Category Archives: Obesity - Page 4

Thoughts on Obesity Inspired by Stephan

Posted by on June 2, 2011 58 comments

Stephan Guyenet recently did a great podcast with Chris Kresser, discussing the relationship between food reward and obesity. At his blog Whole Health Source he has been expanding upon the podcast with a series titled “Food Reward: A Dominant Factor in Obesity.”

Stephan is a neurobiologist and an expert in the role of the brain in obesity – something I know little about – so it was delightful to have a chance to learn from him.

Today I will try to place Stephan’s ideas in a larger context. I will argue that the concept of a fat mass setpoint is best understood as a dynamic equilibrium among many organs of the body, including the brain; and that food reward is a very important factor in the obesity epidemic because it helps explain many aspects of weight gain and loss and explains why many people are so eager to eat toxic and malnourishing foods, but that it may be going too far to call it a “dominant” factor in obesity.

Metabolic Damage

In some ways I think we know about the causes of obesity than about its nature. It’s very easy to induce obesity in both animals and humans: feed a malnourishing diet providing calories in the form of a combination of wheat, fructose, and polyunsaturated fats.  The links between these toxic foods and obesity are discussed in our book and in several blog posts (see Why We Get Fat: Food Toxins, Jan 20, 2011, and Wheat and Obesity: More from the China Study, Sep 4, 2010). Malnutrition contributes to obesity by promoting metabolic syndrome and appetite (see Choline Deficiency and Plant Oil Induced Diabetes, Nov 12, 2010).

Grains, fructose sugars, and omega-6 vegetable oils provide about 60% of calories in the modern diet, up from less than 10% in the Paleolithic. The strongest rise has been in omega-6 and fructose consumption since about 1970. At the same time, there has been a shift from home cooking of fresh foods to industrially processed and preserved foods. Lack of freshness and industrial processing can significantly increase food toxicity. With these shifts, obesity rates have skyrocketed.

It seems clear that these toxic, malnourishing diets can induce “metabolic damage”: biological changes that alter the way energy is metabolized and energy expenditure is managed – changes that bring about and maintain obesity.

What Are the Sites of Metabolic Damage?

In the obese, altered biology has been detected in many organs. Examples include:

  • Liver
  • Adipose tissue
  • Brain
  • Skeletal muscle
  • Gut and gut flora
  • Endocrine organs (thyroid, adrenals, pituitary)

Metabolic damage is a complex topic in part because so many parts of the body experience it, and interactions between these organs are crucial to understanding obesity.

Any good theory of obesity will have to explain the damage that occurs in all of these organs. It will also have to explain the interactions and interdependencies among these organs.

Stephan: The Brain’s Sub-Systems Matter

Stephan has taught us an important fact: that the brain has two connected but somewhat independent organs that participate in obesity:

  • The energy homeostasis system
  • The food-reward system

The energy homeostasis system is located in the hypothalamus and listens to the hormone leptin, which is released by adipose cells. More leptin indicates more fat mass (but not everyone has the same leptin level for the same amount of fat). The energy homeostasis system adjusts activity and thermogenesis (“calories out”) to achieve its desired leptin level – which translates to a desired fat mass “setpoint.”

The food-reward system influences appetite (“calories in”). It evolved for the purpose of getting us to eat the most healthful and beneficial foods. Thus, starches and fats, staples of the Perfect Health Diet, are good at stimulating the food reward system. Eating large amounts of a single flavor is boring; variety – which minimizes the dose of any one toxin, and ensures a diversity of nutrients – is higher in reward.

So one part of the brain manages “calories in” with an eye toward being well nourished, while another part manages “calories out” with an eye toward achieving just the right amount of fat.

What could go wrong?

Misdirected Food Reward

Unfortunately, a reward system that evolved in the Paleolithic is not necessarily a good guide to navigating modern foods:

  • New foods have come into existence – agriculturally produced cereal grains, hybridized for greater toxicity; refined fructose-rich sugars; and vegetable seed oils high in omega-6 – that didn’t exist in our evolutionary past. These toxic but malnourishing foods confuse the food reward system by invoking the same signals highly nutritious Paleo foods do – starch; fat; salt – but lack nutritional value, and indeed can act as poisons.
  • Food scientists have learned how to design toxic and malnourishing foods that hyperstimulate the food reward system. They stimulate addictive behavior: when you eat one, you want another one, and another. All aspects of the food are designed to trick the food reward system into wanting more – even color.

In this modern environment of industrially processed toxic foods, following our innate food preferences may easily lead us to eat unhealthy diets. It may also lead us to eat more calories than we need, creating a “positive energy balance” that Stephan associates with inflammation.

Food Reward Paradoxes

Food reward is rather hard to make sense of. Many commenters have noted this, and Stephan had to do a post clarifying what he means by food reward:

Food reward is the process by which eating specific foods reinforces behaviors that favor the acquisition and consumption of the food in question.  You could also call rewarding food “reinforcing” or “habit-forming”, although not necessarily in an addictive sense.

A seeming paradox is this: On the one hand, the food reward system evolved to guide us toward healthy foods, as Stephan says:

Food reward is essential for survival in a natural environment, because it teaches you what to eat …

Yet in the modern environment eating high-reward foods is supposed to impair health and cause obesity.

This is of course consistent with our view of obesity – modern industrial foods are toxic and malnourishment – but the mechanisms involving the food reward system are still a bit confusing.

One confusing aspect is that Stephan has spoken of the reward value of macronutrients, with carbs and fat being generally more rewarding than protein, and a carb-fat mix being most rewarding.

This does explain certain observed facts: that “lean meat and vegetables” diets, which are high in protein and therefore low in food reward, tend to induce immediate weight loss. Many popular diet books – Atkins, the Eades Protein Power books, the Dukan Diet – recommend such diets; immediate weight loss helps the diets go viral.

Yet it is not clear that it is consistent with all the facts. In particular high food reward may be consistent with good or ill health, obesity or slenderness. Some of the healthiest weight loss diets, such as ours, are high in food reward (see Low-Protein Leanness, Melanesians, and Hara Hachi Bu, Jan 27, 2011; Perfect Health Diet: Weight Loss Version, Feb 1, 2011).

The food reward system evolved to make us healthier. So it would seem to be the modern environment, especially newly available types of high-reward but unhealthy food, that is the cause of obesity. Food reward enters into obesity only because the food reward system no longer guides us to the optimal foods.

On our view, that toxicity is what matters most, the combination of wheat and fructose with polyunsaturated fats creates obesity, while the combination of safe starches with saturated and monounsaturated fats makes one slender. Yet both may have the same proportions of carb and fat! So it is not clear why food reward is a “dominant factor in obesity” if obesity-causing and obesity-curing diets may have similar food reward.

