Endocannabinoids, Fat, and Rats

There has been a flurry of rather interesting my-style Evolutionary Psychiatry papers out this week.  Tomorrow (I hope), I'll review some findings about probiotics, gut microbiota, and brain function (in rodents, alas), and there is also a paper Jamie sent me about how breakfast staple types are correlated with gray matter and cognitive function in healthy children (If you have but two breakfast choices and you are forced to rely on correlative data, should you feed your children bread or rice if you are playing it safe and interested in protecting their growing brains?  Guess.)  Jamie might blog that one first, actually.  Who knows.  Today, though, I'm looking at the paper Endocannabinoid signal in the gut controls dietary fat intake published in PNAS.   

First off, I've added two new blogs to my "Of Like Minds" listing on the right,  Chris Kresser's Healthy Skeptic, and Anastasia's Primalmeded.  I've been meaning to add Chris for some time, but never really got around to it.  He's terrific and thoughtful.  Anastasia is a mom and medical student in Australia.  I find her relatively new blog to be no-nonsense and refreshing.

Now, the endocannabinoid paper.  Well.  If you haven't seen them yet, I've covered endocannabinoids previously:

Omega 3s, Mice, and Receptors for Funny Cigarettes

More on Endocannabinoids *cough* with a Focus on Obesity Regulation

A Summary of Endocannabinoids and Obesity

For some background in rat studies, I am far more familiar with the binge eating literature than the obesity literature.  All the bingeing literature I'm aware of has been done with omega 6 fats (usually Crisco, though trans-fat free Crisco was used for more recent studies) and grains and sugar, and the consistent findings are: Rats will binge on sugar or fat (omega 6).  Only the combination of sugar and fat resulted in weight gain (otherwise bingeing rats will make up for extra calories by spontaneously restricting at other times).  One study showed bingeing rats maintained their weight but increased fat mass bingeing on crisco (I think.  I have to recheck that one.  I'll check and edit later if I am misremembering.)  

The major distinction in this literature comparing rats to humans is that humans do not typically binge on fat alone, but are far more likely to binge on pasta, bread, sweet foods, chocolate, and salty snacks.  The bingeing literature may not have the same focus and may not be as important to the overall state of obesity as the straight-up obesity literature - but with respect to "munchies" and endocannabinoids, I think it is a fair backdrop.

Alrighty then.  In the new paper, researchers gave rats "sham" feedings of (okay, three guesses as to what they used as the fat?  Pasture butter?  Coconut oil?  Lard?  WRONG) corn oil, a mixed "nutritionally complete" diet, sugar solutions, and protein solutions.  How do you sham feed a rat?  Well, very unpleasantly.  You install an aluminum cannula into the stomach and let the liquid food drain out as you allow the rats to eat a liquid diet of the aforementioned macronutrients.  Mmmm.  A spoonful of corn oil.  Delicious.

Here is what the researchers think about eating fat:

Mammals have an adaptive advantage in seeking fat-rich foods, which are nutritionally essential but scarce in most natural habitats.  This innate preference can become maladaptive… when it is not limited by environmental constraints.  Indeed, the unrestricted availability of fatty foods, which characterizes diets of industrial societies, is considered to be a key contributing factor for obesity, diabetes, and cardiovascular disease.

Now a little review of endocannabinoids.  They are a happy little family of omega-6 derived bioactive molecules that bind to the cannabis receptors (CB1 and CB2).  These receptors are also activated by cannabis.  The two best studied endocannabinoids are 2-AG and anandamide.  

The researchers in this study were trying to further elucidate the mechanisms by which endocannabinoid feedback goes between the mouth, gut, and brain.  It has been found previously that CB1 receptors on the tongue modulate neural activity elicited by a sweet taste (1).  Neural signals from nutrients - including fats and sugars, are transmitted from the mouth to the brain via the cranial nerves (specifically V, VII, IX, and X).  The twelve pairs of cranial nerves shoot out directly from the brain rather than being shuffled through the spinal cord first.  Most of them predictably control stuff in the head and neck.  One of the cranial nerves, the vagus (X), takes a long trip down to the gut, and seems to be responsible for a lot of the brain regulation of the gut and digestive system, and carries the feedback between the two areas.  

So, what happened with the sham feeding of sugar solution, protein solution, corn oil, or a mixed liquid diet and brain and nerve activity in these rats?  Levels of the endocannabinoids 2-AG and anadamide were increased in the jejunum  (the middle part of the small intestine) of rats fed the corn oil or mixed liquid diet, but not in rats fed the protein or sugar solutions.  None of the solutions changed the jejunal content of oleoethanolamide, a fat-derived molecule that typically signals satiety and is usually released by the small intestine in response to the ingestion of fat.  

