What if gluten sensitivity doesn’t exist?

How can I possibility make that statement?  Two recent best-selling diet books have maintained that gluten makes us fat and dumb (1,2). Billions of dollars are spent on gluten-free (but carbohydrate-rich) food products.  And people feel better when they don’t eat bread.

Before explaining my statement, let me make two things very clear.  First, I am not a big believer in bread.  In 1997, in a Time magazine interview I said, “If all the bread left the face of the earth, we would have a much healthier planet.” (3)  I stand by that statement.

Second, gluten “sensitivity” is not celiac disease.  Celiac disease is a clinically proven autoimmune response to the proteins in gluten (4).  I know since my wife has severe celiac disease.

However gluten sensitivity is different.  Most of the people who pretend to be experts in gluten sensitivity usually have no background in gastrointestinal research.  After all, why try to back up your claims with real research that is very difficult to do?  So it came as a great initial salvation to those people when a real expert from Australia published a paper indicating that gluten sensitivity may exist but with no clues to the mechanism (5).  In this study subjects with irritable bowel syndrome (IBS) and no evidence of celiac disease were put on a gluten-free diet for six weeks and then either challenged daily with muffins and bread either containing gluten (16 grams per day) or without gluten.  Even though both groups were on a gluten-free diet, they were both having more symptoms, although the group getting the extra gluten had more symptoms of IBS, including being more fatigued than the control group (5).

gluten-chart-0

What was also strange about the results of this study was there were no differences in the intestinal inflammation or any increase in the permeability of the intestinal wall in either group.  This caused the researchers to ponder if they had been too simplistic in their experimental design.   So they went back to do another experiment in which a diet that was far more rigorous in reducing other potential food allergens, such as FODMAPs, which stand for Fermentable, Oligo-, Di-, Monosaccharides And Polyols.  These are poorly absorbed short-chain carbohydrates, which means that many of these dietary carbohydrates reach the colon where the trillions of bacteria are waiting to begin fermenting them. FODMAPs are found in foods, such as those containing free fructose (found in apples, cherries, pears, asparagus, artichokes, etc.), foods that can be easily broken down into free fructose (such as high-fructose corn syrup and table sugar), free lactose (found in milk, yogurt, soft cheeses, etc.), polymers of fructose known as fructans (found in peaches, artichokes Brussels sprouts, fennel, onion, wheat, barley, and rye), polymers of galactose known as galactans (found in legumes, chickpeas, lentils, etc.) and polyols (found in apricot, avocado, blackberries, plums, cauliflower, mushrooms, snow peas, etc.).  This is a lot more complex dietary undertaking than putting all of your bets on gluten (6).

So when the researchers repeated their experiment and removed many of the FODMAPs from the diet of the sufferers with “gluten sensitivity” and then added back bread and muffins consisting of either high gluten (16 grams per day), low gluten (2 grams per day), or a placebo, they got a very different response as shown below (7).

gluten-chart

Now you get a very different picture than the earlier study in which the researchers had not removed many of the FODMAPs from the diets of their subjects.  Furthermore, there was no increase in fatigue in those getting the gluten compared to the placebo, even though more than half of the subjects had the genetic susceptibility marker for celiac disease (DQ2 or DQ8 positive HLA), and a quarter of them had anti-bodies to gliadin (one of the proteins in the overall family of protein collectively called gluten).

These new results with the low-FODMAPs diet led the researchers to conclude:  In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with non-celiac gluten sensitivity placed on diets low in FODMAPs.  That’s a mouthful, but in essence the benefits of a gluten-free diet may not be the removal of gluten but the removal of various FODMAPs found in the wheat, rye, and barley that just happen to also contain gluten.

What remains unknown is whether it is the FODMAPs or a unique bacteria composition in the guts of the “gluten-sensitive” people interacting with the FODMAPs that can cause the problems that lead to IBS and the designation of being “gluten-sensitive”.

However one thing is certain: This new research will not stop the continuing flow of “gluten-free” products rich in carbohydrates coming from the food industry and more popular diet books “discovering” the real reason we are getting fatter and dumber.  Maybe I was on the right track in 1997 when I stated that bread removal is not such a bad idea for mankind.  That’s because I also believe that it is increased diet-induced inflammation, not simply gluten, that is the real cause of our growing epidemics of obesity, type 2 diabetes, and Alzhemier’s.

References

1.  Davis W.  Wheat Belly: Lose the Wheat, Lose the Weight, and Find Your Path Back to Health. Rodale Books.  Erasmus, PA (2011)

  1.  Perlmutter D.  Grain Brain: The Surprising Truth about Wheat, Carbs, and Sugar-Your Brain’s Silent Killers. Little, Brown and Company.  New York, NY (2013)
  2.  Ratnesar R.  “Against the grain.”  Time. December 15, 1997 (1997)
  3. Fasano A. Gluten Freedom: The Nation’s Leading Expert Offers the Essential Guide to a Healthy, Gluten-Free Lifestyle. Wiley.  New York, NY (2014)
  4. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, and Gibson PR.  “Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.”  Am J Gastroenterol 106:508-514 (2011)
  5. Gibson PR and Shepherd SJ.  “Food choice as a key management strategy for functional gastrointestinal symptoms.” Am J Gastroenterol 107:657-666 (2012)
  6. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, and Gibson PR.  “No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.” Gastroenterology 145:320-328 (2013)

The Real Facts about Metabolically Healthy Obesity

One of great paradoxes of our obesity epidemic is that many obese individuals appear to be quite healthy. This makes the true believers in the Holy Grail of BMI as the standard for good health quite livid. They know in their hearts that obesity is a mortal sin. Early this year the Centers for Disease Control (CDC) published another in a long series of articles demonstrating that being overweight significantly decreases your likelihood of dying compared to being “normal weight” (1). Immediately Harvard Medical School went on a rampage crying foul. So you can imagine the delight of the weight-loss experts when a new meta-analysis demonstrated that “there is no healthy pattern of increased weight” (2). Take that, you silly scientists at the CDC. Unfortunately, this article represents another case of a meta-analysis creating meta-confusion.

