Groovy Probiotics

Music to start - classical again, let's go Russian with Rimsky-Korsakov and Procession of the Nobles (right click in new tab).

News next - This post will most likely be the last one for a week or more, though I'm updating a couple of older posts for Psychology Today and may post a link tomorrow.  I'm on vacation.  Whew.

Update on the July Whole30 - finishing up Day 14, and the main thing I'm finding is that it is difficult to eat quite enough.  I've lost a dress size (and I'm not trying to restrict calories), but can be a bit cranky before meals, and after the first week I've not been particularly hungry.  Though I love the freedom and convenience of rather frequent intermittent fasting, it has also been nice to simply eat three meals a day and throw in an extra banana, some berries, or a few macadamia nuts for snacks.  No "cheating" except for a half teaspoon of honey in tea on Monday morning (I had a good reason for it). All cravings for chocolate and Diet Coke were pretty much done by the end of the third or fourth day.  The honey ingestion didn't reawaken any of that.

Vacation will up the ante.  It will be difficult to be eating out at restaurants all the time and be as sure as one ought to be in the Whole30 about ingredients.  We'll see how it goes.  I'm not going to throw in the towel if I realize something is screwed up, and will likely just try to order steak as much as possible.  Veggies may be difficult as they are usually cooked with butter or covered with soybean-oil based salad dressing.

Now the paper!  This one is on the hypothetical side - all tell, no show, but rather fun.  I believe Chris Kresser tweeted it to my attention, or it could have been Dallas and Melissa.  Both of them sent me probiotics papers so thanks to both!

Ahem.  Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics.

The down-low is that probiotics are thought to modulate the production of inflammatory particles (cytokines), affect the adhesion of pathogens to the gut mucosa, and other groovy things.  However, no one really knows how they do what it is that they do.  There are now several studies with intriguing evidence that probiotics can affect the brain (one of which I wrote about earlier this week).  One study even showed anxiety reduction in human volunteers (and mice) with administration of Lactobacillus helveticus and B. longum.  Again, since disorders that affect the gastrointestinal tract seem to co-exist quite frequently with anxiety, depression, and other mood disorders, probiotics and gut health may have "profound clinical implications."

There is a great deal we don't know.  Many of the organisms can't be cultured.  It's difficult to study the secret life of the wee beasties while the host is walking around doing the day to day.  There are zillions of varieties of beasties, and typically the probiotics used for studies depend on what company is supplying them rather than a more specific rationale or knowledge of the effects of each species.

So what, exactly, do we know?  As far back as 1929 it was discovered that human carriers of certain Clostridium species who were given epinephrine to treat hives died suddenly of gas gangrene (oops).  For 60 years, it was thought the epinephrine somehow suppressed the immune system, leading to the sudden fulminant infection.  In the early 1990s, however, it was found that yes, indeed, gut bacteria could respond directly to human neurochemicals (such as epinephrine).  It has been further proven (with the flurry of recent papers) that the communication between the beasties and the brain is a two way street.  Neurochemicals are highly conserved in evolution - bacteria, plants, insects, and fish all produce forms of the neurochemicals called the catecholemines.  Thus it makes sense that bacteria in our gut can communicate directly with using, to some extent, the same "language" as our mammalian brains.  

Lactobacillus and Bifidobacterium species are known to produce GABA.  Escherichia, Bacillus, and Saccharomyces produce norepinephrine.  Candida, Streptococcus, Escherichia, and Enterococcus produce  serotonin.  Bacillus and Serratia produce dopamine, and Lactobacillus species produce acetylcholine.  That's pretty much the entire hit parade of major neurotransmitters (there's histamine and glutamate and a few others - and histamine is known to be produced by some bacteria that infect shellfish, for example, causing food poisoning).  

The most interesting case here is GABA, the major inhibitory neurotransmitter in the nervous system (it chills things out) - and there are whopping amounts made by the bacteria in fermented foods, and is also found in yogurt and typical probiotic capsules.  GABA also turns out to be anti-inflammatory in the gut itself, decreasing the release of inflammatory cytokines.  Thus there is a plausible mechanism by which certain probiotics could decrease inflammation and aid symptoms of conditions such as IBD or IBS, and, considering the vagus nerve and all it's tendrils in the gut, have direct communication via the neurotransmitter GABA to the brain.