Interestingly, severing the vagus nerve in these rats stopped the production of the endocannabinoids when the rats were sham-fed the corn oil.  This would suggest that feedback from the brain is required to produce endocannabinoids in the small intestine in response to a corn oil signal from the small intestine.  

The researchers did some more complicated work studying different entities along the metabolic pathways of the endocannabinoids to figure out exactly how the endocannabinoid levels increased.  Sham-feeding of corn oil didn't affect the generation of 2-AG, but did seem to slow down the natural breakdown of 2-AG (which is typically done via hydrolysis, biochem nerds.)  As for anandamide, the other popular endocannabinoid, sham-fat feeding both increased its production and decreased its breakdown.

In another twist of the study, the researchers measured the amount of corn oil or regular chow the rats consumed while they infused rimonabant, a cannabis receptor inverse agonist (in simplistic terms, it blocks the ability of the endocannabinoids to activate the cannabis receptors) into the jejunum.  The rats ate much less corn oil when they had guts full of rimonabant, and to a lesser extent, less regular chow.  Thus the researchers conclude that eating fat increases a positive feedback mechanism causing increased ingestion of foods (especially more fat) via a endocannabinoid signal between the gut and the brain along the vagus nerve.  They were excited to try gut-specific cannabis receptor blockers that wouldn't have all the pesky anxiety, insomnia, and depression side effects that rimonabant (which is active in the brain) does as a treatment for obesity.  It is also known (in rats) that small-intestine levels of 2-AG and anandamide rise in repsonse to food deprivation and fall upon refeeding, suggesting they may signal energy balance and promote caloric intake.

And, last but not least, the discussion goes into details about how reward area dopamine stimulation is affected by feeding rats fat-rich foods.  I don't have time to chase down all those papers right now, but let's guess which fat was used in those studies as well…

My take?  Sure, play it safe. Don't eat spoonfuls of corn oil.  Especially if you are a rat.  But elucidating some of these pathways is definitely interesting.  If there is some reason we should be extrapolating the sham feeding results to whole, real food eating in humans, please explain.  It seems to me the finding that the normal small intestinal fat satiety feedback molecule, oleoethanolamide, was not elevated with sham-feeding of corn oil or the mixed diets or sugar or protein suggests this model is incomplete at best.  

Healthy Skeptic Podcast

I was very honored to be asked to be interviewed on the Healthy Skeptic Podcast by the amazing Chris Kresser - here's the link:

Healthy Skeptic Podcast, Episode 13

There's also a new paper claiming that eating fat increases appetite by modulating the endocannabinoid system - when I checked earlier the paper wasn't up on pubmed yet but I will track it down and see if it passes the sniff test.

In the meantime, enjoy the podcast!

Diet-Induced Obesity and Brain Changes

At the beginning of this year, an interesting French study was published, Changes in Brain Activity After a Diet-Induced Obesity.  Don't get too excited - they used pigs, not humans, specifically "mini-pigs," which sound awesome.  In short, they put two sets of pigs on either standard pig crap lab diet with controlled calories to keep them lean, or a crap lab diet with extra carb and extra fat ad libitum for 5 months.  They did SPECT scans of the pigs' brains before and after, and also (in a separate paper) were able to determined that the now-obese pigs had insulin resistance.

First, though, let's start with some human data and take a tour of some parts of the brain.  Let's introduce ourselves to the prefrontal cortex.  Okay, so when Tom Naughton does his head bangs on his desk, I'm guessing he's whacking his prefrontal cortex (which we are going to call the PFC).  It's the area that hangs out over your eyes.  Fortunately this habit has not seemed to harm his brain function, if his recent terrific articles are any measure.