When you state that someone is metabolically healthy obese, it means just that—they are healthy. So how can you look at someone and say they are healthy? You have to look for accepted signs of health, not whether or not they fit into designer clothing. Fortunately, there is a health ranking of obese individuals that is not based on their actual weight. It is called the Edmonton Obesity Staging System (EOSS). Obviously to be included in this ranking system, an individual has to be obese (BMI > 30). But now they are ranked in terms of health as shown below:

Stage 0: Normal blood pressure, blood glucose, and blood lipid levels and no physical or psychological impairment to being obese.

Stage 1: Existence of subclinical risk, such as borderline hypertension, impaired fasting glucose, elevated liver enzymes, mild physical symptoms, and mild impairment of well-being.

Stage 2: Established chronic disease (hypertension, type 2 diabetes, sleep apnea, osteoarthritis, etc.) and moderate limitations in physical and psychological well-being.

Stage 3: Established end-organ damage (heart attack, stroke, heart failure, etc.) and significant physical and psychological impairment.

Stage 4: Essentially the walking dead.

My definition of a healthy obese individual is someone who has an EOSS Stage 0 ranking.

So using these EOSS definitions and the NHANES III data from 1988-1994, how many people with excess weight are actually healthy using the standard definitions of excess weight: Overweight being a BMI of 25-30, Grade 1 Obesity having a BMI between 30-35, Grade 2 Obesity having a BMI between 35-40, and Grade 3 Obesity having a BMI > 40?

Overweight Obese 1 Obese 2 Obese 3
U.S. Population 50M 23M 10M 6M
Stage 0 15% 8% 5% 5%
Stage 1 28% 19% 17% 10%
Stage 2 47% 59% 64% 67%
Stage 3 10% 14% 14% 14%

The total number of overweight and obese Americans falling within the four rankings of EOSS accounted for nearly 90 million Americans. You can also see that there is great heterogeneity within each category of excess weight, but between 5 to 8% of obese patients are quite healthy regardless of their weight.

If you have an EOSS Stage 0 ranking regardless of your weight, you are healthy. Obviously, the more things wrong with you health-wise regardless of your weight, the more likely you are to going to have even more health problems in the future.

And here is the problem with the article that generated so much glee at Harvard Medical School—the researchers didn’t distinguish between truly healthy obese (EOSS Stage 0) and not-so-healthy obese (EOSS Stage 1). In fact, 9 of the 12 studies they included for their meta-analysis defined being “healthy” as not having metabolic syndrome (2). To have metabolic syndrome requires having three very different unhealthy factors. The other 3 studies included defined “healthy” as having two or less risk factors for metabolic syndrome. This means someone with hypertension, elevated blood glucose, or elevated triglycerides would be considered “healthy” in this meta-analysis (2). I guess I come from the old school, in that I wouldn’t consider such people healthy.

Now if you go back to the earlier study published by the CDC, these researchers used a very simple clinical end point that can’t be fudged (1). This end point is called death. Their data clearly points out that overweight people had a significantly a lower death rate than normal-weight people. That’s a hard fact. And the Grade 1 Obese individuals have about the same death rate as normal-weight individuals. If the CDC had used the EOSS system instead of relying on BMI, then it is likely that every grade of obese person with an EOSS Stage 0 would be living longer than normal-weight individuals.

Another recent study has indicated that metabolically healthy obesity (again using mixed patient populations) may be a transitory stage (4). However that study also used a combination of EOSS Stage 0 and Stage 1 patients within their definition of “metabolically healthy obese”. When you separate the truly healthy obese (EOSS Stage 0) from the not-so-healthy (EOSS Stage 1), you find that EOSS Stage 0 patients (regardless of their levels of obesity) maintain their health over a long time period (more than 16 years) as shown below (3).

Obesity-chart

The EOSS Stage 1 individuals in all weight classes become progressively less healthy with time. So if you combine the truly healthy obese (EOSS Stage 0) with not so healthy obese (EOSS Stage 1), then you might come to the wrong conclusion that the concept of metabolically healthy obesity doesn’t exist (2,4).

So what’s the real linkage between weight and mortality? It depends on your levels of cellular inflammation as I explained in my book Toxic Fat, published in 2008. And the less cellular inflammation you have at any weight, the healthier you are. The best measure of your levels of cellular inflammation is the AA/EPA ratio. It should be between 1.5 and 3. The average AA/EPA ratio for Americans is about 19 (5). As you reduce cellular inflammation, the severities of all forms of chronic disease are reduced regardless of your weight.

References

  1. Flegal KM, Kit BK, Orpana H, and Graubard BI. “Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.” JAMA 309:71-82 (2013)
  2. Kramer CK, Zinman B, and Renakeran R. “Are metabolically healthy overweight and obesity benign conditions?” Annals of Internal Medicine 159: 758-769 (2013)
  3. Padwal RS, Pajewshi NM, Allison DB, and Sarma AM. “Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity.” Can Med Assoc Journal 183:E1059-E1065 (2011)
  4. Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, Taylor AW, and Adams RJ. “Diabetes and cardiovascular disease outcome in the metabolically healthy obese phenotype.” Diabetes Care 36:2388-294 (2013)
  5. Harris WS, Pottala JV, Varvel SA, Borowski JJ, Ward JN, and McConnell JP. “Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.” Prostaglandins Leukot Essent Fatty Acids 88:257-263 (2013)

Don’t confuse me with the facts

The last couple of months have been hard on obesity experts as they have learned that maybe the obvious is not so obvious.