One possible explanation is that food reward is strongly influenced by subtle changes in the intensity of flavors and flavor associations. Seth Roberts today has a post illustrating this: a reader lost almost all excess weight simply by shifting from Coke and Pepsi to iced tea flavored with a cup of sugar per gallon. Seth writes:

His drink was pleasant enough. It derived pleasure from flavor (tea), sweetness (sugar), and sourness (lemon juice).

Of course Coca-Cola is flavored, sweet, and acidic. Why does one drink cause weight loss and the other obesity?

Seth’s correspondent had drank the iced tea daily for 3 years. If rewarding food is food that people keep returning to, then it seems the iced tea was as rewarding as the Coca-Cola. On the other hand, if the only way we have to judge that iced tea is low in food reward is that it leads to weight loss, or that Coca-Cola is high in food reward is that it leads to weight gain, then the theory becomes circular. Is there some independent way of judging food reward?

Toward a Food-Reward Theory of Obesity

To expand this into a theory of obesity, one has to address both the “calories in” and “calories out” sides of the equation; and also the “body composition” issue – if you have more calories in than out, where do they go? To fat or muscle?

Food reward obviously influences “calories in.” But to be “a dominant factor in obesity” the food reward system has to influence “calories out” as well. How does it do this?

Stephan believes that there is “reciprocal regulation” between the food reward system and the brain’s energy homeostasis system, so that when highly rewarding food is available the food reward system persuades the hypothalamus to accept a higher fat mass.

I’m not aware that Stephan has indicated whether he thinks the food reward system can have any influence on body composition.

So the food-reward theory of obesity seems to be only a partial explanation of obesity. Yet there is evidence for it.

Evidence: Weight Plateaus

The greatest merit of the theory is that it explains why weight tends to reach plateaus and stay at specific weights as long as the diet remains unchanged.

I’ve previously shown this plot from Seth Roberts:

Note how every time he adopted a new diet or lifestyle, weight changed rapidly at first and then settled at a plateau. On low-carb, Alex lost 50 pounds in his first year and then spent most of 2003 at 200 pounds with little change. On the Shangri-La diet he lost 30 pounds in six months and then spent a year at a plateau of 190 pounds. A vegan diet moved him to a plateau at 230 pounds, where he seems to have spent about 8 months.

This is exactly what the food-reward theory predicts. A diet stimulates the food-reward system and leads to setting of the fat mass setpoint. Different food rewards, different setpoints. Manipulating food reward, as in Shangri-La Diet or low-carb high-protein dieting, lowers the setpoint.

But here are two things to consider:

(1)   There is no evidence that the setpoint that is ultimately reached is the optimal weight. Often the plateau weight is still abnormally high, even on low-carb Paleo or Shangri-La Diets.

(2)   There is no evidence that reaching a “normal” weight through a low food reward diet is the same as achieving health.

I think we have to ask the question: what is our goal?  Is it weight loss, or is it returning to optimal health?  If the latter, does a diet that achieves weight loss by manipulating food reward improve health?

This issue came up in the podcast and Stephan’s answer was that a low food reward diet reduces calorie intake leading to negative or neutral energy balance. In many studies, positive energy balance is associated with increasing inflammation while calorie restriction is associated with improved biomarkers and reduced inflammation. So low food reward diets may well be health improving.

I think this quite likely, but here are two possible objections:

(1)   Low food reward dieting has transient and reversible benefits. The period of positive or negative energy balance is transient on all diets; eventually weight settles at a plateau and neutral energy balance is once again attained. So if energy balance is all that matters, the health benefits of a low food reward diet will also be transient. If the low food reward diet is not maintained for life, then eventually a switch to a higher food reward diet will introduce a period of health damage that may exactly compensate for the benefits won during the transition to the low food reward plateau.

(2)   Low food reward dieting is suboptimal for health. If food reward evolved to lead us to the healthiest diet in the evolutionary milieu, isn’t the best health to be achieved by eating for HIGH food reward and living in the evolutionary style eating evolutionary foods?

The first issue tells us that for real health benefits, the low food reward diet has to be a lifelong practice, or else there has to be an independent effect of fat mass on health, with elevated fat mass impairing health regardless of energy balance.

The second issue is particularly interesting in light of the fact that some aspects of Stephan’s diet, which he describes in his podcast with Chris Kresser, seem designed to reduce the food reward of his diet. For instance, he minimizes spices or salt, and avoids between-meal snacks.

Salt is a source of food reward. It also may improve health, as it seemed to do in the recent study published in the Journal of the American Medical Association in which people eating 6 g/day (highest third of salt consumption) were only one-fifth as likely to die of heart disease as people eating less than 2.5 g/day (lowest third).

So should we target low food reward, or high food reward but with evolutionary foods in an evolutionary lifestyle?

Our weight loss advice (See Perfect Health Diet: Weight Loss Version, Feb 1, 2011) is essentially the latter. We favor a mixed carb and fat diet with savory sauces and broths that includes high food-reward items like salt. We disagree with the “lean meat and vegetables” approach to weight loss dieting, although we acknowledge that it usually brings on rapid initial weight loss.

I should say that Stephan’s diet, described in the podcast, is very close to ours. It could be described as a high-carb version of the Perfect Health Diet, with diversity of carbs increased by using detoxification procedures like soaking, sprouting, and fermenting to increase the number of “safe starches.” In describing his diet, he mentioned eating rice but not other cereal grains.

So it seems the differences between Stephan’s diet and ours are rather subtle. But one could argue that the differences between the sugared iced tea and Coca-Cola which Seth’s correspondent drank are also subtle. In the food reward theory of obesity, little changes in flavor can make a big difference in weight.

Does Food Reward Explain Obesity – Or Weight?

I think it’s important to distinguish between the disease of obesity – the health disorder characterized by metabolic damage – and the condition of being fat. Consider:

  • An obese person whose metabolic damage was suddenly and completely cured would be healthy but still fat, because it would take some time to lose weight. But the weight would fall off rapidly.
  • One could be slender and yet still have the disease of obesity, if metabolic damage persisted. If the site of metabolic damage is elsewhere than adipose cells, then liposuction might make a person slender but it wouldn’t cure obesity. The weight would return. This is in fact what happens.

Looking back at Alex Chernavsky’s weight chart, it’s clear that low-carb and Shangri-La diets reduced his weight. It’s not obvious that any diet cured his obesity.

Likewise, we’re all familiar with young people who eat massive quantities of junk food and remain slender. The high food reward diets, even toxic and malnourishing diets, seem not to cause weight gain until some kind of metabolic damage occurs.

It seems that metabolic damage – the disease of obesity – is a prerequisite for food reward to matter.

Stabby found an interesting paper that addresses this. They write:

Only some of the leptin-resistance models (leptin antagonist blockade and aged obese rats) exhibit heightened weight and adiposity gain on a chow diet, while all models discussed demonstrate obesity in the presence of an HF diet. Thus, the leptin resistance appears to be reinforcing “reward eating” beyond caloric energy requirements….