Now the prefrontal cortex is more developed and extensive in humans than any other primate,  and it is responsible for what is called "executive function."  That is, the PFC helps us predict outcomes, prioritize, modulate our emotions to socially acceptable norms, and helps us sort out the best options given conflicting data (reasoning, basically).  It is a bit like a policeman for your brain - sure, it would be super fun to get drunk as a skunk and throw beer bottles off your roof at the neighbors  - but your policeman says, er, no, that might get you in trouble.  Drinking alcohol, in fact, disinhibits the PFC which enables you to ask out the girl you wouldn't have approached sober.  Of course, if you are making a selection with impaired reasoning, the girl you ask out might not look quite so good to you sober…

But back to obesity.  Our brains do play a major role in whether we gain fat or not.  And part of what happens in obese humans is that the prefrontal cortex seems to be less active than in lean humans.  This finding is especially interesting in obesity, as the PFC sends nerve fibers to the core appetite regulation part of the brain (the "central orexigenic network") - presumably, when fully active, the policeman is shaking his night stick at you when you want to go to the fridge for that second helping of ice cream.  Nuh uh.  You have had enough. If the policeman is offline, it may be easier to consume extra helpings.  (I'm not sure I like the policeman analogy so much - too close to lack of willpower or gluttony and sloth, but it does fit into the model of weird modern food poisoning our brains, so that the reasoning piece of our appetite regulation machinery is shot.)

Now the question is, obviously - do obese humans start out with underactive PFCs, or is it acquired along with obesity? Well, women who were obese with underactive PFCs  regained their frontal lobe function with successful weight loss.*  This evidence would suggest that underactive PFCs aren't hard-wired, but depend upon the environment, including nutrition.  However, a study going the opposite direction - starting with lean humans and making some obese with controlled overfeeding for an extended period is a tough sell to the institutional review board these days.  So it is easier to use mini-pigs, who also seem to have particularly well-developed PFCs.

Let's look at the experiment.  17 pigs, 9 kept lean and 8 made obese.  One of the SPECT scans in one of the obese pigs was "unusable" so the data is for 9 lean and 7 obese.

The standard diet was composed of 33% barley, 25% wheat bran, 12% soy shell, 10% wheat, 10% sunflower meal, 6% soy meal, and other minor components.  Fat provided 2.17% of the total nutritional value.

Well, if in much of pig evolutionary history they were set loose in a warehouse of a cardiologist's favorite Power Bar ingredients, perhaps this is what the minipigs would eat these days and stay nice and lean and metabolic syndrome free.  In this experiment the pigs were fed 102 calories per kilogram each morning, and the pigs dutifully ate their swill in one meal and did their piggy things and stayed lean.  Since calories are calories…though I will get back to the standard diet later...

Now the obese diet:

…eight animals were fed with a Western Diet (WD) enriched with carbohydrates and lipids offered ad libitum during 5 months (one ration offered at 0900 hours and calculated to exceed daily calorie consumption of the animals.  The WD was composed of 32.65% wheat, 15% soy meal, 12% wheat bran, 10% barley, 10% sunflower oil, 10% cornstarch, 5% saccharose, and other minor components.  Fat provided 22.74% of the total nutritional value.

Gak!  Enough said.  I wonder if this was that high-oleic sunflower oil.  Anyway….

The results of the experiment - well, one interesting thing is that the dietary pattern of the fattening pigs changed.  The control pigs ate all their food at once, each morning, but as the "Western Diet" pigs became more obese they would eat 4-5 meals a day, and then spontaneously fast for a day or several days.  By the end of the 5 months, the lean pigs weighed 38 kg on average (which is about where they started).  The obese pigs weighed 67.1 kg.  That's pretty impressive for five months.  The day before the final brain imaging, the lean pigs ate 1561 calories each, and the obese pigs ate 2183 calories each.

And, as expected, the brains of the obese pigs did indeed have decreased activity in the PFC, both in the dorsolateral prefrontal areas and the anterior prefrontal cortex.  In addition, there was a lessening of activity in some brain areas associated with the "reward system" (specifically the nucleus accumbens, the ventral tegmentum, and the nucleus pontis), which is consistent with the addiction literature - people who are addicted to something have less activation of the reward areas of the brain in response to the addictive stimulus than people who are not addicted.  Thus addicted people need more and more of the stimulus to feel reward.

A key finding is that the decreased activation of the PFC correlated significantly with the final weight of the pigs - so the more obese they became, the more depressed their PFC function tended to be.

So, we have learned that in mini-pigs, sunflower oil, wheat bran, cornstarch, and sacchralose is a quick recipe for obesity, and that pigs on a similar diet minus so much cornstarch and oil will stay the same weight as long as you feed them controlled calories… (which is something of a weakness of the study if they were trying to prove that sunflower oil and starch make you fat, which they weren't, but it would have been interesting to see what happened if both groups were fed ad libitum. )

So, in all likelihood, given the corresponding human data in the reverse trial and observationally, the PFC does indeed play an important role in feeding signals and hunger/satiety states.  And I'll quote the researchers here:  "Whether the alteration of the brain dopamine system and prefrontal cortex metabolism is a cause or a consequence of obesity is still unknown.  The answer brought by our study is that less activation of the prefrontal cortex is definitely an acquired anomaly related to obesity, and not a "hard-wired" feature."