It started out in October with an article in the New England Journal of Medicine on the substitution of sugar-sweetened beverages with politically correct sugar-free beverage replacements (1). Everyone from Mayor Bloomberg to Dr. Oz knows that soda makes you fat. It is so obvious there is no need to confirm this “fact”. Almost out of due diligence, Harvard Medical School did a two-year study just to confirm this most obvious obesity fact that sugar-sweetened soda makes you fat. Researchers took obese adolescents, who were confirmed soda (containing evil fructose) drinkers. Half were used as the control group; the other half as the experimental group, who were sent regular supplies of “good” beverages (not fruit juices) to replace the sugar-sweetened sodas. They also got motivational phone calls on a monthly basis to urge them on and also to tell them not to watch as much TV.

It worked. At the end of two years, they were drinking fewer sugar-sweetened beverages, watching less TV, and consuming fewer calories and far less sugar than the control group. All of these changes in their lifestyles were strongly statistically significant.

So how did this affect their obesity compared to the control group? There was no difference! Maybe there were just incompetent researchers. I think not, because the research was led by one of the most respected obesity researchers in the world. Maybe the facts that were so obvious to Mayor Bloomberg and Dr. Oz were not so obvious after all.

This was bad enough, but then another article appeared in the January issue of the New England Journal of Medicine stating that we actually know virtually nothing about the treatment of obesity (2). Oh, yes, you can make a lot of correlations (like not drinking sugar-sweetened soda, eating fewer calories and watching less TV) that are associated with lower weight, but no scientific data are there to support this. In fact, the only things we can really be scientifically certain about treating obesity are gastric bypass surgery, some prescription drugs that suppress appetite (like amphetamines) and following a highly structured meal plan using meal replacements with a defined composition. These three factors cause weight loss compared to control groups.

Gee, after 30 years of our obesity epidemic (and millions of research dollars) you would think we would have some more solid scientific data. It turns out that obesity research is more like religion—don’t confuse me with the facts.

Why do we have such ignorance about what causes obesity, let alone how to treat it ? Some of the reasons come from recently published genetic studies with genetically inbred mice (3). Using more than 100 different genetically pure strains with a highly defined diet (rat food pellets), it was found that once they are switched to a high-sugar, high-fat diet that some of the genetic strains gain weight, and some don’t. In fact, the differences in fat gain were nearly 600% among different strains.

What does this mean for humans? Classical genes don’t change quickly; however, epigenetic markers that turn genes on and off can change within one generation. Here lies the problem. Our obesity epidemic is not because of making either bad food or lifestyle choices, but may be due to changes in food composition that our parents were eating that modified the expression of our genes in the womb.

The most likely suspect gene-altering drama is increased consumption of omega-6 fatty acids, such as linoleic acid, which lower the percentage of omega-3 fats in the diet (4). I described this in greater detail in my book “Toxic Fat” (5). Simply stated, in a period of 50 years, we have been become genetically altered by increasing linoleic acid to gain weight rapidly and make it difficult to lose. Those epigenetic changes will not evaporate with simple slogans found on TV talk shows or from a politician’s mouths. They will take probably three generations to return to what they were in an earlier time, and only if there is a radical restriction in the linoleic intake by humans.

Meanwhile, prepare yourself for more political (and scientific) blowhards who have all the answers to a very complex set of problems resulting from a continued modification of our genes and those of our children, making us overweight, sicker, and aging faster.

References
1. Ebbling CB et al. “A randomized trial of sugar-sweetened beverages and adolescent body weight.” N Engl J Med 367:1407-1416 (2012)
2. Casasa K et al. “Myths, presumptions, and facts about obesity.” N Engl J Med 368:446-454 (2013)
3. Parks BW et al. “Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.” Cell Metabol 17:141-152 (2013)
4. Hanbauer I et al. “The decrease of n-3 fatty acid energy percentage in an equicaloric diet fed to B6C3Fe mice for three generations elicits obesity.” Cardio Psychiartry Neurology 2009: 867041 (2009)
5. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)

Harvard explains why people regain weight with the Atkins diet

A study from Harvard Medical School explains that even though people can lose weight on a ketogenic diet, all lost weight usually rapidly returns.

Ketogenic diets have been recommended for decades for rapid weight loss. The most famous is the Atkins diet. Ketogenic diets are based on high-protein and very low-carbohydrate intake. For the past 40 years such diets have been routinely used in America for weight loss, yet America remains in the midst of a growing epidemic of obesity. While ketogenic diets can induce initial weight loss, all lost weight usually rapidly returns, resulting in more weight (and even more fat) than when the person started the ketogenic diet.

For many years it was thought that such weight regain was due to poor dietary compliance. Now Harvard Medical School in an article in the June 27, 2012, issue of the Journal of the American Medical Association shows the reason for weight regain is more ominous than simple dietary non-compliance. In carefully controlled studies Harvard researchers demonstrated that on a ketogenic diet the levels of the hormone cortisol increase by 18%, and the levels of active thyroid hormone (T3) control metabolism decrease by 12% (1).

The effect of increased cortisol is to cause rapid fat accumulation, as any patient who has ever used prescription cortisol-like drugs knows. It also causes depression of the immune system, loss of memory, and thinning of the skin. These are also hallmarks of the acceleration of the aging process. Furthermore, the lowering of the active form of the thyroid hormone slows down the metabolism, making even seemingly small increases in calorie intake result in increased body fat accumulation. Besides setting you up to regain all the lost weight, the Atkins diet apparently also increases the rate of aging.

However, many people seem willing to continue to try such ketogenic diets in hopes of losing weight quickly. Yet highly controlled studies I published in the world’s most prestigious nutrition journal in world more than six years ago demonstrated that is simply not a true statement (2). In this study either a ketogenic diet (the Atkins diet) or a non-ketogenic diet (the Zone Diet) were compared in obese individuals. For the first six weeks all meals for both groups were prepared in a metabolic kitchen at Arizona State University (in essence treating subjects like lab rats). Both diets contained an equal number of calories.

When it came to weight loss, the subjects following the Zone Diet actually lost slightly more weight than as those on the ketogenic diet during the initial six-week period as shown in Figure 1.