Leptin receptors … act through the JAK-STAT signaling pathway and decrease food consumption upon leptin action. The fact that a chronic reduction in leptin receptor activity in the VTA by siRNA knockdown enhances sensitivity to highly palatable food underscores an important role of leptin receptor function in the regulation of reward feeding behavior (24).

In other words, leptin resistance may have to exist before high-reward foods induce “reward feeding behavior,” or excessive consumption of calories. Likely it has to exist also before the fat mass setpoint is altered from normal.

If obesity (the disease) must exist before food reward becomes a factor in obesity, then it hardly seems likely that food reward is a dominant factor in obesity the disease. It is rather a dominant factor in how much an obese person weighs. That is a different thing.

Fat Mass Setpoint as a Dynamic Equilibrium

Early in this post I listed a half dozen sites of metabolic damage; the brain was only one. I believe that the fat mass setpoint is not controlled by any one metabolic organ, but rather that it is a dynamic equilibrium that is influenced by the whole body.

In other words: metabolic damage anywhere will affect the fat mass setpoint. The brain is not unique in its metabolic role. There are a myriad of ways to alter the fat mass setpoint, and they don’t all involve food, the food reward system, or even the brain.

Is the Brain the Pre-Eminent Site of Metabolic Damage?

Food reward looks to be important because changing the food reward of the diet changes the fat mass setpoint. Reduce food reward and weight drops; raise food reward and weight (usually) increases. This occurs in humans as well as lab animals, as Alex Chernavsky’s chart shows.

But all this really shows us is that food reward is a lever that we can use to adjust weight. It doesn’t tell us that it is the only or most important lever.

Food reward is a very easy lever for scientists to manipulate. It’s easy to replace rodent chow with Cheetos and see what happens. It’s a bit harder to adjust the state of the liver, the adipose tissue, the thyroid, or skeletal muscle.

When those other sites of metabolic damage are manipulated, does the fat mass setpoint change as dramatically as it does when food reward is manipulated?

I think it does. Consider this classic study by Maria Rupnick and colleagues. Giving or withholding angiogenesis inhibitors causes mice to cycle between obese and normal weight:

In some ways this weight cycling is more dramatic than any of the food reward studies, because weight in leptin-impaired (ob/ob) mice goes all the way back to normal with angiogenesis inhibition. And it is thought that the angiogenesis is occurring purely in adipose tissue, not in the brain – so it would seem that this is a clean manipulation of adipose tissue only. Perhaps adipose tissue angiogenesis is a “dominant factor in obesity.”

Many other manipulations of adipose tissue change the equilibrium weight (the “fat mass setpoint”). For instance:

  • The level of activation of PPAR-gamma affects the amount of leptin released per unit fat mass. PPAR-gamma deficiency leads to hypersecretion of leptin from adipocytes; mice become very slender and adipocytes very small because the brain thinks the body is fat. These mice never develop insulin resistance. PPAR-gamma can be influenced by diet.
  • The number of eosinophils – a type of white blood cells – controls whether adipose tissue macrophages are in a pro-inflammatory or anti-inflammatory state. This in turn controls whether adipose cells are insulin resistant or insulin sensitive, with implications for obesity and diabetes. This is one possible pathway by which gut flora may affect obesity, since the types of gut flora influence eosinophil counts.

It’s starting to look like metabolic damage in the adipose tissue alone may be sufficient to induce obesity.

We’ve previously discussed the fact that choline deficiency induces obesity, primarily (it is thought) through effects in the liver. It is likely that alternating high-choline and zero-choline diets would induce fluctuations similar to those in Maria Rupnick’s angiogenic mice. Choline deficiency induced obesity suggests that metabolic damage to the liver alone may be sufficient to induce obesity.

It may be that every organ with a role in metabolic regulation can be manipulated in some way to induce obesity. It looks like the fat mass setpoint is a dynamic equilibrium which depends on the state of every one of the organs involved in metabolic regulation.

If every site of metabolic damage matters and is influential on weight, then it would seem an exaggeration to describe food reward as a dominant factor in obesity. It is an important factor, but not obviously more important than any of the other systems or organs involved in metabolic regulation.

Conclusion

I am grateful to Stephan for sharing his knowledge of the food reward system and the neurobiology of obesity. I immensely enjoyed listening to his podcast and reading his blog posts, and look forward even more to future posts so I can chase references.

But nothing he said has caused me to change my views of obesity or of the best weight loss diet:

  • I think the focus should be on recovering health by curing metabolic damage.
  • I think our evolved preference for tasty foods including starches, fat, salt, and other “high reward” flavors indicates they are healthy, and therefore that a diet rich in such foods is most likely to cure metabolic damage.
  • I think it is essential to stay away from toxic, malnourishing foods made from wheat, fructose sugars, omega-6 oils, and bioactive compounds like MSG; and instead to eat foods that accord with our evolutionary history.

In one sense I think Stephan is right to call food reward a dominant factor in the obesity epidemic. If industrial food designers weren’t trying to make toxic foods rewarding, we might not have an obesity epidemic. People consume large quantities of toxic malnourishing foods because industrial food designers have learned how to conceal their poor taste and make them hyperstimulate our food reward system.

But looking at biology, I have a hard time believing that the food reward system in the brain is a dominant site of metabolic damage. The liver, adipose tissue, and hypothalamus seem likelier candidates to me. So if your goal is not merely to manipulate weight, but to cure the disease of obesity, then I think it is necessary to look not at food reward, but at food toxicity, nutrition, chronic infections, and gut flora. Those are the levers the obese should look to for a cure.

Omega-3s, Angiogenesis and Cancer: Part II

Posted by on April 29, 2011 62 comments

On Tuesday (Omega-3 Fats, Angiogenesis, and Cancer: Part I, April 26, 2011) I introduced the issue of possible relationships between omega-3 fatty acids, their lipid peroxidation products, and diseases of angiogenesis such as cancer, and promised to discuss a possible mechanism today.

It may be well, however, to start by saying a little bit more about the Brasky paper [1] linking prostate cancer to DHA.

Denise Minger’s Commentary on the Brasky Paper

Denise Minger wrote a commentary on this paper for Mark’s Daily Apple, which is excellent. Her conclusion – “given the oxidation-prone nature of all polyunsaturated fats, a massive intake of omega-3’s – despite their brilliance in moderation – could potentially do more harm than good” – is the proper one.

A few of Denise’s observations, however, could stand elaboration.

The study measured the fraction of serum phospholipid fatty acids in various polyunsaturated and trans-fat species, not dietary intake. This is the right parameter to measure, as fatty acid profiles can be measured precisely while dietary intakes assessed through questionnaires are notoriously unreliable. Also, phospholipids are the fats in cell membranes, and these are the ones involved in the inflammatory signaling pathways long thought to drive cancer risk. So cell membrane lipid measurements have the best chance to demonstrate a link to cancer risk.