*I framed that sentence the way the mini-pig paper did, using "regained frontal lobe function" - however,  in the original paper the womens' frontal lobe function was not measured prior to the weight loss, so it is also possible that the women who successfully lost weight were a subset who had better frontal lobe function - but in that study the obese women had decreased PFC metabolism, the lean and formerly-obese women had PFC metabolism indistinguishable from each other.

Also - for more dopamine/frontal lobe/obesity discussion - a post from last year, ADHD and Obesity.

Primal Docs and a Whole30

Hello there!  Happy July.  I've barely had a moment to do anything but tweet and follow the latest posts, but I did find this paper from January that I had meant to blog about - I believe Jamie sent it to me, and he did write about it… but it is interesting enough for a second look to be sure.   I'll have a blog up on that one tomorrow.

Before that, though, I'd like to point your compasses to a couple of things.  First off, Chris Armstrong of The Celiac Handbook approached me after reading my Wheat and Schizophrenia post over at Psychology Today.  Turns out that Chris himself basically follows a primal/paleo lifestyle,  and he developed the website Primal Docs in order to create a resource for people to find physicians (typically MDs or DOs) who would support and understand that lifestyle.   You'll notice I'm one of the doctors over there, along with John Biffra and a growing group of very healthy-looking folks!  I have to say it does disturb me that so many doctors seem to be struggling with metabolic syndrome these days.  If doctors can't keep themselves healthy with all that supposed discipline and knowledge, how is it that everyone else can?  And sure, doctors are only human, and perhaps it is good for a doctor to be a patient every now and again, but on the other hand, I wouldn't go to a mechanic whose car is always broken down.

Secondly, beginning yesterday I started a stricter little stint of paleo eating called the Whole30.  The plan was designed by Dallas and Melissa Hartwig of Whole9Life, and in full disclosure they did send me a complimentary copy of their handbook, though they did not ask me to follow the program or mention them on my blog.  The Whole30 is a bit different than my typical routine because there is to be no cheating, no added sugars, no sugarfree gum, no sugar substitutes (which I don't use except for the occasional Diet Coke.  I know.  I know.  I'm addicted.  I can stop drinking it for long periods, but I still crave it for some reason, and I would actually drink regular Coke instead, except that it is so sweet I can't stand it… so...)  no alcohol, no white rice or white potatoes, and no dairy of any kind.

In my ordinary day-to-day eating I don't consider wine or dark chocolate a "cheat," white potatoes and white rice I consider perfectly fine though a bit less nutrient dense calorie per calorie than other foods, and I will regularly partake of some high-fat dairy (maybe some yogurt or heavy cream once a week, cheese once or twice a week, and pasture butter on a near daily basis).  Also, every once in a while I will cook some things with raw honey or real maple syrup and I don't give it a second thought.  Once a month I have some honey in my tea, even.  Otherwise, I'll eat just about anything (such as a couple of slices of pizza, ice cream, bbq ribs from a restaurant, a miniature snickers bar from my daughters' halloween stash, mexican food complete with refried beans and a *few* corn chips, some restaurant french fries, even a cookie) maybe once every couple of weeks.  What Mark Sisson would consider the "20%" I suppose, though it wouldn't equal nearly 20% of my diet if you don't count the white rice and potatoes or dark chocolate - I've had Mexican food probably twice this year so far, BBQ ribs twice, pizza (my most common cheat) once a month - you get the idea.

And in the past, maintaining my normal weight was a constant battle of exercising and accounting for macronutrients and scarfing down low-fat yogurt and cottage cheese… any night out at a restaurant or extra ice cream or whatever would have to be meticulously made up for, or my weight would creep up.  Ever since switching to the paleo lifestyle (including IF), as long as I stick to it the majority of the time, I've been able to eat whatever I want (every now and again), decrease the amount of time spent exercising, and my weight doesn't budge.  Which is nice.  It takes all the worry out of eating, and some of the naughtiness out of cheating.  I don't cheat because I'm craving (except the Diet Coke, which is the only cheat I'm ashamed of…), I cheat because Mexican Food can taste good, especially if you don't eat it all the time.