Figure 1. Weight Loss (Zone Diet in open circles, Atkins diet in black squares)

Relative to fat loss on the non-ketogenic Zone Diet, their loss of body fat was again superior to the Atkins diet as shown in Figure 2. Fat loss is far more important than weight loss since all the health benefits from weight loss come from the loss of excess body fat; not from the loss of retained water or loss of muscle mass.

Figure 2. Fat Loss (Zone Diet in open circles, Atkins diet in black squares)

When the subjects continued on the respective diets for another four weeks (but now preparing meals on their own), those subjects on the non-ketogenic Zone Diet continued to lose even more weight and body fat, whereas those on the ketogenic Atkins diet did not. They had reached a plateau. The new research from Harvard Medical explains why.

One of the major problems in following a calorie-restricted diet is lack of energy. In this same study, the subjects on the Zone Diet demonstrated improved daily energy compared to those on the Atkins diet. In another publication using the same subjects, we also demonstrated that those subjects following the Zone Diet had greater performance in endurance testing compared to those following the ketogenic Atkins diet (3).

Figure 3. Energy levels (Zone Diet in open circles, Atkins diet in black squares)

For the past 40 years, ketogenic diets (like the Atkins diet) have failed to treat obesity in America. That is why one relies upon science, not hype, to determine which is the best diet to lose weight (and really body fat), keep it off, and increase energy. Continuing research from Harvard Medical School since 1999 demonstrates that the Zone Diet is the best dietary program to accomplish both goals (1,4-7). And the one thing Harvard will always tell you is that they are never wrong.

References

  1. Ebbeling CB, Swain JF, Feldman HA, Wong WA, Hachey DL, Garcia-Logo E, and Ludwig DD. “Effects of dietary composition on energy expenditure during weight loss maintenance.” JAMA 307: 267-2634 (2012)
  2. Johnston, C.S., Tjonn, S., Swan, P.D., White A., Hutchins H., and Sears B. “Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets.” Am J Clin Nutr 83: 1055-1061 (2006)
  3. White AM, Johnston CS, Swan PD, Tjonn SL, and Sears B. “Blood ketones are directly related to fatigue and perceived effort during exercise in overweight adults adhering to low-carbohydrate diets for weight loss: A pilot study.” J Am Diet Assoc 107: 1792-1796 (2007)
  4. Ludwig, DS, Majzoub AJ, Al-Zahrani A, Dallal GE, Blanco I, and Roberts SB. “High glycemic index foods, overeating, and obesity.” Pediatrics 103: e26 (1999)
  5. Agus MSD, Swain JF, Larson CL, Eckert EA, and Ludwig DS. “Dietary composition and physiologic adaptations to energy restriction.” Am J Clin Nutr 71:901–907 (2000)
  6. Pereira MA, Swain J, Goldfine AB, Rifai N, and Ludwig DS. “Effect of low-glycemic diet on resting energy expenditure and heart disease risk factors during weight loss.” JAMA. 292: 2482-2490 (2004)
  7. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, and Ludwig DS. “Effects of a low–glycemic load vs. low-fat diet in obese young adults”. JAMA 297: 2092-2102 (2007)

What is Cellular Inflammation?

People (including virtually all physicians) are constantly confused what cellular inflammation is. So I decided to take the opportunity to explain the concept in more detail.

There are two types of inflammation. The first type is classical inflammation, which generates the inflammatory response we associate with pain such as, heat, redness, swelling, pain, and eventually loss of organ function. The other type is cellular inflammation, which is below the perception of pain. Cellular inflammation is the initiating cause of chronic disease because it disrupts hormonal signaling networks throughout the body.

Definition of Cellular Inflammation

The definition of cellular inflammation is increased activity of the gene transcription factor know as Nuclear Factor-kappaB (NF-κB). This is the gene transcription factor found in every cell, and it activates the inflammatory response of the innate immune system. Although the innate immune system is the most primitive part of our immune response, it has been resistant to study without recent breakthroughs in molecular biology. In fact, the 2011 Nobel Prize in Medicine was awarded for the earliest studies on the innate immune system and its implications in the development of chronic disease.

There are several extracellular events through which NF-κB can be activated by distinct mechanisms. These include microbial invasion recognized by toll-like receptors (TLR), generation of reactive oxygen species (ROS), cellular generation of inflammatory eicosanoids, and interaction with inflammatory cytokines via defined cell surface receptors. We also know that several of these initiating events are modulated by dietary factors. This also means that appropriate use of the diet can either turn on or turn off the activation of NF-κB. This new knowledge is the foundation of anti-inflammatory nutrition (1-3).

Understanding Cellular Inflammation

Although the innate immune system is exceptionally complex, it can be illustrated in a relatively simple diagram as shown below in Figure 1.

Figure 1. Simplified View of the Innate Immune System

Essential fatty acids are the most powerful modulators of NF-κB. In particular, the omega-6 fatty acid arachidonic acid (AA) activates NF-κB, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) does not (4). Recent work suggests that a subgroup of eicosanoids known as leukotrienes that are derived from AA may play a significant factor in NF-κB activation (5,6)

Extracellular inflammatory cytokines can also activate NF-κB by their interaction with specific receptors on the cell surface. The primary cytokine that activates NF-κB is tumor necrosis factor (TNF) (7). Toll-like receptors (TLR) are another starting point for the activation of NF-κB. In particular, TLR-4 is sensitive to dietary saturated fatty acids (8). The binding of saturated fatty acids to TLR-4 can be inhibited by omega-3 fatty acids such as EPA. Finally ROS either induced by ionizing radiation or by excess free radical formation are additional activators of NF-κB (9).

Anti-inflammatory Nutrition To Inhibit Cellular Inflammation

Anti-inflammatory nutrition is based on the ability of certain nutrients to reduce the activation of NF-κB.

The most effective way to lower the activation of NF-κB is to reduce the levels of AA in the target cell membrane thus reducing the formation of leukotrienes that can activate NF-κB. Having the patient follow an anti-inflammatory diet, such as the Zone Diet coupled with the simultaneous lowering omega-6 fatty acid intake are the primary dietary strategies to accomplish this goal (1-3).