Denise makes the important point, however, that the connection between dietary fish oil intake and serum fatty acid profile is not simple. Higher DHA intake raises phospholipid DHA levels, but lower intake of non-omega-3 fats also raises the DHA fraction. She points to a study [2] comparing a low-fat diet (20% fat, 6.7% PUFA, n-6:n-3 ratio 11.1) to a high-fat diet (45% fat, 15% PUFA, n-6:n-3 ratio 12.3).  The low-fat diet had more of its fat in the form of long-chain omega-3s, but the specific DHA intake on the diets was not reported. Membrane DHA ended up 28% higher on the low-fat diet.

So if DHA is dangerous, low-fat dieters will be in the most trouble. Another reason to eat a high-fat diet!

Does this affect our interpretation of the Brasky study? I don’t think it affects it much, because study participants were healthy at the start of the study with no history of cancer and macronutrient intakes don’t vary a lot among the general public. Americans vary surprisingly little from the median of about 50% carbs, 15% protein, and 35% fat – so it’s likely that the quartile with high tissue DHA levels were also high fish oil consumers.

However, study participants were followed for 7 years, at which point their prostate cancer status was assessed. Incidence of low-grade prostate cancers had no association with start-of-the-study DHA intake, but incidence of high-grade prostate cancers was strongly associated.

Here are a couple of possible explanations for this pattern:

  1. DHA is bad: DHA doesn’t drive early cancer development but does drive late-stage cancer growth – i.e. the transition from low-grade to high-grade cancer. So the DHA consumers got the high-grade cancers. Angiogenesis does, in fact, drive the shift from low-grade to high-grade cancer, so a DHA-angiogenesis association would be consistent with this explanation.
  2. Hospital diet advice is bad: DHA was a marker at the start of the study for conscientious, educated, disciplined persons who followed health advice and ate fish oil. When these people were diagnosed with low-grade cancer, they followed the dietary advice of their cancer dietitian. The dietitian’s advice?  Eat lots of wheat, whole grains, legumes, and vegetable oils. It could be the conscientious folks who followed bad diet advice from the hospital dietitian who got the high-grade cancers.

So there is a possible confounding effect.

Another of Denise’s assertions is that there is an “otherwise consistent train of research showing that DHA seems protective at best (and neutral at worst).” Now it is true that there are more studies showing DHA to have benefits against cancer than harm. But this trend is hardly consistent, and the vast majority of studies have failed to detect a relationship.

In the comments to Tuesday’s post, eric linked to a 2005 meta-review of studies on omega-3 fats and cancer. [3] The reviewers looked at 1,210 journal articles and found a mixed bag of mostly insignificant evidence:

Significant associations between omega-3 consumption and cancer risk were reported for lung cancer in two studies; for breast cancer in one; for prostate cancer in one; and for skin cancer in one. However, for lung cancer, one of the significant associations was for increased cancer risk and the other was for decreased risk (four other risk ratios were not significant for lung cancer). For breast cancer, five other estimates did not show a significant association. Only one study assessed skin cancer risk. No effects were reported for cancers of the aerodigestive tract, bladder cancer, colorectal cancer, lymphoma, ovarian cancer, pancreatic cancer, or stomach cancer. Thus, omega-3 fatty acids do not appear to decrease overall cancer risk.

Data were insufficient to permit assessment of a temporal or dose-response relationship. [3]

So the score was 4 studies finding that DHA is associated with less cancer, 1 that it is associated with more, and a boatload that it had no association.

Now there are two ways of interpreting this general insignificance of DHA against cancer. One is to note that there are slightly more studies showing DHA to have benefits than harm, and therefore to judge that DHA might be helpful against cancer.

But another, equally plausible, interpretation is this. Most Americans eat far too much omega-6, and their omega-6 to omega-3 tissue ratio is too high, which is pro-inflammatory via the COX-2 pathway. Eating omega-3s including DHA reduces inflammation by downregulating the COX-2 pathway. This accounts for the well-attested benefits of DHA against cardiovascular disease. Now, cancer is promoted by COX-2 pathway inflammation, which is why COX-2 inhibitors such as aspirin and ibuprofen are protective against cancer. [4] DHA’s action to downregulate this pathway must generate an anti-cancer effect. But, unlike aspirin and ibuprofen, DHA has no observable effect on overall cancer risk. This suggests that DHA has other effects, unrelated to its anti-inflammatory activity, that are cancer promoting. These counterbalance the benefits from its anti-inflammatory effect. If DHA has pro-angiogenic effects that are independent of COX-2 mediated inflammation, then this could account for the observations.

One reason an association of DHA with high-grade cancer may have been missed is that it would be detected only in large studies able to segregate cancers by grade. Brasky et al note:

In the European Prospective Investigation into Cancer and Nutrition (EPIC) (12), the highest quintile of percent DHA was associated with elevated risks of both low-grade (relative risk (RR) = 1.53, 95% CI: 0.96, 2.44) and high-grade (RR = 1.41, 95% CI: 0.76, 2.62) prostate cancer. They also reported significant positive associations of the percent EPA with high-grade prostate cancer (RR = 2.00, 95% CI: 1.07, 3.76). Given that the Prostate Cancer Prevention Trial and the European Prospective Investigation into Cancer and Nutrition, the 2 largest studies of blood levels of phospholipid fatty acids, reported increased risks of high-grade prostate cancer with high levels of ω-3 fatty acids, it remains a possibility that these fatty acids promote tumorigenesis. [1]

If there were no other evidence linking DHA to angiogenesis, the Brasky and EPIC study associations would be interesting, but unlikely to change anyone’s mind. Denise points out the need for other evidence – especially, mechanistic evidence – to make the connection more plausible:

We haven’t sleuthed out any mechanism that could explain why DHA (but not other polyunsaturated fats) promotes rapid tumor growth.

And this is where today’s post comes in. In fact, there is a known mechanism by which DHA but not other polyunsaturated fats can promote rapid tumor growth. Shou-Ching told me about it a few months ago.

DHA and Angiogenesis in Macular Degeneration

Let’s start by going back to 2003 and a paper on the role of a compound called carboxyethylpyrrole (CEP) in age-related macular degeneration (AMD). [5] AMD is an eye disease caused by improper angiogenesis. Basically, malformed blood vessels overgrow the eye, causing retinal detachment and blindness. It afflicts 35% of those over age 75, and is the leading cause of blindness in developed countries. CEP? Well, the paper explains:

Free radical-induced oxidation of docosahexaenoate (DHA)-containing lipids generates ω-(2-carboxyethyl)pyrrole (CEP) protein adducts that are more abundant in ocular tissues from AMD than normal human donors…. The CEP adduct uniquely indicates oxidative modification from DHA derivatives because CEP protein modifications cannot arise from any other common polyunsaturated fatty acid. [5]

CEP is uniquely produced by oxidation of DHA, not other PUFAs. Its abundance depends on DHA abundance, availability of retinyl proteins, and the level of oxidative stress.