The first three months of paleo I was very strict with my plan, which was also dairy-free, alcohol free, and entirely gluten-free.  While doing that plan, I stumbled upon the Primal Blueprint and what then was PaNu and Whole Health Source and did a lot more of my own investigating, which led me to my blog, of course, and eventually reading Perfect Health Diet.  Thus developed my day to day eating, which is sort of a cross between PB and PHD, and right now I only supplement with a multimineral in the morning and magnesium at night.

I haven't been super-strict since July of last year, which is also when I stopped losing weight, I think.  So in combination with CrossFit I wanted to see if I could get a bit leaner, and the support of the Whole30 twitter crowd seemed like a good way to do it.  I feel good for the most part - maybe I will even feel better.  Who knows.  And while I don't think a tiny bit of casein in pasture butter or a tiny bit of honey in my tea or a glass of wine or white rice and white potatoes are major problems, the idea of the Whole30 is to banish any sugar cravings (which I don't think I have - unless that is part of the Diet Coke monster - though it is not just the aspartame, as I don't crave Diet Pepsi or those weird diet iced teas and Diet Dr. Pepper I gave up years and years ago because gives me a sugar crash, weirdly enough - it's just Diet Coke.  Very strange.  What do they put in that stuff?), and to have your diet consist entirely of very nutrient-dense foods.  While moderate alcohol and white potatoes and white rice are fairly innocuous, they do reduce the nutrient density of the day.

Right now I'm in the middle of Day 2, and have a bunch of veggies and high quality protein at the ready, and will be substituting sweet potatoes and squash and probably a second daily serving of fruit for the white potatoes and rice, and coconut oil and olive oil for my usual butter.  I'm not gonna lie - because I don't want to cook two separate meals all the time, and I like to get K2 into the kids, I'll be using pasture ghee from time to time, and I'm going to consider that Whole30 compliant too.  This bit is a little deviation from Dallas and Melissa's advice - It's just 30 days, just do what we say and don't tweak.  But I'm fairly certain that will be my only deviation.  A lovely chilled glass of pinot grigio (and the fizz from the Diet Coke, I suppose) has been replaced with San Pellegrino Sparkling Natural Mineral Water and lime.  It's inexpensive, has some minerals, and I always feel very sophisticated drinking it.

I do have a vacation planned in a few weeks - and that will be the hardest week of the Whole30, I'm sure.  Well, we will see how it goes!

Two ADHD Posts At Psychology Today

How Does Diet Affect Symptoms of ADHD?

Can a Multivitamin Help Treat ADHD?

Diet and Dementia - A New Study Part 2

Last week I introduced us to a new diet and dementia paper.  For the most part I presented the results and fumbled around with the interpretation, but didn't quite know what to make of it, given a lack of details about the actual diets in the paper.  I contacted the researchers, who were kind enough (in fact, they were very kind in their emails!) to send me a bit of information about the methods and a sample daily diet.  So now I can fumble around some more.

Let's start with Big Picture context.  I tend to forget sometimes that thoughtful and well-meaning people still believe that Animal Fat is Bad and Simple Carbs are Bad and that we should all be eating cardboard (er, I mean fiber-rich foods), skim milk, olive oil (in moderation), and skinless chicken breasts.  I'm also perhaps a little too comfortable with the fact that not only do thoughtful and well-meaning people have that view, but that they think my view (that Animal Fat is Good and Macronutrients Aren't as Important as You Think Absent Insulin Resistance or Other Issues Such as Dementia In Which Case You Should Be Eating More Fat) is lunacy.  I mean, my kids get whole milk yogurt still, and they are both over two, the age when fat becomes Bad according to the USDA.  (Okay, I'll stop with the capital letters now…)  

Part of the reason that I'm comfortable being thought a lunatic is that I think most people secretly believe psychiatrists are lunatics anyway.  There is almost always a bit of a double-take when I tell people my profession.  In medical circles, I will get a "oh, she's one of those" sort of look.  Among lay folk (at a party, for example), people will suddenly clam up or begin telling me their life stories and all about the different psychiatric medicines they've tried.  Psychiatrists are a bit of a puzzle - what is it we do, anyway?  I think of what psychiatrists do thusly: we look at big, complex puzzles comprised of experience, world view, psychology, environment, and biology and try to figure out how to help someone (typically presenting with emotional issues, though this day and age it could be anything) manage all the factors that could be contributing to the problem.  That holistic view of problem-solving health problems makes a psychiatrist somewhat uniquely suited to examining Evolutionary Medicine, but perhaps that is my bias.  :-)

Speaking of bias, this week I read with great interest (as always) Paul and Shou-Ching Jaminet's Perfect Health Diet blog, particularly Blood Lipids and Infectious Disease Part 1.  In the comments I linked to an commentary on a study about cholesterol and all-cause mortality in Honolulu from the Lancet, the money quote being here:

Sir—The central, surprising, finding from our study was that low serum cholesterol, persisting for 20 years, increased subsequent all-cause mortality. We have no logical explanation for this finding, nor, apparently, do any of our correspondents.