Another effective dietary approach (and often easier for the patient to comply with) is the dietary supplementation with adequate levels of high-dose fish oil rich in omega-3 fatty acids, such as EPA and DHA. These omega-3 fatty acids taken at high enough levels will lower AA levels and increase EPA levels. This change of the AA/EPA ratio in the cell membrane will reduce the likelihood of the formation of inflammatory leukotrienes that can activate NF-κB. This is because leukotrienes derived from AA are pro-inflammatory, whereas those from EPA are non-inflammatory. The increased intake of omega-3 fatty acids is also a dietary approach that can activate the anti-inflammatory gene transcription factor PPAR-γ (10-12), decrease the formation of ROS (13) and decrease the binding of saturated fatty acids to TLR-4 (14). This illustrates the multi-functional roles that omega-3 fatty acids have in controlling cellular inflammation.

A third dietary approach is the adequate intake of dietary polyphenols. These are compounds that give fruits and vegetables their color. At high levels they are powerful anti-oxidants to reduce the generation of ROS (15). They can also inhibit the activation of NF-κB (16).

Finally, the least effective dietary strategy (but still useful) is the reduction of dietary saturated fat intake. This is because saturated fatty acids will cause the activation of the TLR-4 receptor in the cell membrane (8,14).

Obviously, the greater the number of these dietary strategies implemented by the patient, the greater the overall effect on reducing cellular inflammation.

Clinical Measurement of Cellular Inflammation

Since cellular inflammation is confined to the cell itself, there are few blood markers that can be used to directly measure the levels of systemic cellular inflammation in a cell. However, the AA/EPA ratio in the blood appears to be a precise and reproducible marker of the levels of the same ratio of these essential fatty acids in the cell membrane.

As described above, the leukotrienes derived from AA are powerful modulators of NF-κB. Thus a reduction in the AA/EPA ratio in the target cell membrane will lead to a reduced activation of NF-κB by decreased formation of inflammatory leukotrienes. The cell membrane is constantly being supplied by AA and EPA from the blood. Therefore the AA/EPA ratio in the blood becomes an excellent marker of the same ratio in the cell membrane (17). Currently the best and most reproducible marker of cellular inflammation is the AA/EPA ratio in the blood as it represents an upstream control point for the control of NF-κB activation.

The most commonly used diagnostic marker of inflammation is C-reactive protein (CRP). Unlike the AA/EPA ratio, CRP is a very distant downstream marker of past NF-κB activation. This is because one of inflammatory mediators expressed in the target cell is IL-6. It must eventually reach a high enough level in the blood to eventually interact with the liver or the fat cells to produce CRP. This makes CRP a more long-lived marker in the blood stream compared to the primary inflammatory gene products (IL-1, IL-6, TNF, and COX-2) released after the activation of NF-κB. As a consequence, CRP is easier to measure than the most immediate inflammatory products generated by NF-κB activation. However, easier doesn’t necessarily translate into better. In fact, an increase AA/EPA ratio in the target cell membrane often precedes any increase of C-reactive protein by several years. An elevated AA/EPA ratio indicates that NF-κB is at the tipping point and the cell is primed for increased genetic expression of a wide variety of inflammatory mediators. The measurement of CRP indicates that NF-κB has been activated for a considerable period of time and that cellular inflammation is now causing systemic damage.

Summary

I believe the future of medicine lies in the control of cellular inflammation. This is most effectively accomplished by the constant application of anti-inflammatory nutrition. The success of such dietary interventions can be measured clinically by the reduction of the AA/EPA ratio in the blood.

References

  1. Sears B. The Anti-Inflammation Zone. Regan Books. New York, NY (2005)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Sears B and Riccordi C. “Anti-inflammatory nutrition as a pharmacological approach to treat obesity.” J Obesity doi:10.1155/2011/431985 (2011)
  4. Camandola S, Leonarduzzi G,Musso T, Varesio L, Carini R, Scavazza A, Chiarpotto E, Baeuerle PA, and Poli G. “Nuclear factor kB is activated by arachidonic acid but not by eicosapentaenoic acid.” Biochem Biophys Res Commun 229:643-647 (1996)
  5. Sears DD, Miles PD, Chapman J, Ofrecio JM, Almazan F, Thapar D, and Miller YI. “12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice.” PLoS One 4:e7250 (2009)
  6. Chakrabarti SK, Cole BK, Wen Y, Keller SR, and Nadler JL. “12/15-lipoxygenase products induce inflammation and impair insulin signaling in 3T3-L1 adipocytes.” Obesity 17:1657-1663 (2009)
  7. Min JK, Kim YM, Kim SW, Kwon MC, Kong YY, Hwang IK, Won MH, Rho J, and Kwon YG. “TNF-related activation-induced cytokine enhances leukocyte adhesiveness: induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-kappaB activation in endothelial cells.” J Immunol 175: 531-540 (2005)
  8. Kim JJ and Sears DD. “TLR4 and Insulin Resistance.” Gastroenterol Res Pract doi:10./2010/212563 (2010)
  9. Bubici C, Papa S, Dean K, and Franzoso G. “Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance.” Oncogene 25: 6731-6748 (2006)
  10. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, and Varghese Z. “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-gamma-dependent mechanism.” Kidney Int 67: 867-874 (2005)
  11. Kawashima A, Harada T, Imada K, Yano T, and Mizuguchi K. “Eicosapentaenoic acid inhibits interleukin-6 production in interleukin-1beta-stimulated C6 glioma cells through peroxisome proliferator-activated receptor-gamma.” Prostaglandins LeukotEssent Fatty Acids 79: 59-65 (2008)
  12. Chambrier C, Bastard JP, Rieusset J, Chevillotte E, Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville M, and Vidal H. “Eicosapentaenoic acid induces mRNA expression of peroxisome proliferator-activated receptor gamma.” Obes Res 10: 518-525 (2002)
  13. Mas E, Woodman RJ, Burke V, Puddey IB, Beilin LJ, Durand T, and Mori TA. “The omega-3 fatty acids EPA and DHA decrease plasma F(2)-isoprostanes.” Free Radic Res 44: 983-990 (2010)
  14. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, and Hwang DH. “Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.” J Lipid Res 44: 479-486 (2003)
  15. Crispo JA, Ansell DR, Piche M, Eibl JK, Khaper N, Ross GM, and Tai TC. “Protective effects of polyphenolic compounds on oxidative stress-induced cytotoxicity in PC12 cells.” Can J Physiol Pharmacol 88: 429-438 (2010)
  16. Romier B, Van De Walle J, During A, Larondelle Y, and Schneider YJ. “Modulation of signaling nuclear factor-kappaB activation pathway by polyphenols in human intestinal Caco-2 cells.” Br J Nutr 100: 542-551 (2008)
  17. Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, and Clinton SK. “Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.” Am J Clin Nutr 91: 1185-1194 (2010)

