessed by PET-CT scanning that measured the uptake of a glucose isotope, 18F-fluorodeoxygluxose (18F-FDG). Example scans are shown below.
Under the thermoneutral condition of 72°F, very little of the 18F-FDG was taken up by brown fat, as shown by the lean subject on the far left. However, when the temperature was decreased to 61°, brown fat activity was significantly increased in the lean subject (center picture). It was also increased in the overweight subject seen on the right, but not as much. For the entire group, the activity of the brown adipose tissue was greater in the lean subjects than it was in the overweight ones. There was a a positive correlation between brown adipose activity and resting metabolic activity and a positive correlation with brown adipose activity and the core temperature under thermoneutral conditions. Overall, the study found that inreased BMI, but not increased age, was significantly associated with a decrease in brown adipose tissue activity.
None of these studies establishes the idea that being overweight reduces the ability of our bodies to cope with a mild exposure to cold, or that having a reduced ability to do adaptive thermogenesis makes us obese. On the other hand, they do raise the interesting possibilities that (1) losing weight might help us increase our ability to do adaptive thermogenesis, or (2) perhaps forcing our bodies to do adaptive thermogenesis might increase our ability to lose weight. As scientists love to say at the end of articles, more study is needed.
Saturday, October 2, 2010
Last time we looked at the possibility that genetics may determine whether a person is able to lose more weight on a low-carb diet or on a low-fat diet. The jury is still out on that.
However, two articles from 2005 suggest that insulin sensitivity may play an important role in whether low-carb diets or low-fat diets work better for weight loss for particular people. The first of these, Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women, was published in Obesity Research. The second, A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE trial was published in Diabetes Care. Both articles were short, sweet and to the point. And both concluded that if you're insulin-sensitive, you will probably do better on a low-fat calorie-restricted diet, but if you are insulin-resistant, you can expect better weight loss on a low-carb calorie-restricted diet.
The two studies were quite similar to each other, as outlined in the table above. Subjects were randomized into high-carb/low-fat (HC/LF) and low-carb/high-fat (LC/HF) diet groups. In both cases, high-carb was defined as 60% of calories, while low-carb was defined as 40% of calories. Not a dramatic difference, but because all the food was provided for the participants, it was possible to be fairly certain of what the subjects had consumed. (The amount of study food eaten plus any additional food eaten was taken into account.) In all cases, participants received a restricted number of calories.
The variable of interest in these studies was insulin resistance. In the Obesity Research study, insulin resistance was determined by measuring fasting insulin levels. Insulin-sensitive (IS) individuals were defined as those with a fasting insulin below 10 mU/L and insulin-resistant (IR) subjects were defined as those with a fasting insulin above 15 mU/L. Subjects with a fasting insulin between those two values were excluded from the study. In the Diabetes Care study, insulin resistance was determined by administration of a 75 gram oral glucose tolerance test. The subjects whose plasma insulin at 30 minutes post-glucose was less than 66 mU/L were termed low insulin secreters and those whose plasma insulin at 30 minutes was above 66 mU/L were termed high insulin secreters.
As expected, all groups lost a significant amount of weight. The findings are summarized in the two figures below. (I have modified both figures from their original forms to make it easier to compare them.)
The Obesity Research article stated that they expected a loss of approximately 1 kilogram of body weight for every 7300 deficit in calories. Therefore, their 16 week study should have produced a weight loss of at least of 6.1 kilograms, and this was indeed the case.
What was surprising was that two of the groups lost almost twice that amount of weight: the insulin-sensitive (IS) subjects who ate high-carb/low-fat (HC/LF) and the insulin-resistant (IR) subjects who ate low-carb/high-fat (LC/HF). A similar result is seen in the Diabetes Care article. All of those subjects lost an average 6 kilograms or more of body weight, but among the high insulin secreters, significantly more weight was lost when they followed a low-carb/high fat diet as compared with a high-carb/low-fat diet. Among low insulin secreters, there was a tendency to lose more weight with a high-carb/low-fat diet, but in this case the difference was not statistically significant.
It pains me to say it, but a low-carb/high-fat diet may not be the best weight loss diet for everybody. From these two studies, a person who is still insulin-sensitive could well find that a low-carb diet might actually be their worst choice. It would still work, but not as well as a low-fat/high-carb/calorie-restricted diet. On the other hand, for a person who is insulin-resistant (and if you're not insulin-resistant when you're young, you tend to get that way as you get older), a low-carb/high-fat/calorie-restricted diet appears to work the best. For whatever reason, if you follow the diet indicated by your insulin sensitivity, chances are good that you will not only lose the amount of weight predicted by the decrease in your caloric intake, but a few extra kilograms as well.