CEP is elevated in AMD. The correlation is strong: a person in whom the immune system is trying but failing to clear elevated CEP levels almost invariably has macular degeneration (AMD):

Of individuals (n = 13) exhibiting both antigen and autoantibody levels above the mean for non-AMD controls, 92% had AMD. [5]

So CEP is a great marker for AMD. Is it causal?

Well, first it’s worth noting that the retina is uniquely vulnerable to DHA oxidation:

Although rare in most human tissues, DHA is present in ~80 mol % of the polyunsaturated lipids in photoreceptor outer segments (13). The abundance of DHA in photoreceptors, the high photooxidative stress in retina, and the fact that DHA is the most oxidizable fatty acid in humans (13) suggests that DHA oxidation products may have possible utility as biomarkers for AMD susceptibility. [5]

Oxidation is linked to AMD, and antioxidants slow AMD progression:

Oxidative damage appears to contribute to the pathogenesis of AMD (4) based on epidemiological studies showing that smoking significantly increases the risk of AMD (1, 24). The molecular mechanism for how smoking enhances the risk for AMD is not known. We speculate that reactive oxygen and nitrogen species derived from tobacco smoke in the lungs leads to oxidative protein modifications in the blood that contribute to drusen formation and choroidal neovascularization. Results from a recent clinical trial (5) also demonstrate that the progression of AMD can be slowed in some individuals by high daily doses of antioxidant vitamins and zinc. Direct evidence of oxidative damage in AMD donor eye tissues include elevated levels of CEP adducts uniquely derived from the oxidative fragmentation of DHA (6). [5]

This is where things stood in 2003. By 2010 this group, led by Case Western Reserve University chemist Robert G. Salomon, had established that administering CEP to mice can cause AMD:

To test the hypothesis that this hapten is causally involved in initiating an inflammatory response in AMD, we immunized C57BL/6J mice with mouse serum albumin (MSA) adducted with CEP. Immunized mice develop antibodies to CEP, fix complement component-3 in Bruch’s membrane, accumulate drusen below the retinal pigment epithelium during aging, show decreased a- and b-wave amplitudes in response to light, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. Inflammatory cells are present in the region of lesions and may be actively involved in the pathology observed. [6]

This constitutes the first really good animal model for AMD. [6]

How does this relate to cancer? That leads us to a Nature paper from October 2010 [7], from the group of Tatiana Byzova at the Cleveland Clinic.

DHA, Immunity, and Angiogenesis

This is a rich paper. Briefly, CEP has a physiological function: it is transiently elevated in wounds and recruits immune cells from bone marrow to the site of the wound. These immune cells further increase oxidative stress and promote angiogenesis; CEP levels are highest at the time of peak angiogenesis. CEP is highly elevated in cancers. Unlike in wounds, where CEP is elevated for a few days, in cancers CEP elevation is chronic.

Here’s a staining comparing CEP in normal skin and in melanoma:

The CEP is co-localized with CD68, a glycoprotein which binds to LDL and is found on macrophages, and with CD31, a membrane marker of neutrophils, macrophages, and endothelial cells. CEP is marking endothelial cells and white blood cells in angiogenic vessels, and possibly LDL.

It turns out that CEP drives angiogenesis by attaching to an immune receptor, Toll-like receptor 2 (TLR2). There are two major pathways for angiogenesis: one driven by vascular endothelial growth factor (VEGF), which is dominant in conditions of hypoxia (oxygen starvation), and one by TLR2. Of these, the TLR2 pathway may in some contexts be more important. Here are pictures of wound healing in mice:

On the upper left is a normal mouse. On the upper right is a similar wound treated with the VEGF inhibitor AAL-993. This wound is rather like a cancer treated with the VEGF inhibitor Avastin. Wound healing is slightly impaired, but still works.

On the lower left is a similar wound with no VEGF inhibition, but the TLR2 pathway blocked by TLR2 knockout. The wound can’t scab and doesn’t heal successfully. If TLR2 is knocked out and VEGF inhibited, there is no wound healing at all (lower right).

You can accelerate angiogenesis and wound healing by adding CEP to the wound.

In the bottom row, CEP has been added. Left is without VEGF inhibition, right with.

If you administer CEP-neutralizing antibodies to a normal wound, wound healing takes more than twice as long. This confirms that angiogenesis driven specifically by CEP (and therefore by DHA oxidation) is part of healthy wound healing.

Tumors use these same pathways to generate vessels and feed their growth. As the paper notes:

[T]umors implanted in TLR2-/- mice exhibited dramatically decreased vascularization and increased areas of necrosis. [7]

Here’s the paper’s conclusion:

Altogether our results establish a novel mechanism of angiogenesis that is independent of hypoxia-triggered VEGF expression. The products of lipid oxidation are generated as a consequence of oxidative stress and are recognized by TLR2, possibly in a complex with TLR1 on ECs, and promote angiogenesis in vivo, thereby contributing to accelerated wound healing and tissue recovery. If high levels of CEP and its analogs accumulate in tissues, it may lead to excessive vascularization, e.g. in tumors. Contribution of the CEP/TLR2 axis to angiogenesis varies in different physiological settings possibly depending on the extent of oxidative stress. CEP-driven angiogenesis may be an attractive therapeutic target, especially in cancers resistant to anti-VEGF therapy. Inflammation and oxidation-driven angiogenesis may occur in other pathologies, for example atherosclerosis, where arterial thickening can depend on its microvasculature. In these settings, there is an extensive generation of oxidative products which might promote atherogenesis via TLR2. Indeed, it was shown that TLR2?/? mice are protected from atherosclerosis, and this effect could be mediated by cells other than bone marrow-derived29. Thus, along with pathogen- and danger-associated molecular patterns, TLR2 recognizes an oxidation-associated molecular pattern. This new function of TLR2 as a sensor of oxidative stress reveals the shortcut link between innate immunity, oxidation and angiogenesis. [7]

Connection to Vitamin A

DHA is oxidized to a compound called HOHA which then combines with a protein, generally a retinyl (vitamin A-derived) protein to form CEP.

Cancers generate lots of CEP from DHA, and perhaps one way they do that is by generating lots of retinyl proteins. Cancers are known to have disturbed vitamin A biology with lots of retinyl:

Disturbance in vitamin A metabolism seems to be an important attribute of cancer cells. Retinoids, particularly retinoic acid, have critical regulatory functions and appear to modulate tumor development and progression. The key step of vitamin A metabolism is the esterification of all-trans retinol, catalyzed by lecithin/retinol acyltransferase. In this work we show that malignant melanoma cells are able to esterify all-trans retinol and subsequently isomerise all-trans retinyl esters into 11-cis retinol, whereas their benign counterparts – melanocytes are not able to catalyze these reactions. Besides, melanoma cell lines express lecithin/retinol acyltranseferase both at the mRNA and protein levels. In contrast, melanocytes do not express this enzyme … [8]

I haven’t looked much into this literature but it may speak to higher cancer risk with excessive vitamin A intake. Thus high-vitamin A cod liver oil may be a double risk for cancer patients.