Changing gene expression

I have often stated that the real power of the Zone Diet is to change gene expression, especially the expression of anti-inflammatory genes. What I never realized is how rapid gene expression could occur. Now, new research from Norway gives me the answer (1). It takes about 24 hours!

This pilot study is on the effect of diet on gene expression in healthy obese individuals. Interestingly, when the researchers calculated the estimated daily calorie requirements for these subjects necessary to maintain their weight, they were surprised that they were already eating 250 fewer calories per day than predicted to maintain their current weight. So much for the “fact” that obese individuals are fat because they eat more calories than they need to maintain their weight. In fact, this observation was confirmed in an earlier study in which the number of calories consumed by obese and lean individuals did not vary, but the obese individuals consumed fewer meals consisting of larger servings (2).

So what the Norwegian researchers did was simply maintain the same number of calories the subjects were already eating and change the macronutrient balance to be very close to the Zone Diet (30 percent carbohydrates, 30 percent protein, and 40 percent fat). Then the subjects consumed six meals containing about 460 calories evenly spaced throughout the day so that the total calories consumed at any one time was moderate. Just making those two simple dietary changes resulted in more than an eight-pound weight loss in 28 days. The levels of body fat didn’t change since the number of calories consumed was exactly the same as they were previously consuming. However, it appears that evenly spacing the meals and reducing the calorie size of the meals resulted in less insulin production and therefore less retained water.

Then they looked to see if they could find any changes in gene expression in both the fat cells and the blood with the dietary changes. Amazingly they found dramatic changes in only 24 hours. Of the 16,000 genes they could identify, about 60 percent remained unchanged in their expression, but 40 percent were either turned on (i.e., up-regulated) or turned down (i.e., down-regulated). Interestingly, the changes seen in the first 24 hours were held constant throughout the 28 days of the experiment.

Upon further analysis, the up-regulated genes corresponded to those that had anti-inflammatory properties, and the down-regulated genes were those associated with chronic disease conditions, such as diabetes and heart disease. Furthermore, since these changes in gene expression occurred within 24 hours of the dietary change, they could not be attributed to any change in body weight and fat loss.

Fortunately, I had the opportunity to have dinner with the lead author of the study to discuss her work while I was in Europe last week. She told me that she has expanded the number of subjects in several new trials, and the results remain the same. I also found out that she has been following my work for many years.

This type of study only confirms the power of genetic analysis to demonstrate how a highly structured diet with the correct macronutrient content can rapidly alter genetic expression and hence controls your future health. But the door swings both ways. An unbalanced diet will have just the opposite genetic effects. While I have always been impressed by the power of the Zone Diet, this new experimental data takes my respect for the Zone Diet to a new level of awe, even by me.

References

  1. Brattbakk H-R, Arbo I, Aagaard S, Lindseth I, de Soysa AK, Langaas M, Kulseng B, Lindberg, and Johansen B. “Balanced caloric macronutrient composition down regulates immunological gene expression in human blood cells-adipose tissue diverges.” OMICS 15: doi:1089/omi.2010.0124 (2011)
  2. Berg C, Lappas G, Wolk A, Strandhagen E, Toren K, Rosengren A, Rosengren A, Thelle D, and Lissner L. “Eating patterns and portion size associated with obesity in a Swedish population.” Appetite 52: 21-26 (2009)

Eat Less, Get Hungry

Telling an obese person simply to eat less rarely succeeds. Is it because they are weak-willed individuals or is there something more complex going on? New research indicates the latter. A new article in Cell Metabolism showed that during extreme calorie restriction, the levels of fatty acids begin to rapidly rise in the blood as the body begins breaking down stored fat for energy. These newly released fatty acids from the fat cells can then enter into the brain (the hypothalamus to be exact) and cause the self-digestion of cells in the hunger neurons (1). This self-digestion of the cells in the hunger neurons produces a rise in the very powerful hunger hormone (AgRP) from the same bundle of neurons. Not surprisingly, the urge to eat becomes almost overpowering. This begins to explain why very low calorie diets can cause rapid weight loss, but are rarely successful in keeping the weight off.

This is why very low calorie diets that promise quick weight loss invariably cause the rapid release of stored fatty acids that promotes constant hunger. This is clearly not a sustainable way to maintain long-term weight management.

Of course the question might be whether it is all fatty acids or just one that causes the problem of cellular death in the hunger neurons? I believe the answer comes back to the usual suspect, arachidonic acid (2). It has been known for 20 years that when you put obese individuals on a very low calorie diet there is a rapid increase in the levels of arachidonic acid levels in the blood (3). Arachidonic acid can easily cross the blood brain barrier and enter into the hypothalamus. Since arachidonic acid is a powerful promoter of cell death (4), increased concentrations inside the hypothalamus may be the primary accelerator of the death of the hunger neurons. Increased levels of arachidionic acid in the blood are also the underlying cause of insulin resistance because of its effect on the generation of cellular inflammation (2). So as you build up the levels of stored arachidonic acid in the fat cells, caused by the Perfect Nutritional Storm (2), you are almost ensuring constant hunger when you try to lose weight quickly by following very low calorie diets. To make matters even worse, as arachidonic acid levels also build up in the brain increasing the production of endocannabinoids (5). These are the hormones that give you the continual munchies (they are related to the active ingredient in marijuana).