The author of the paper outlines some straightforward methods by which the individual effects of the probiotic species could be systematically characterized and studied.  He has developed a framework for the promising new field of microbial neuroendocrinology.  Of course his interest is along the lines of mining microbes for human use - it seems to me our ancestors and their fermented traditions have been mining microbes for these uses for some time, without all the species typing and science.  

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Wheat, Rice, and Children's Brains

There is another post-worthy probiotics paper on the hopper, but before that I wanted to cover an article called Breakfast Staple Types Affect Brain Gray Matter Volume and Cognitive Function in Healthy Children (freely available on PLoS one).  I like some parts of this paper, though it is observational in nature, so keep that in mind.

As we all know, our big old brains develop not only prenatally, but also throughout childhood and adolescence.  In children, several studies have been done showing nourishing breakfasts help cognitive performance compared to skipping breakfast - especially the "high quality" breakfasts, with one study showing that a breakfast of low glycemic index foods having an immediate positive effect on attention throughout the morning (1).

In other introductory information, many studies in children have been able to correlate the amount of brain gray matter (vs. white matter) and IQ, especially gray matter in the prefrontal and orbitofrontal cortex and the cingulate gyrus.  Therefore, since breakfast types affect cognitive function, and brain structure can correlate with IQ, does breakfast type correlate with brain structure and IQ?  I don't know.  Let's find out.

These Japanese researchers (funded by a national Young Scientists' grant) studied 290 healthy children ages 5-18 years.  In Japan, apparently boiled white rice or white bread make up a typical breakfast.  (I remember eating a lot of this cereal plus sugar in skim milk when I was a kid. Kapow!)  The scientists were able to split the children into groups of habitual rice-eaters, habitual white bread eaters, and those who consumed both regularly.  Then they tested the IQs (using standard measures for kids <16 and a separate standard test for 16 and older), scanned the kids in a MRI, and collected their data.  Questionnaires were filled out by the kids or their parents with respect to morning eating habits, health, wealth, etc.

Using varying statistical techniques and a couple varieties of imaging data collection, the researchers found that the gray matter ratios (gray matter volume divided by intracranial volume) were significantly higher among the rice eaters vs. the white bread eaters, even after adjusting for age, gender, wealth, average weekly frequency of eating breakfast, and number of breakfast side dishes.  The Verbal IQ in the rice group averaged 104.7, in the bread group 100.3.  The Performance IQ was 102.1 in the rice group and 97.9 in the bread group.  This difference was non-significant.

As the kids became older, the differences in gray matter ratio increased between bread and rice groups.  Overall, calories consumed among rice eaters were slightly lower than those who habitually ate bread.

Now the researchers spend a lot of time talking about how all of these findings can be explained by the lower glycemic index of rice compared to white bread.  They feel that low GI foods provide steadier blood glucose levels, and "stable and efficient glucose supply is important for neurons."  It is notable that "cerebral metabolic rates of glucose utilization are approximately two times higher in children compared with adults." (Could be why children seem to have so much more of a natural "sweet tooth" than most adults).  The researchers also felt that since white bread has more fat than white rice, that the increased fat content might be a problem for the brains of white bread eaters (they suggest fat decreases neuronal plasticity).  I rather strongly disagree with them here and will have to pull their supporting paper when I have a minute� right now I have to finish up and dash off to work.

So all told, this study is only an observation, and causal factors cannot be determined with this dataset.  And I think the whole high GI/low GI chase is probably a red herring.  These Japanese kids were all likely relatively low-fat and high carb compared to say, American kids of the same age, and I do tend to think that healthy, low-toxicity carbs and fruit are fine for kids, who are not as likely to have leptin resistance as their adult counterparts.  As for the fat issue - I think a common sense way to think about this issue is to look at neonates.  They are the extreme version of the child, after all, and everyone can agree about the best food for them (human breast milk).  Neonates need a diet high in sugar (though lactose does not contain fructose) and 50% fat with lots of saturated fat.  I don't see how fat can be vital for the baby brain but somehow becomes toxic for the growing child brain.  I wish someone could explain that to me in a way that makes any physiologic sense, because it seems to be taken for truth by so many medical professionals and scientists.   If you can explain exactly when and how fat becomes toxic (somewhere presumably between the ages of 3 and 5, which is when ancestral humans were weaned?) drop me a comment.  "Lipotoxicity" doesn't count without more information as to the specific mechanism - neither do studies poisoning animals and/or humans with large amounts of corn oil or trans fats.

I'm perfectly willing to accept that the bread, derived from wheat, has toxic factors that cause inflammation or hurts the microbiota or interfere with absorption of minerals or whatever, and theoretically could be a casual factor as part of the differences seen in the children's brains in this paper.  My kids get rice and potatoes and fruit and milk as carb staples, in addition to meat, fish, nuts, and vegetables.  All in all, I believe metabolic flexibility and low-toxicity and premium quality food for premium micronutrients are the most important things for a healthy diet and a healthy brain.

End note - thanks to Jamie for the paper!!!  Also, Blogger comments were acting up for a few days.  If you asked me a question in the last few posts, I've been meaning to chime in when I get a moment.  Don't despair.

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More Fun With the Gut Microbiota and the Brain (In Mice)

Everyone has been tweeting this new paper, and I have to say, it's a doozy.  I don't recommend that many papers, as most are fairly painful to read (though many papers are full of interesting facts, they don't teach scientists how to write), but if you can get your hands on this one, please do so.

The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice

Let's dive in.  Ooh, I like the first part:

The intestinal microbiota is a vast ecosystem that shapes a wide variety of host functions, both within and outside the gastrointestinal tract.

Y'all may recall my previous article in which we have evidence that your commensal beasties, which make up 90% of your cells, also control a mouse's brain (and possibly yours.)  And something like this paper and this experimental design excite me more than the endocannabinoid/rat paper I wrote about yesterday.  I don't doubt that we probably have endocannabinoid receptors for corn oil (which may be activated by all kinds of fats) in our guts, or ones for sweets in our mouths, I'm just not sure what it means when isolated in that way via the sham-feeding and with creepy rat chow liquid diets that immediately drain out and dribble onto the rat cage in a gross gut slurry.  However, we do have to keep in mind that these are rodents who diverged from the family tree many many many millions of years ago�

Back to beasties.  They have found that colonization of germ-free mice with Bacteroides species affect the expression of messenger RNA that encode for immune and smooth muscle function, gut permeability, and the gut nervous system.  Regulation of body weight and pain perception in the skin have also been shown to be affected by changes in microbiota.

In healthy folks, the intestinal microbiota are diverse, and the species relatively stable.  In conditions such as inflammatory bowel disease (Crohn's and ulcerative colitis => IBD) and in irritable bowel syndrome (IBS), the beastie species are less diverse and tend to be unstable over time.  In both IBD and IBS, depression and anxiety are common, and associated with worse gastrointestinal disease.  In IBS, studies have shown 50-90% of the people affected also have psychiatric symptoms.   But are the psychiatric symptoms caused by the discomfort and stress of living with irritable or inflammatory bowel conditions, or are the symptoms caused by the same pathology that causes the gut issues - which includes alteration in the intestinal microbiota.

Previous experimental evidence that gut bacteria affect the brain includes:

1. In mice, microbiota have been shown to affect the hypothalamic-pituitary response to stress.
2. Oral antibiotics seem to help people suffering from neurological complications of end-stage liver disease.
3. Pathogenic bacteria introduced into the gut causes anxiety-like behavior in mice.

For this experiment, the researchers obtained some regular and germ-free mice who lived thereafter in level II biocontainment.  Some of the germ-free mice remained germ-free.  Others got fecal transplants from other mice that had known bacterial species on board.  Some of the mice got a whopping dose of antibiotics (that were "nonabsorbable" so presumably only affected the gut microbiota - a separate experiment by which a small amount of antibiotics were injected systemically in some mice acted as a back-up control and did not affect the gut microbiota).  Control mice lapped up sterile water instead.

The mice's gut contents were extracted, cultured, and the bacterial DNA and RNA were characterized via polymerase chain reaction and gel electrophoresis, so you could see what kind of beasties survived the various treatments in each experimental and control group of mice.  The mice also underwent behavioral testing - how open they were to exploration, how quick they were to step off a raised platform, etc.

In addition (these researchers were pretty darn thorough) - the gut linings were examined for signs of inflammation, and cytokines and neurotransmitter levels in the small intestine and colon were measured.  The brains (specifically sections of the hippocampus and amygdala) were extracted and measured for levels of brain-derived neurotrophic factor (BDNF).  BDNF is a brain fertilizer whose levels in the hippocampus and amygdala correlate with depression and anxiety symptoms.  Low BDNF in the hippocampus is generally bad news and are associated with depression and anxiety symptoms.  Antidepressants are thought to work by increasing levels of BDNF there.  In the amygdala, the fear center of the brain, lower levels of BDNF seem to correlate with less fear.  

Still with me?  How about a song.  The Strokes - Taken For A Fool (right click to open in new tab or window if you don't want to be shipped away from this page.)

Results.  Well, whopping antibiotic administration did affect the beastie species in the guts of the mice.  Lactobacilli and Actinobacteria populations increased with the treatment,  while the Bacteroides and gamma-proteobacteria decreased (including Shigella and Klebsiella).  The mice who had been exposed to antibiotics were more exploratory and less apprehensive than the control mice.  After two weeks, however, the behavioral testing of the control and antibiotic-treated mice when back to being the same, and measures of their beastie populations showed they went back to normal.  In the germ-free mice, antibiotic administration did nothing to affect their behavior, showing once again it was likely the alterations in the beastie population that caused the behavioral change in the experimental group.  And, finally, germ-free mice who got the fecal transplants showed changes in behavior after being colonized compared to the germ-free controls.

So you see, these researchers went backwards, forwards, and sideways to prove their findings.  Pretty cool, really.

More results.  Mice who got the whopping dose of antibiotics had higher levels of BDNF in the hippocampus and lower amounts of BDNF in the amygdala compared to control mice.  These BDNF levels are what you would expect if you have less anxious and fearful mice who are more open to exploring than controls.  The antibiotic-treated mice did not have any changes of cytokines in their guts to suggest increased inflammation, or any increased pathologic inflammatory markers under microscope, and there were no changes in gut neurotransmitters.  SO - the behavior and BDNF changes had nothing to do with gut inflammation or the enteric nervous system (at least involving the neurotransmitters they tested, which included all the biggies).

The results of this study provide strong evidence for a microbiota-gut-brain-axis that influences brain biochemistry and modulates behavior in adult mice.

In another paper, researchers showed that mice lacking a gut sympathetic nervous system (via severing the vagus nerve or using chemical neurotoxins that kill the sympathetic nervous system) were not affected by the addition of Campylobacter (a gut pathogen) to the gut, which induced anxiety in normal mice.   Thus the anxiety behavior seemed to be mediated via communication between the gut and brain via the vagus nerve.  In the current paper, a group of mice who had a severed vagus nerve and another group who had been exposed to the neurotoxin had the same results as the mice with untouched nervous systems, thus the change in behavior and changes in BDNF in the brain brought on by antibiotic treatment in the gut occurred through another mechanism - the researchers thought substances produced by the gut bacteria likely acted directly or indirectly on the central nervous system somehow.

Another recent paper showed that mice fed a beef-enriched diet for three months in early childhood (mouse puppyhood?) had improved memory compared to rats fed standard rat chow.  (I'm not sure exactly if that can be linked entirely to the gut bacteria, but it is mentioned in this paper and I thought it was a cool fact.)

These researchers have already shown that administration of probiotics could normalize behavior in mice who showed alterations in behavior and mild to moderate gut inflammation.

All told, I think these scientists are beginning to elucidate a pretty fascinating area of interest to psychiatrists, gastroenterologists, and mouse enthusiasts everywhere.

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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.  

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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!

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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.

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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!

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