Here is a graph of their data.


And another money quote (these are both from the author's letter replying to other commentary about the findings):

We agree that the association between low cholesterol and mortality is only that; we are sorry that Cuchel and Rader infer a causal relation, since that was not our intent.

Yes, a correlation is merely a correlation.  But when correlations are always pretty darn consistent (and the most recent PHD post links to 50 studies showing the same correlation, especially true in the elderly), it is important to put our thinking caps on and try to figure out why (correlatively-speaking)  higher cholesterol doesn't seem to be killing people as fast as having low cholesterol does, despite the fact that health-minded people have been busy eating good diets and taking meds to lower that cholesterol for a generation.  Instead of putting on the thinking caps, the researchers in the Lancet conclude "we have no logical explanation" and timidly suggest that the elderly not be treated quite so aggressively with cholesterol-lowering medications.  Which is nice and conservative of them, and fine, but how about a sentence with some thought about why cholesterol might be good for us, since our bodies go through all that trouble to make it, after all, and how we might go about proving causality from these correlations?


So, with the world view of the conventional nutritional researcher firmly in mind, let's go back and look at the Diet and Dementia paper and the actual diets.


A reminder, in this study, 20 healthy older adults (mean age 69) and 29 adults with mild cognitive impairment (mean age about 68) were put on a LOW (low fat, low glycemic carbohydrate) diet or a HIGH (high fat, high saturated fat, high glycemic carbohydrate) diet for 4 weeks.  A number of biomarkers related to cholesterol and dementia were measured, and the researchers felt it came out as a clear win for the LOW diet.


I listed most of the results in my previous post, and what I think is the most interesting finding of the paper is how the mild cognitive impairment patients responded quite differently (typically, in more extreme fluctuations of biomarkers, and sometimes opposite trends) to the dietary changes than the healthy controls.  For simplicity's sake, I will focus just on the mild cognitive impairment patients in this post.


First, more details about the diets, about which we were told the macronutrient ratios and the fact that food was delivered twice-weekly to the participants. Here was my question to the researchers:

Would you be able to be more specific about the diets themselves?  For example, was the HIGH diet carbohydrate primarily sugar or starch?  Were the foods more heavily processed (for example, the equivalent of Jenny Craig meals delivered twice weekly) or more whole foods?  Were the saturated fats animal fats, trans fats, or coconut or palm oil? 

And the initial reply:

The HIGH diet carbohydrates were a combination of sugars and starches. Some of the foods were processed, but many were not. The saturated fats were primarily animal-derived.

The researcher cc'd the nutritionist from the study, who very helpfully took time out of her day to send me a sample day's menu and some more about the methods.

Please see attached for a copy of a sample day from each diet. To keep participants as blinded as possible, we deliberately included food items on both diets that seemed healthy/unhealthy. 

And the menus:

LOW diet

Breakfast

Egg-white and lowfat cheese on a sprouted wheat English muffin

Fruit cocktail, canned in juice

Snack

Lowfat fruit yogurt

Whole grain granola

Lunch

Grilled low-fat mozzarella, tomato, and basil sandwich on sourdough bread

Beef and barley soup Peanut M&Ms

Snack

Whole grain Chex with raisins, cashews, and chocolate chips

Dinner

Roasted pork tenderloin with roasted apples and onions

Bulgur wheat with apricots and almonds 

Green beans

Snack

Blueberry crisp with lowfat whipped topping

HIGH diet

Breakfast

Buckwheat pancakes with butter and sugar- free syrup

Milk, 2%

Snack

Whole milk mozzarella cheese 

Saltine crackers

Lunch

Grilled turkey and cheddar on white bread 

Cream of Tomato soup

Snack

Honey roasted Chex mix

Dinner

Beef stroganoff with rice noodles Broccoli with butter

Snack

Nilla wafers 
Vanilla ice cream


Okay.   From a "paleo" perspective  the  difference I can see between the two diets (neither of which I would eat personally) is, indeed, more simple starches and sugars  in the HIGH diet and more animal fat in the HIGH diet (butter, milk-fat, and cream).  Both diets are chock full of grains and what I would consider "industrially processed" food rather than whole foods.   I would knock the HIGH diet for the sugar and the refined flour and sugar-free syrup.  I would knock the LOW diet for the use of fake fats (lowfat whipped topping) and grains.  I could see how both could be toxic to our delicate physiology.