So is there any good news in all of this research? Yes as long as you develop a lifetime dietary strategy for reducing arachidonic acid and the cellular inflammation it causes as well as following a reasonable low calorie diet that supplies adequate levels of fat to moderate the release of stored fatty acids from the fat cells. It means following an anti-inflammatory diet with adequate protein using low-glycemic load carbohydrates and fats very low in omega-6 fatty acids, but adequate in monounsaturated and omega-3 fats.

That’s why you never want to start any type of weight loss program without adding omega-3 fatty acids to counteract the released of stored arachidonic acid from the fat cells. Not only will these omega-3 fatty acids reduce the degradation of the hunger neurons thereby reducing the release of powerful hunger hormones during calorie restriction, but they will also inhibit the release of endocannabinoids in the brain (6). The combination of the two events will ensure weight loss without hunger and that’s sustainable.

References

  1. Kaushik S,Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, and Singh R. “Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance.” Cell Metabolism 14: 173-183 (2011)
  2. Sears B. Toxic Fat. Thomas Nelson. Nashville, TN (2008)
  3. Phinney SD, Davis PG, Johnson SB, and Holman RT. “Obesity and weight loss alter serum polyunsaturated lipids in humans.” Amer J Clin Nutr 53: 831-838 (1991)
  4. Pompeia C, Lima T, and Curi R. “Arachidonic acid cytotoxicity: can arachidonic acid be a physiological mediator of cell death?” Cell Biochemistry and Function 21:97-104 (2003)
  5. Kim J, Li Y, and Watkins BA. “Endocannabinoid signaling and energy metabolism: A target for dietary intervention.” Nutrition 27: 624-632 (2011)
  6. Oda E. “n-3 Fatty acids and the endocannabinoid system.” Am J Clin Nutr 85: 919 (2007)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

Preventing obesity through prenatal nutrition

It is obvious that pediatric obesity is a growing problem. However, compared to adult obesity, it is a relatively new problem. In a new article to be published in the Journal of Adolescent Health, it is pointed out that while childhood obesity has increased some 300 percent since 1960, most of that increase only began in the mid 1990s (1). This is well after the beginning of the climb of adult obesity, which started in the 1980s. Why the lag time? I believe it may have been caused by the amplification of any genetic predisposition to obesity by prenatal programming in the womb. That means you had to have obese mothers whose own hormonal changes and diet were altering the fetal programming of their children, thus amplifying their likelihood for obesity after birth.

This possibility makes sense based on results from another recent article that demonstrates that the lower the omega-3 fatty acid status in the mother, the more likely the child would be obese by the age of 3 (2). In this particular study, researchers found that by age 3 about 10 percent of the children were already obese. What they also analyzed was even though virtually all the women were consuming very low levels of omega-3 fatty acids during pregnancy, the higher the levels of the omega-3 fatty acids in mother’s diet, or her blood, and especially in the blood from the umbilical cord to the fetus, the lower the levels of obesity in the child three years later after birth.

Of course, lower levels of omega-3 fatty acids usually indicate higher levels of omega-6 fatty acids, giving rise to an unbalanced ratio of omega-3 to omega-6 fatty acids. This is why the highest correlation with increased childhood obesity was found with an increasing ratio of arachidonic acid to EPA and DHA in the blood of the mother and also in the umbilical cord of the fetus. This makes perfect sense since it is known from animal studies that the higher the omega-6 to omega-3 ratio in the diet of the mother, the greater the obesity in the offspring (3-5).

So if you want to begin to decrease childhood obesity, it is probably best to start in the womb of the mother with appropriate prenatal nutrition using appropriate levels of omega-3 fatty acids. This would prevent the fetal programming of the unborn child that would lead to rapid accumulation of excess body fat after birth. I think this makes a lot more sense than telling obese children to “eat less and exercise more” after their genetic expression has been altered in the womb. And if this makes sense, then doesn’t it also strongly suggest that feeding children more omega-3 and less omega-6 fatty acids after birth will silence the activation of ancient genes that make them fat and keep them fat (6).

References

  1. Lee H, Lee D, Guo G, and Harris KM. “Trends in body mass index in adolescence and young adulthood in the United States: 1959-2002.” J Adolescent Heath DOI:10.1016/jadolheath2011.04.019 (2011)
  2. Donahue SMA, Rifas-Shiman SL, Gold DR, Jouni ZE, Gilman MW, and Oken E. “Prenatal fatty acid status and child adiposity at age 3.” Am J Clin Nutr 93: 780-788 (2011)
  3. Korotkova M, Gabrielsson BG, Holmang, A, Larrson BM, Hanson LA, and Strandvik B. “Gender-related long-term effects in adult rats by perinatal dietary ratio of n-6/n-3 fatty acids.” Am J Physiol Regul Integr Comp Physiol 288: R575-579 (2005)
  4. Ailhaud G, Guesnet P, and Cannane SC. “An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development?” Br J Nutr 100: 461-470 (2008)
  5. Massiera L, Barbry P, Guesnet P, Joly A, Luquet S, Moreihon-Brest C, Moshen-Kanson T, Amri E-Z, and Ailhaud G. “A western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations.” J Lipid Res 51: 2352-2361 (2010)
  6. Massiera Saint-Marc P, Seydoux J, Murata T, Kobayshi T, Narumiya S, Guesnet P, Amri E-Z, Negrel R, and Alhaud G. “Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?’ J Lipid Res 44: 271-279 (2003)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

If you’re fat, you may be OK

It is well known from epidemiological studies that about 30 percent of obese individuals and 50 percent of overweight individuals are relatively healthy in terms of cardiometabolic risk factors (1). The same study also indicated that about 25 percent of normal-weight individuals have significant cardiometabolic risk. A follow-up study indicated individuals defined as “metabolically healthy obese” are not at any long-term risk of heart disease (2).