Conclusion

It looks like we have a recipe for angiogenesis:

DHA + retinyl + oxidative stress = angiogenesis

This recipe is invoked normally and properly during wound healing. But it is also invoked excessively in pathological contexts – notably in cancers and age-related macular degeneration, probably also in other angiogenesis-associated diseases such as arthritis, rosacea, obesity, psoriasis, endometriosis, dementia, and multiple sclerosis.

In the case of cancer, DHA oxidation to CEP might transform miniscule, harmless cancers to high-grade, life-threatening cancers.

Should this possibility affect our dietary omega-3 recommendations? Well, we need to know the relative importance of the three ingredients on the left side of the above equation in producing angiogenesis. Chris Kresser wondered in the comments Tuesday whether oxidation may be the key factor:

I question whether DHA supplementation would truly play a causative role in the absence of a *pro-oxidative environment*.

In other words, perhaps in someone eating a SAD, not exercising, under a lot of stress, etc. DHA is more easily oxidized and thus potentially carcinogenic.

But in someone that is keeping all other oxidative risk factors low (i.e. they’re avoiding n-6, exercising, managing stress, reducing exposure to chemical toxins, etc.) I tend to doubt that supplementing with DHA could cause significant harm.

That’s the last piece of the puzzle: how do we minimize the level of oxidized DHA?

As I replied to Chris in the comments, low-carb Paleo dieters are not out of the woods in regard to oxidative stress. Oxidative stress is generated normally during metabolism, immune function – and by cancers. If anti-oxidant minerals like zinc, copper, and selenium and vitamins like vitamin C are deficient, then oxidative stress can be very high on a low-carb Paleo diet.

At the moment, I think it’s prudent to eat no more than 1 pound of salmon or similar cold-water fish per week, to avoid further EPA/DHA supplements, and to avoid low-fat diets which tend to elevate membrane DHA levels. Moderate omega-3 consumption is especially important for those suffering from diseases of pathological angiogenesis – especially cancer. DHA is essential for good health – but in excess, it is probably dangerous.

References

[1] Brasky TM et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. Am. J. Epidemiol. April 24, 2011 DOI: 10.1093/aje/kwr027 (Will be at http://pmid.us/21518693.)

[2] Raatz SK et al. Total fat intake modifies plasma fatty acid composition in humans. J Nutr. 2001 Feb;131(2):231-4. http://pmid.us/11160538.

[3] MacLean CH, Newberry SJ, Mojica WA, et al. Effects of Omega-3 Fatty Acids on Cancer. Summary, Evidence Report/Technology Assessment: Number 113. AHRQ Publication Number 05-E010-1, February 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3cansum.htm.

[4] Harris RE. Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell Biochem. 2007;42:93-126. http://pmid.us/17612047.

[5] Gu X et al. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem. 2003 Oct 24;278(43):42027-35. http://pmid.us/12923198.

[6] Hollyfield JG et al. A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol. 2010 Jun;41(2-3):290-8. http://pmid.us/20221855.

[7] West XZ et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature. 2010 Oct 21;467(7318):972-6. http://pmid.us/20927103.

[8] Amann PM et al. Vitamin A metabolism in benign and malignant melanocytic skin cells: Importance of lecithin/retinol acyltransferase and RPE65. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22779. [Epub ahead of print] http://pmid.us/21465477.

Why Did We Evolve a Taste for Sweetness?

Posted by on March 24, 2011 83 comments

After I did my post on Seth Roberts’s new therapies for circadian rhythm disorders, Seth learned of my experience with scurvy and blogged about a similar experience of his own.

Seth made the important point that food cravings are driven by nutritional deficiencies – a point I heartily agree with, which is why it’s so important for those seeking to lose weight to be well nourished – and asked, “Why do we like sweet foods?” His suggested answer was that the taste for sweetness encouraged Paleo man “to eat more fruit so that we will get enough Vitamin C.”

This led to a fascinating contribution from Tomas in the comment thread:

I have read several books on the Traditional Chinese Medicine and they attributed that increased craving for sweets is in fact signaling some serious nutritious deficiencies. They said that it’s in fact meat or starches or other nutritionally dense foods that will soothe the craving, but sweets are more readily available. The taste of meat is in fact sweet as well.

In my experience this seems (the TCM view) to be true. I always have been very skinny, but eating enormous amounts of sweets. After I switched to a proper, paleo-like diet, the situation changed in many aspects and I no longer have such strong cravings and slowly I am gaining some weight.

Shou-Ching and I have great respect for the empirical claims of Traditional Chinese Medicine, and so I found this a fascinating idea. Is our modern taste for sweets actually derived from a taste that evolved to encourage meat eating?

Human tastes

It is generally agreed that animals evolved the sense of taste to detect nutrients and toxins:

Taste helps animals to decide whether a food is beneficial for them and should be consumed or whether it is dangerous for them and should be rejected. Probably, taste evolved to insure animals choose food appropriate for body needs. [1]

The five basic human tastes are sweet, salty, sour, bitter, and umami. Each taste detects either a nutrient class we need or toxins we should avoid:

  • Sweet – carbohydrate.
  • Salty – electrolytes.
  • Sour – acids.
  • Bitter – toxins.
  • Umami – glutamate and nucleotides.

Electrolytes are essential to life, and toxins best avoided, so the evolution of salty and bitter tastes is easy to understand. The umami taste is mainly a sensor for natural (healthy) protein. The sour taste is interesting, in that it is attractive in small doses but aversive in large. Seth argues that low-dose sourness is desirable because it leads us to seek out fermented foods, which supply probiotic bacteria and their fermentation products such as vitamin K2. If so, it is natural that strong sourness, indicating high bacterial populations, would be aversive.

But what of the sweet taste? Is it really a sensor for carbohydrates? If so it does a rather poor job. The healthiest carbohydrate source – starch, which is fructose-free – hardly activates this taste, while fructose, a toxin, activates it in spades. If this taste evolved to be a carbohydrate sensor, it should have made us aversive to the carbohydrates it detects, as the bitter taste makes us avoid toxins. But sweet tastes are attractive!

Sweetness activators

It turns out that the sweetness receptors are complex; many things activate them, and they appear to serve multiple functions.

Wikipedia (“Sweetness”) notes:

A great diversity of chemical compounds, such as aldehydes and ketones, are sweet.

Some of the amino acids are mildly sweet: alanine, glycine, and serine are the sweetest. Some other amino acids are perceived as both sweet and bitter.

The sweetness of some amino acids would seem to support Tomas’s assertions that sweetness detect meat: perhaps it is detecting amino acids. But this seems a bit odd: there is another taste, umami, that detects protein. Would we really need two taste receptors for protein? And lean meats don’t taste sweet.

A possible clue is that the sweet tasting amino acids are hydrophobic, while hydrophilic (or polar) amino acids are not sweet.