With that in mind, let's take another look at the biomarker changes and interpretations for the cognitively impaired patients before and after four weeks on the diet:


The HIGH diet increased insulin resistance and that LOW diet decreased it.   The HIGH diet was 45% fat (25% saturated fat) and 35-40% high glycemic carbohydrates, compared to the LOW diet ( 25% fat (7% saturated fat), 55-60% carbohydrate).  I'm not sure what to make of that finding.  On the positive side for the LOW diet, eating more cardboard and less sugar increased insulin sensitivity.  Another interpretation is that lowering the carbs in the HIGH diet increased physiologic insulin resistance, but it certainly wasn't a "low carb" diet by any means.  


In the HIGH diet LDL increased by 20 points in the MCI patients, and on the LOW diet it dropped by 10 points.  Most modern nutritional researchers would call this finding a clear win for the LOW diet - keeping in mind the physiologic findings in dementia and the perspective and insight of Stephanie Seneff, however, I'm not so sure.  In dementia, lower lipid levels are found in the spinal fluid compared to non-demented controls.  To me, the jump in LDL (which was actually much higher than the jump in the healthy controls) could be the MCI patients way of trying to make the most of the animal fat and getting desperately needed saturated fat, fat soluble vitamins, CoQ10, and cholesterol into the besieged brain.  But then, everyone knows I'm a psychiatrist so I must be a lunatic…


On the LOW diet, HDL went down by 8 points in the MCI patients, and on the HIGH diet it went up by 4 points.  Everyone would have to agree this is a likely "win" for the HIGH diet.  I consider HDL a marker for rapid cholesterol and fat turnover, which I would consider good.  The less old rotten oxidized fats floating around, the better.


Then we get to some more specific biomarkers for dementia - and here is where you get to a very confusing picture comparing MCI patients to controls.  Some of these markers went down in controls (which the researchers considered bad) and up in MCI patients (which the researchers also considered bad.)  Their reasoning followed an "inflection point" model, where people developing dementia have increasing levels of certain biomarkers, to a point where dementia is inevitable, at which point the levels of these biomarkers begin to drop as dementia progresses.  Therefore, an increasing level in a healthy control would be bad (bringing you closer to the point of no return) and an increasing level in a dementia patient would be good (bringing you back closer to the inflection point and closer to health).  LDL is a good example.  LDL levels tend to be higher in carriers of ApoE4 (the risky genotype for developing Alzheimer's - Dr. BG has done some great posts about E4 recently), but LDL levels tend to drop before dementia develops.  


I think a higher LDL might be representative of the brain and body doing it's best to fill the brain with yummy delicious brain fat and nutrients.  In the conventional sphere, since high LDL is Bad, high LDL must be part of the pathologic process destroying the brain (probably through inflammation, though I haven't been sold on any reasonable physiologic method by which higher sat fat could cause inflammation - lipotoxicity seems to depend on hyperglycemia).  Conventional wisdom has no explanation for why lipids drop prior to the development of dementia, which is why it is considered reasonable to give someone with dementia statins.  Which I think is a bit of lunacy.  But once again… I'm the lunatic here.  Never forget that.


Back to the paper!  ApoE levels go down on the HIGH diet and increased on the LOW diet in MCI folks - again, this would fit the model that ApoE takes cholesterol into the brain, so you have to be more aggressive about scavenging cholesterol on a low fat diet.  The researchers don't believe cholesterol goes from the circulation into the brain and link some papers with that view.  Senoff believes differently and links other papers and describes the mechanism by which ApoE helps the astrocytes escort LDL from the circulation across the blood brain barrier.  Given that autopsy studies show that cholesterol levels in the CSF are similar to those in the circulation, it seems logical that these two systems have ways of communicating and equalizing.  Well.  We'll have to let the separate sets of researchers duke it out on that one.  


On the LOW diet, amyloid levels went up.  On the HIGH diet, they stayed the same.  (I think this is a win for more fat, but the researchers interpreted that differently as one of those markers related to the inflection point, and they went so far as to explain that for this biomarker, the HIGH diets probably couldn't do more damage in an "already extant" process in the brain, whereas in the controls, where amyloid went up on the HIGH diet, the HIGH diet was clearly damaging).  


F2-isoprostanes (derived from omega 6 fats and a marker of inflammation) decreased in the LOW diet and stayed the same on the HIGH diet in the MCI folks.  The HIGH diet increased F2-isoprostanes in the controls.  Since a 45% fat diet designed by a nutritionist probably has more omega 6 than a 25% fat diet (but who knows, the 45% fat was 25% saturated fat, the 25% diet only 7% sat fat, so maybe it is a wash. Depends how much mono they ate) - and there is also all that sugar in the HIGH diet, so I don't even know how to look at inflammation in these diets.


So, what does it all mean?  What I see, with my biases and knowledge base, is some evidence showing that increasing fat in the diets of MCI patients is probably a good idea, though I can see how both diets could be inflammatory and damaging so I wouldn't personally pick either.  The researchers, with their biases and knowledge base, feel that the HIGH diet is a disaster and that this study presents strong preliminary evidence that the LOW diet is preferable for everyone, MCI patients and controls.  The researchers have PhDs in nutrition - I'm just a clinical psychiatrist with a hobby (oh, wait, I'm a professional nutrition writer now too!  I keep forgetting that…).  You decide whom you want to believe.

The Creative Advantage

One thing I hardly ever do is discuss what most people would consider real "Evolutionary Psychiatry."  That is,  how do diseases such as schizophrenia or autism, which in their worst forms are obviously so detrimental to evolutionary fitness that they would seem to represent a genetic dead end, continue in the gene pool.  It doesn't make much sense at first glance.  However, one could postulate that, just as the heterozygote carriers of sickle cell anemia are relatively protected against malaria, having some schizophrenia-risk genes could convey some sort of benefit for close relatives.  And one must also consider the possibility that the schizophrenia phenotype is worse now than it may have been for much of human history - with plenty of vitamin D, no wheat (speculatively :-) ) or common modern pathogens, it is possible the schizophrenia may not have developed as fully or been as debilitating.

Given dopamine's role in creativity, motivation, and drive, the suspected genetic advantage of being a relative of a schizophrenic is that you may have a bit of extra dopamine, but not so much it will make you psychotic.  Psychotic thought is disjointed and disorganized - creative thought is taking seemingly unrelated or unexpected ideas and bringing them together in a novel way.

Sounds reasonable.  But what about the data proving it?  Well, there has been a lot of speculation looking back at known geniuses and their psychopathologies.  It is felt it is no coincidence that many geniuses were not particularly psychologically healthy.  A more recent study selected 30 creative writers at a workshop and compared them to controls - writers had higher rates of affective disorders (several variations of this study have been done with the same results).  Studies of bipolar individuals showed they scored higher on scales measuring creativity than folks with unipolar depression or non-creative controls - the bipolar folks scored the same as creative healthy controls.

In Iceland, the histories of 486 male relatives of schizophrenics were investigated - these men were more likely to be prominent historically than the general population, and there was a significant increase in those who were specifically successful in creative endeavors.

But all those studies are small, and many rely on historical records.  However, a brand new paper from the British Journal of Psychiatry documents a large, population based study of 300,000 individuals with severe forms of affective disorders or schizophrenia from a large population registry in Sweden, where there is data on hospital admissions, diagnoses, IQ, occupation, and detailed family records as well.  The were able to find several tens of thousands of folks with bipolar disorder and schizophrenia, and over two hundred thousand diagnosed with unipolar depression.

The results?  People with schizophrenia and bipolar disorder (with the effect stronger in schizophrenia) were more likely to have parents and siblings who were in creative professions.  Bipolar patients also were more likely to have creative offspring.  The ORs aren't huge - ranging from around 1.2 to 1.6, but the bars don't cross the 1.0 line suggesting a real correlation.  There were no strong statistically significant correlations between having a relative with unipolar depression and engaging in creative professions (described as "including scientific and artistic occupations.")  As one would expect for a genetic link, as relationships got further away (half-siblings, cousins, etc.) the correlations weakened accordingly.

The reverse sort of "non-creative" correlation was also true - folks with schizophrenia were significantly less likely to have relatives who were accountants and auditors.

And the IQ connection (only measured in men in this Swedish registry) - those in creative professions had a higher IQ on average, however, the IQs of people with schizophrenia, unipolar depression, bipolar depression and their relatives were lower on average than people without any of the three diagnoses.  IQ was accounted for in the correlations we talked about in the previous paragraphs and did not weaken the genetic association between creativity and severe psychiatric illness (specifically bipolar disorder and schizophrenia).

Well.  That is all very interesting!  I might go on to be a real Evolutionary Psychiatrist after all.