Is the world turning upside down?

I explained the reasons behind these paradoxical observations in my most recent book, “Toxic Fat,” published three years ago (3). It simply depends on what type of fat cells you have. If you have healthy fat cells (“good” fat), they will pull excess arachidionic acid out of the bloodstream and store it in the fat cells. This buried arachidonic acid can spread inflammation to other organs that ultimately results in the appearance of cardiometabolic risk factors. On the other hand, if you have “bad” fat (unhealthy or sick fat cells), they are not very effective in removing arachidonic acid from the bloodstream. Once this happens, circulating arachidonic acid can metastasize like a cancer to other organs. This begins a very slippery slope toward the early development of cardiometabolic diseases, such as diabetes and heart disease. Finally, you get to the stage of dying fat cells that are surrounded by inflammatory macrophages. Now you are in true trouble as the previously stored arachidonic acid is more rapidly released back into the bloodstream.

Now let's fast forward to a new article in the Journal of the American College of Cardiology (4) that simply confirms what I wrote about fat cell inflammation three years ago. As with the earlier epidemiological study, researchers found that about 30 percent of the obese subjects had little inflammation in their fat cells as indicated by the absence of inflammatory macrophages. This percentage of obese patients was essentially identical to that found in the earlier epidemiological study (1). When the arterial blood flow of the metabolically healthy obese was compared to lean subjects, the rates were virtually identical, whereas the arterial blood flow rates were much lower (that's bad) in the obese subjects who had significant fat cell inflammation.

Unfortunately, their characterization of inflamed fat cells was incorrect. What they were really looking at was dying fat cells. The fat cells of these so-called metabolically healthy obese subjects were already sick (i.e., bad fat) since there were metabolic markers (hyperinsulinemia, increased TG/HDL ratios, elevated blood glucose and increased CRP levels) that indicated that inflammation was already spreading to other organs (such as the liver, muscles and pancreas).

The best way to know if you have truly healthy fat cells (no matter how many you have) is to have a low AA/EPA ratio in the blood. This remains the best clinical marker of the true health of the adipose tissue. If you have healthy fat cells (good fat), then you can expect cellular inflammation in other organs will be reduced leading to a longer and better life no matter what your weight.

References

  1. Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, and Sowers MR. “The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population.” (NHANES 1999-2004) Arch Intern Med 168: 1617-1624 (2008)
  2. Wildman RP. “Healthy obesity.” Curr Opin Clin Nutr Metab Care 12: 438-443 (2009)
  3. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  4. Farb MG, Bigornia S, Mott M, Tanriverdi K, Morin KM, Freedman JE, Joseph L, Hess DT, Apovian CM, Vita JA, and Gokce N. “Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity.” J Am Coll Cardiol 58: 232-237 (2011)

Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.

Obesity continues to climb

Last week the Robert Wood Johnson Foundation reported that more than 12 states now have adult obesity rates greater than 30 percent, and that one in three children are either overweight or obese. However, 16 years ago, no state in the United States had an adult obesity rate greater than 20 percent. So in less than a generation, adult obesity has skyrocketed. Yet at the same time, according to the Centers for Disease Control, the percentage of overweight people has remained fairly constant since 1960, while the percentage of obese individuals has increased significantly since 1980. What this suggests is that there is a genetic component that can be activated in those individuals predisposed to gain weight. Once activated, accumulation of excess fat accelerates.

I feel the driving force between this activation of genetic factors is the increasing inflammatory nature of the American diet. We know that it is elevated insulin levels that make us fat and keep us fat. But what really causes insulin to become elevated in the first place? The simple explanation is that it comes from eating excess carbohydrates. However, that is too simplistic an explanation since one-third of adult Americans who are thin are also eating excess carbohydrates.

A more comprehensive answer is it’s insulin resistance that causes elevated insulin levels. Insulin resistance is a consequence of disturbances in the body’s insulin-signaling pathways in the cell caused by cellular inflammation. My most recent book, “Toxic Fat,” goes into great detail on this subject (1). But simply stated, the more cellular inflammation you have in your cells, the greater the likelihood of insulin resistance. And if you are genetically prone to gain weight, increasing insulin resistance will really pack on the extra fat. More insidious is that insulin resistance also creates a “fat trap” through which incoming dietary calories are trapped in your fat cells and can’t be released to provide the necessary energy the body needs. This means you are constantly hungry.

If you are surrounded by cheap processed foods (rich in omega-6 fatty acids and refined carbohydrates), then you are going to quench that hunger with those foods that increase cellular inflammation to even greater levels. The end result is an increasing rise of obesity.

But the fastest growing segment of the overweight and obese population is not adults, but children under the age of 5, with 20 percent now either overweight or obese before entering kindergarten (2). You can’t blame school lunches for this because they are not in school yet. What you can blame is epigenetics (3). This is how the metabolic future of the child can be greatly determined in the womb by the inflammatory nature of the mother’s diet. When these children are born, their altered genetics make them sitting targets for a world full of inflammatory food. Unless you change the foundation of the food supply to become more anti-inflammatory (less omega-6 fatty acids and a lower glycemic load), then the future for these children is incredibly bleak.

References

  1. Sears B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
  2. Kim J, Peterson KE, Scanlon KS, Fitzmaurice GM, Must A, Oken E, Rifas-Shiman SL, Rich-Edwards JW, and Gillman MW. “Trends in overweight from 1980 through 2001 among preschool-aged children enrolled in a health maintenance organization. Obesity 14: 1107-1112 (2006)
  3. Lustig RH editor. “Obesity Before Birth.” Springer. New York (2011)


Nothing contained in this blog is intended to be instructional for medial diagnosis or treatment. If you have a medical concern or issue, please consult your personal physician immediately.