Proteins that are hydrophobic end up lodging in cell membranes alongside lipids; proteins that are hydrophilic dissolve in water and reside apart from the fat. Glutamate and nucleotides, which are detected by the umami taste, are hydrophilic and water-soluble.

So maybe the umami taste detects proteins that aren’t associated with fat, while the sweet taste detects proteins that are associated with fat.

Indeed, a leading theories of sweetness holds that compounds must be hydrophobic, or fat-associated, in order to invoke the sweetness taste:

B-X theory proposed by Lemont Kier in 1972. While previous researchers had noted that among some groups of compounds, there seemed to be a correlation between hydrophobicity and sweetness, this theory formalized these observations by proposing that to be sweet, a compound must have a third binding site (labeled X) that could interact with a hydrophobic site on the sweetness receptor via London dispersion forces. Wikipedia (“Sweetness”)

The sweet taste seems to work in collaboration with the bitter taste to regulate toxin avoidance. Wikipedia (“Sweetness”) again:

Sweetness appears to have the highest taste recognition threshold, being detectable at around 1 part in 200 of sucrose in solution. By comparison, bitterness appears to have the lowest detection threshold, at about 1 part in 2 million for quinine in solution.[4] In the natural settings that human primate ancestors evolved in, sweetness intensity should indicate energy density, while bitterness tends to indicate toxicity[5][6][7] The high sweetness detection threshold and low bitterness detection threshold would have predisposed our primate ancestors to seek out sweet-tasting (and energy-dense) foods and avoid bitter-tasting foods. Even amongst leaf-eating primates, there is a tendency to prefer immature leaves, which tend to be higher in protein and lower in fibre and poisons than mature leaves.[8]

This makes some sense: we need a certain number of calories per day, and since “the dose makes the poison,” what determines the toxicity of the diet as a whole is not the amount of toxins in a food, but the ratio of toxins to calories. In an evolutionary setting, our ancestors needed to eat foods with a low toxin-to-calorie ratio in order to minimize daily toxin intake.

So if sweetness is an “energy density” detector, it should be especially strongly activated by fatty foods. If it detects fat-associated compounds, then it would do so.

Why not detect fats directly? In natural foods, fats are bound in triglycerides or phospholipids which are chemically inert. So they won’t bond to taste receptors. Free fatty acids will, but these are not present in fresh foods and would probably indicate some kind of degradation of the food. In fact there seems to be a taste receptor for free fatty acids, CD36 [2], but this may be an aversive sensor for decayed food.

Interestingly, color also affects sweetness:

The color of food can affect sweetness perception. Adding more red color to a drink increases its sweetness with darker colored solutions being rated 2–10% higher than lighter ones even though it had 1% less sucrose concentration.[26] Wikipedia (“Sweetness”)

So red meats are sweetest. Richard Nikoley would approve.

Summary and A Puzzle

A plausible inference would be:

1.      The sweet taste evolved primarily to encourage the eating of fatty, energy-dense meats; and of essential fat-associated micronutrients such as choline and inositol.

2.      The sweetness of fruit may result from plants having evolved a way to hijack the sweetness receptors, and animal food preferences, for their own purposes.

This still leaves a few puzzles. Why, Seth asks, do we tend to neglect sweet tastes when we are hungry, but after dinner is done crave sweet desserts?

Here’s something to consider. Fats are a special macronutrient. We have unlimited storage space for fats, in our adipose tissue, but very limited storage space for other calories. Once we’re full, of course we should lose our appetite for calories we cannot store. But for fats, why not get a little extra in case food is scarce in days to come? There’s always room for a little more fat.

Implications for Binge Eaters

Correct me if I’m wrong, but when people go on an eating binge, they go for sweets.

Presumably, they have a craving for the sweet taste – which, evolutionarily, may be a craving for fatty meats and fat-associated micronutrients.

But if they’ve imbibed the anti-fat propaganda of recent decades and are afraid to eat fat, binge eaters must follow their taste buds to sugars – which unfortunately fail to satisfy any of the micronutrient deficiencies the sweet craving is designed to redress.

Perhaps, then, a good fatty steak, preferably accompanied by some liver and cream sauce, would be the best cure for binge eating. It would satisfy the craving, but also satisfy the underlying nutritional need that generated the craving.

Implications for Weight Loss

If, as I believe, the key to weight loss and curing obesity is eliminating appetite, then it’s important to eliminate any deficiencies of fat-associated micronutrients. Micronutrient deficiencies trigger food cravings, and deficiencies of fat-associated micronutrients will trigger a craving for sweets.

In the modern world, we know how a craving for sweets is likely to be satisfied – by eating sugary, nutrient-poor foods. Unfortunately these foods do not contain the fat-associated nutrients (such as choline) whose deficiency is probably driving the craving. So the craving persists unabated no matter how many sugars are eaten.

Persistent food cravings despite an excess of caloric intake is probably a necessary (though not sufficient) condition for obesity to develop. Unsatisfied cravings probably make weight loss extremely difficult.

What of Vitamin C?

Vitamin C – ascorbic acid – is an acid so it directly activates the sour taste.

So perhaps the sour taste evolved to help us get vitamin C. This would actually complement Seth’s idea that the sour taste encourages us to eat fermented foods. Fermented foods are high in vitamin C.

I had a fairly severe case of scurvy and don’t recall being attracted to sweet flavors. Instead, I was ravenously hungry. My appetite generally, not craving for any particular taste, was promoted. If anything, I was less attracted to sweet tastes. So I think it’s plausible that vitamin C deficiencies may lead to a general appetite upregulation, or to cravings for sour foods, rather than a craving for sweets.

Conclusion

Our evolved taste receptors can tell us a lot about what our bodies need. Food cravings are a pretty good sign of an unsatisfied nutrient deficiency.

But sometimes, it’s less than obvious what a craving signifies. Our modern food environment is so different from the Paleolithic: We have many industrially produced foods designed to fool our Paleolithic taste buds into eating nutritionally unsatisfying calories.

Humans evolved, not in the forests where fruit was available, but in open woodlands where tubers and other tasteless starch sources were abundant but fruit rare. In this context, our cravings for sweet foods may have been directing us to eat animal fats.

It may be that the cravings for sweets often experienced by binge eaters and the obese are really a craving for animal fats. If you feel drawn to sugar, perhaps you should ask yourself: Steak or salmon?

References

[1] Bachmanov AA, Beauchamp GK. Taste receptor genes. Annu Rev Nutr. 2007;27:389-414. http://pmid.us/17444812.

[2] Laugerette F et al. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J Clin Invest. 2005 Nov;115(11):3177-84. http://pmid.us/16276419.

Perfect Health Diet: Weight Loss Version

Posted by on February 1, 2011 396 comments

We started 2011 with a discussion of Experiences, Good and Bad, On the Diet; which led us into the issue of weight loss, especially for peri-menopausal and older women.

This is an especially poignant issue for erp, who is 76 years old and would like to lose weight for her upcoming knee replacement surgery, but cannot walk.