Sunday, August 22, 2010
We now have three articles in three respected journals showing that weight loss over 1-2 years on a low-carb diet is equal to or better than the weight loss seen on a low-fat diet. The figure above illustrates the weight loss in the first of those three publications, the A to Z Weight Loss Diet Study.
Although the A to Z Study showed that women in the Atkins arm of the study lost the most weight on average over a year, the researchers noticed that within each diet group, the individual weight change ranged from a loss of over 30 pounds to a gain of about 10 pounds. It seemed that another factor besides low-carb helped to determine the efficiency of weight loss for particular individuals. The scientists speculated that genetic differences might be at work.
The first discussion of the interaction of genes and the A to Z Weight Loss Diet showed up in a lifestyle article in the Wall Street Journal. The article described how Mindy Dopler Nelson and Christopher Gardner attempted to contact the 301 women in the original A to Z study and found about 140 who were willing to submit DNA by means of a cheek swab. The swabs were sent off to Interleukin Genetics and were analyzed for three genes that had been shown to have some relationship to body weight in at least three clinical studies.
The Interleukin Genetics site has a summary describing the science behind its weight management genetic tests. Briefly, the panel involves five variations in four genes. These involve single nucleotide polymorphisms (SNPs) that subtly change proteins involved in body weight by changing one of the amino acids in the protein sequence in question. Proteins, as you will recall, are linear strings of amino acids. The particular sequence and identity of the amino acids determines how the protein folds and how it interacts with other molecules within the body. Change one of the amino acids and you'll modify the way the protein works.
The first protein tested in the panel is fatty acid binding protein 2, or FABP2. FABP2 is a protein found in epithelial cells of the small intestine, and it influences fat absorption. When the alanine at position 54 of FABP2 is substituted with a threonine, this causes increased absorption of dietary fatty acids by the intestine. (The specific scientific references for these claims and the ones for the other genes listed below can be found in the Interleukin summary publication linked above.)
The peroxisome proliferator-activated receptor-gamma (PPARG) protein is expressed in fat cells and plays a role in adipogenesis. When there is a proline at position 12 of the protein, the person carrying that gene variant will find it easier to gain weight as a result of fat in the diet. By contrast, people with an alanine at position 12 of the PPARG protein will tend to lose weight more easily.
The beta-2 adrenergic receptor (BAR2) gene is involved in mobilization of fat from adipocytes in response to hormones like epinephrine and dopamine. There are two important polymorphisms of BAR2, one at positon 27 and another at position 16.
Women with glutamine at position 27 show no risk of obesity on a high carbohydrate diet, while women with a glycine at that position showed an increased risk of obesity when they adhered to a high carbohydrate diet.
Individuals who carry a glycine at position 16 of the BAR2 protein are at higher risk of weight gain over their lifetimes than those who carry an arginine at that position. Glycine-16 individuals are also less likely to lose weight in response to an exercise program.
Another type of beta adrenergic receptor, BAR3, is found in visceral adipose tissue and is involved in regulation of lipolysis, that is, the breakdown of fat. This gene was not considered in the reanalysis of the A to Z Diet Study, but it is interesting nonetheless. People with an arginine at position 64 of the BAR3 protein found it much easier to lose weight in response to exercise than those who carried a tryptophan at position 64. This variation may help explain why some people swear that they can lose weight by exercising, while others swear that exercise makes no difference to their weight loss.
A to Z Reanalysis
When the group at Stanford learned the results of these tests, they were able to group the women in their study into low-carb genotypes and low-fat genotypes. Unfortunately, since we only have press releases to guide us, the specific criteria for the genotypes is unavailable. They did say that when women with the low-fat genotype were on the very-low-fat Ornish diet, they lost an average of 14.1 pounds, while those with that genotype who were on the relatively high-fat Atkins diet averaged a loss of only 2.2 pounds. Women with the low-carb genotype lost an average of 12.3 pounds on the Atkins diet and 3.1 pounds on the Ornish diet.
This study has not yet been published in a peer-reviewed journal, but the findings are interesting nonetheless. It is fascinating to speculate that low-carb and low-fat diet and exercise plans might produce better or worse results depending upon our genes. At the same time it's important to remember that the A to Z participants were premenopausal, non-diabetic white females. Even if the findings of the Stanford group prove significant, it is impossible to tell how they will apply to older people, to diabetics, to nonwhite populations and to men. There are, however, 44 studies cited at the end of the Interleukin Genetics summary article, and these do address the function of the four target genes in many types of patient populations.
If you have $149.00 in extra cash, you might even want to take the test and see if the results comport with your experiences in various weight loss approaches. I have no financial interest in Interleukin Genetics, but would be very interested to see if there is any validity to using genetics as a strategy to assist in weight loss.