This is the toughest possible scenario for weight loss:

  • Whether for genetic (X vs Y chromosome) or hormonal reasons, women are more prone to putting on weight than men. (Men are more prone to diabetes.)
  • Hormonal changes after menopause seem to make it tougher for women to lose weight.
  • A petite woman doesn’t need as many calories as a larger person … but her micronutrient needs, and thus her appetite, may still be high.
  • Aging brings more efficient energy utilization and reduced energy expenditure. Thus, the elderly have a smaller energy “sink” in which to dispose of excess fat. A teenager can eat like a horse and stay thin; not so an older person.
  • An injury that prevents walking makes it even harder to burn off fat. Walking is a tremendous aid to fat loss.

Designing a weight loss diet for someone like erp really forces a hard look at how to optimize a weight loss diet. Get it even a little bit wrong, and the diet either won’t work for weight loss, or will be malnourishing.

The Three Keys for Weight Loss

The three keys for an effective and healthy weight loss diet, as I see it, are:

  1. Elimination of food toxins. Food toxins are the primary cause of obesity and you can’t expect to cure a condition by causing it!
  2. Perfect nourishment. The diet should be as nourishing as possible. The dieter should be in the “plateau range” of every nutrient – vitamins, minerals, organic molecules, carbs, protein, and fats.
  3. Calorie restriction. You have to be in energy deficit to lose weight.

The main food toxins to avoid are fructose, polyunsaturated fat, and wheat (see Why We Get Fat: Food Toxins). In my advice to erp, I suggested replacing some of her fruit with “safe starches” like potatoes, and replacing her PUFA-containing nuts with low-PUFA macadamia nuts or other foods.

But the harder part is achieving a calorie restricted diet when so few calories are being expended, and yet avoiding malnutrition. How may that be done?

Eat Protein and Carbs; Reduce Fat

This may surprise many readers, since we’re fat-friendly, but there should be no reduction in carb or protein consumption on weight loss diets. Calorie restriction should come out of fat.

The Perfect Health Diet “plateau range” for carbs and protein is 600 to 1200 calories. Eating less than 600 combined carb+protein calories per day raises the specter of either protein deficiency (leading to hunger) or glucose deficiency (leading to zero-carb dangers).

So if a typical daily intake is 400 carb calories and 300 protein calories, there’s really not much room to cut protein or carbs.

Remember that the body doesn’t have a significant store of carbs; the body’s total glycogen supply amounts to about a day’s needs. Nor does it have a store of protein, apart from skeletal muscle; and you don’t want to lose your muscle.

But it does have a large store of fat – those adipose cells that you want to shrink.

So to conserve muscle and reduce fat tissue, you have to eat your normal allotment of protein and carbs while restricting fat intake. As long as there is no serious dysfunction of adipose cells, they will release fat as needed to meet the body’s fat needs. And that’s what you want – fat being moved out of adipose cells to be burned.

So your calorie-restricted weight loss diet will be just as nourishing as your regular diet. Only the source of the nourishing fats – adipose cells instead of food – will be different.

Eat Nourishing Fats

But not all fat can be removed from the diet. The reason is that not all nutrients found in fat-containing foods are stored in adipose cells.

You see, fats are stored in adipose cells as triglycerides. But we need to get other lipid molecules, not just fatty acids, from food. The really crucial molecules are the phospholipids, especially phosphatidylcholine.

Choline, inositol, and a few others are organic molecules are bonded to fats in cellular membranes. We need to obtain these from our foods in order to be well nourished.

Diets low in choline strongly promote obesity. Therefore, anyone seeking to lose weight should be sure to eat a choline-rich diet.

The easiest way to do that is to eat 3 eggs a day and a ¼ pound beef liver once a week.

Another type of lipid that may be missing from adipose cells are omega-3 fats. Balancing the omega-6 to omega-3 ratio is helpful against obesity, and most people are omega-3 deficient. So eating up to 1 pound of salmon or sardines per week may assist weight loss.

Beef and lamb – meats that are low in omega-6 fats – would be good choices for any additional meat.

Be Super-Nourished

The body’s appetite regulation mechanisms are highly attuned to your micronutrient needs. Micronutrient deficiencies will tend to induce a strong appetite for food, as your body tries to get you to obtain more nutrition. This could be a major reason why “empty calories” such as cotton candy are fattening.

Our book has some examples of “micronutritious foods”: variety meats, bone soups, seaweed, shellfish, eggs, and vegetables.

Nutritious, low-calorie foods like bone soups can be very helpful for weight loss. Soups can also be a good way for someone who doesn’t like vegetables to obtain them.

In addition, I would recommend that every person on a weight-loss diet take our full supplement regimen: a daily multivitamin, D, K2, C, magnesium, copper, chromium, iodine, and selenium. Also, I would suggest taking our optional B vitamins: thiamin, riboflavin, pantothenic acid, biotin, vitamin B6, vitamin B12, and choline (note the exclusion of niacin and folic acid).

Keeping Calories Down

What is the minimum calorie intake that meets all these nutrient considerations?  Eggs, salmon, and beef have more fat than protein, so if you’re aiming for 400 carb calories and 300 protein calories, you’ll probably eat at least 500 fat calories per day. So it would seem to be impossible to go below about 1200 calories per day while still being well nourished.

The place to cut calories, then, is the extra fats. Perfect Health Diet favorites like butter, coconut oil, and cream are, sadly, top candidates for reduction.

Of course, the more active you are, the more you can include those fats.

For less active people, the Weight Loss Version of the Perfect Health Diet becomes similar to a lot of popular diets. Many diets recommend a roughly even calorie distribution, with 30-40% of carbs, protein, and fats. This is what a calorie-restricted version of the Perfect Health Diet should look like too.

So, the perfect day in a weight loss diet: soup, potatoes or other safe starch, salmon, eggs, vegetables. Not too much fat in the sauces!

A good meal might look like this:


Mash the sweet potato with eggs instead of butter, and this would fit our weight loss recipe.

Conclusion

It’s a little humbling that I’ve started 2011 with 5 posts on the subject of healthy weight loss, but have only scratched the surface of this complex topic.

For instance: In the book we used the rubric “metabolic damage” to describe the biological dysfunction associated with obesity. But we never really chased the complex biology of exactly that damage consists of – and how it can best be healed.

Today, I’ve presented what I believe is the best strategy for healthy weight loss. But other techniques – such as ketogenic dieting, intermittent fasting, exercise, and more – can contribute to healing the metabolic damage of obesity. As 2011 goes on, I’ll return to this topic.

I am intensely interested in the experiences of anyone trying to lose weight using our diet, and I hope that together, we can understand the disease of obesity better, and figure out good ways to achieve both healthy weight loss and a permanent recovery from metabolic damage of all kinds. So please, if you are trying to lose weight, keep me posted on your experiences, whatever they may be!

Related Posts

From 2011:

From 2010: