Sunday, February 27, 2011

Depression and a Leaky Gut

First off, please go by and read That Paleo Guy's account of being in the middle of the latest Christchurch earthquake.  Fortunately he and his loved ones and cat are all okay.  You can also follow his twitter feed here.  I've never been at the epicenter of disaster, and I don't know that I would have acquitted myself quite so well.  I mean, once when I was in college our power was taken out by a storm, and since we lived in a crappy part of town (cheap apartment for college), it took about two weeks to get it fixed, and we congratulated ourselves on the campfire we improvised on the back porch to roast marshmallows by.  But no ground shifted.  I don't think anyone died, though quite a few trees were taken out, and there was some flooding.  Other than that, well, I've seen plenty of death and destruction in the ER and ICU, but those are more or less controlled settings.  Anyway, I hope Jamie's life is back to some sort of normalcy soon.

But for a bit of literary grounding, let's visit John Steinbeck's greatest work, East of Eden.

"But the Hebrew word, the word timshel—‘Thou mayest’— that gives a choice. It might be the most important word in the world. That says the way is open. That throws it right back on a man. For if ‘Thou mayest’—it is also true that ‘Thou mayest not."

I need a song.  Something quiet.  How about Satie's Gymnopedies No. 1? (right click in new tab)

Back to Evolutionary Psychiatry.  During the research for the Wheat and Serious Mental Illness post, I came across this intriguing paper by none other than Michael Maes, the cranky Belgian researcher who has churned out so many fascinating papers on depression and inflammation

Maes and crew took 51 subjects, 23 controls and 28 outpatients with Major Depressive Disorder from the outpatient clinic.  Everyone with substance abuse, anyone on medication, and anyone with chronic fatigue or other autoimmune diseases were excluded.

The basic premise of the experiment was that activation of the inflammatory response system plays a role in the pathology of major depressive disorder.  Our guts are chock full of gram negative bacteria, who have lots of a lipopolysaccharide (LPS) on their little bacterial cell membranes.  If one finds LPS in the bloodstream, that means those naughty bacteria are somehow squeezing through the so-called tight junctions of our intestinal tract - a leaky gut.  That would be bad.  And, not surprisingly, LPS found in the bloodstream ("systemic LPS") results in rapid increases in TNFalpha levels, which might remain elevated for as long as 10 months.  Brain microglia (immune cells in the brain) launch into action to fight the invasion and send out more inflammatory cytokines.  LPS in the system results in elevations of all those cytokines associated with major depressive disorder - TNFalpha, IL-6, IL1beta.  In animal studies, LPS administration results in an appearance of symptoms of poor appetite, psychomotor retardation (meaning lack of normal fidgeting movement, characteristic of depression), malaise, and loss of interest.  These symptoms are very similar to the clinical symptoms of depressive disorders. Increased LPS also seems to induce the catabolism of tryptophan (meaning more tryptophan, the amino acid precursor of serotonin, is chewed up and not used to make serotonin.)

So Maes checked antibodies (IgA and IgM - basically, gut antibodies and freshly minted antibodies) to LPS of 6 different enterobacteria.  Turns out that IgM and/or IgA were significantly elevated against most of the enterobacteria in the subjects with major depressive disorder.

In short, people with major depressive disorders were busy mounting an immune response to bacteria which never should be in the inner sanctum of the body in the first place - bacteria that live in the gut, and ought to stay in the gut.  Symptoms of irritable bowel, fatigue, and "a subjective feeling of infection" were most likely to be associated with a large immune response. 

Maes goes on to describe some interesting characteristics of the leaky gut - he contends that an inflammatory response itself actually worsens the leaky gut, that the activation of interferon gamma and IL-6 help the gram negative bacteria use the lipid rafts to get through the gut lining into the bloodstream.  That is interesting, as inflammatory response is increased in response to stress.  So stressful life events might in themselves increase the permeability of the gut.  (Jamie, do some yoga!).  Other things that induce lipopolysaccharide translocation - alcoholism, infections such as AIDS, inflammatory bowel disease (like ulcerative colitis or crohn's), and autoimmune disorders.

Maes ends his paper by optimistically suggesting that people with major depressive disorder be checked for the presence of leaky guts via measurements of IgM and IgA against LPS, and that those with leaky guts should be treated with a "leaky gut diet." (1) (the reference indicates one can write the Maes researchers to get the details of the diet - which I have done this evening!).

So - once again - don't have a leaky gut!  As Robb Wolf would say, keep your poo where it belongs.

Friday, February 25, 2011

Lithium and Longevity

A new paper was published this week - Low-dose lithium uptake promotes longevity in humans and metazoans.  Now, as a psychiatrist, I'm a lithium fan.  Apparently, it is an essential trace micronutrient (who knew) aside from the uses for decreasing suicide and helping mood stabilization. Want a primer - look at my blog post here.  (Here is the original lithium for treating mania paper by John Cade if you are interested.)

Decreasing suicide?  Yes, well lithium is actually very good at keeping people alive.  Even those with bipolar disorder or major depression who have no real symptomatic improvement seem to have less suicidal thoughts and suicides while on lithium.  Very interesting.  But why?

Let's start with some observational studies.  Back in 1989, Schrauzer and Shrestha published a paper called "Lithium in Drinking Water and the Incidences of Crimes, Suicides, and Arrests Related to Drug Addictions."  They took information about the lithium level in the water of  27 counties in the Great State of Texas.  Seems that counties with higher lithium levels in the water had a statistically significant decrease in the incidence of homicide, suicide, arrests for opiates and cocaine, and violent criminal behavior.  Now to put things into perspective, a high lithium water content translates to about 2mg of lithium a day.  Psychiatric doses start at 300mg daily. 

From the 1989 paper:

Lithium has previously been used to control episodic outbreaks of rage among prisoners and in the management of drug abusers.  Animal experiments have demonstrated that lithium suppresses cocaine-induced super sensitivity... the kindling phenomenon following the chronic application of ... a central nervous system stimulant, and head-twitching in response to the administration of mescaline.  Furthermore, lithium has been found to [improve] distractability... and produce improvement of selective attention to stimuli... it prevents behavioral alterations owing to social isolation, lowers aggressivity owing to confinement... and causes a normalization of spontaneous motor activity.

 Wow!  That's a lot for one little trace mineral.  And observational studies from Japan seem to correlate - back in 2009, researchers there noted that suicide rates decreased with higher amounts of lithium in the water (1)(In Japan, rates of suicide have been distressingly high for the past 15 years - Japan has a suicide rate of 21 per 100,000 individuals per year vs. the US rate of 11 per 100,000 (3)).  And, with the newest paper, longevity in Japan increased with the amount of trace lithium in the water in humans, and the same trace amounts of lithium in a controlled experiment (equivalent to about 2mg of lithium daily) increased the lifespan of the C elegans worms (2)(due to the increased suicide rates in Japan, suicide was controlled for in the numbers, and lithium still seemed to increase longevity in the observational studies.).

So, all old, that is rather interesting.  Trace amounts of lithium seem to improve human behavior in general, and no one knows why. 

Basic science time - lithium looks a lot like sodium.  It has the same number of electrons in the outer shell - the molecule itself is a bit smaller, but the kidneys don't seem to be able to tell the difference.  And, perhaps, neither do the neurons.  So the addition of a bit of lithium to the matrix will decrease the overall sodium gradient in the brain, decreasing neuroxicity, and increasing the efficiency of brain energetics. From the Japanese drinking water, lithium, and suicide study:

It can be speculated that very low but very long lithium exposure can enhance neurotrophic factors, neuroprotective factors and/or neurogenesis, which may account for a reduced risk of suicide.

In addition, lithium is thought to modulate the system of second messengers in the brain, meaning they enhance certain signaling processes.

The authors of these studies get rather enthusiastic, recommending supplementation at a level of about 2mg per day for human populations with the proposed effect to control behavior, increase longevity, and reduce suicide.

On the negative side, some Swedish researchers tested thyroid effects of trace lithium in the water in some villages in the Peruvian Andes (3).  Some of these villages had some 10-20X the natural lithium in the food and water of the Japanese subjects, up to a maximum of 30mg daily (which is, of course, within an order of magnitude of the pharmacologic dose of 300mg).  They found that lithium in the water seemed to decrease active thyroid hormone levels and increase thyroid stimulating levels - lithium as a medicine will tend to cause hypothyroidism.

In another interesting tidbit, they found that natural selenium levels in the water correlated with free T4 thyroid levels.  Only, thing is, selenium is supposed to act to help T4 become active thryoid hormone, T3.  So one would expect selenium levels to correlate with T3 levels and inversely correlate with T4. 

So, all told, lithium is a natural component of drinking water, and observationally decreases suicide and general naughtiness, and increases longevity, but perhaps also decreases thyroid function. 

Something to ponder.

Tuesday, February 22, 2011

More on Wheat and Serious Mental Illness

All right.  Tuesday.  Yesterday at noon local time a big earthquake hit Christchurch, and all of our good wishes are with the people there, especially as one of Evolutionary Psychiatry's best internet friends is Jamie, who lives smack dab in the middle of Christchurch.  Here's a link to the New Zealand Red Cross if you would like to lend a hand.

Before disaster struck, Jamie was kind enough to send me a link to a new paper (free full text) about Bipolar Disorder and gluten markers.  The paper doesn't give us much, but it does stir up some good ol' murk.  So let's investigate.  Bipolar disorder is an illness of mania or hypomania plus or minus depressive episodes.  Bipolar disorder does not equal "moody" or "irritable," though those can certainly be signs.  It's not the disorder unless the symptoms are bad enough to get you into serious trouble.  You spend too much, you sleep around too much, you don't sleep, you are more religious, you are grandiose - in cycles.   And, of course, it is associated with inflammation and metabolic syndrome (1), diabetes (2) and a "western" style diet

I have suspicions about those links.  I'd bet a monkey that a combination of sugar, trans fats and vegetable oil, and high doses of refined wheat products (as I've mentioned before, the evidence against wheat is circumstantial) are culprits behind metabolic syndrome and diabetes.  And maybe a subset of the population suffers at the brain level too and manifests bipolar disorder.  Hey, seems as good a theory as any. 

Wheat has been investigated on and off over the years as a culprit in schizophrenia.  And bipolar disorder and schizophrenia can overlap sometimes in symptoms - while depressed people can be psychotic, a frank manic psychosis will look pretty much the same in the hospital as a schizophrenic psychotic episode, and there may even be some genetic overlaps (3)(4).  The new paper that Jamie sent me is the first to study celiac and wheat-associated antibodies in bipolar disorder.  In schizophrenia, there is a definite increase in wheat-associated antibodies in the serum (5) and these antibodies aren't the same ones that are seen in celiac disease.  Well, with bipolar disorder, seems the same thing is true.  Bipolar folks had a significant IgG gliadin reaction compared to controls, but there weren't really differences with respect to tTG and IgA gliadin antibodies which are typically elevated in celiac disease. 

Ooh ooh ooh, wheat is BAD.  Well, probably, for various reasons.  But, of course, I don't necessarily believe that a positive IgG test to gliadin means one has a sensitivity to gliadin.  I griped about IgG food sensitivity tests not too terribly long ago.  I think a robustly positive IgG test to lots of things means one may have a leaky gut.  Gliadin is a pretty darn common thing to eat, so folks with leaky guts may come up positive for gliadin.  The most robust evidence in humans I've seen for leaky guts linked to wheat (or maybe casein) consumption was from this nifty study in autism (6), where the kids on the GF/CF diets had pretty tight junctions in their guts, especially compared to the autistic kids and their relatives.  Boy, I bet the researchers have really pounced on this diet and mental health link and studied leaky guts in bipolar disorder (7)(9)! Er, no.  But, links have been found between major depressive disorder and leaky guts (8 - an interesting enough paper for another day).

Like I said, murk.  Best I can consolidate from all this information - it may be that folks with bipolar disorder have gut issues, and gut issues are inflammatory issues, and a higher IgG response to gliadin occurs, and inflammation causes the body to release cytokines and general badness, and those cytokines may predispose the genetically vulnerable to psychosis.  Also, there may be particular ick associated with exorphins in wheat being neuroactive.  And is it just wheat?  There's a paper linking recent onset psychosis and schizophrenia to IgG and IgA antibodies to casein (10).  In this study, the severity of psychosis was linked to the level of antibody response to casein (actually, the alpha and kappa subunits moreso than the beta, which is interesting, though first onset psychosis had a robust immune response to the beta subunit).

And I'm not entirely off the wall here, because here is an excerpt of the discussion from paper 10 -

We can speculate that a subset of individuals with recent onset psychosis and/or schizophrenia may have cellular junction pathology that allows peptide fragments generated from the digestion of bovine milk to permeate the intestinal tract, and enter the bloodstream... Dohan... hypothesized that the aberrent proteolysis of milk and grain products may produce small neuroactive peptides that can enter into the circulation and ultimately cross the blood-brain barrier.

So, lesson number one.  Don't have a leaky gut.  Lesson number two.  If your gut is leaky, best to avoid creepy neuroactive peptides.  Lesson number three.  There is nothing horribly definitive here, but plenty to study.

Saturday, February 19, 2011

Basic Science - Energy is Everything

Let's review.  Some 9 months ago, an excitable young psychiatrist of reasonable pedigree launched Evolutionary Psychiatry as a means to explore how the differences between our modern lives and diets compared to traditional/evolutionary experiences may influence the generation of mental illness.  To that end she peeled back the edges of several lines of inquiry - what mental illnesses are increasing rapidly, and what are the theorized reasons as to why?  What are the correlations between mental illness and the known diseases of civilization (heart disease and type II diabetes, primarily, though acne, IBS, and autoimmune diseases of all kinds fall in that rubric)? What dietary factors are drastically different between the nutrient-rich traditional fare and our post-modern industrial food, and what is known about how those dietary factors affect neurotransmitters and brain energetics?  So I read, and read, and read, and depend upon a small cadre of loyal compatriots and commenters with a similar nose for research and a similar goal, and together we have uncovered some interesting things, and nowhere in thousands of pages of reading have I uncovered something that would absolutely refute my original hypothesis.

Part of the story of Evolutionary Psychiatry is the story of its creator and how she [I] thinks.  And when I say I have no patience for philosophy, I mean it.  I've rarely made it past the "God cannot be both benevolent and omnipotent" chapter one of most philosophy books before they are consigned to the dustiest reaches of the bookshelf.  I am left-handed, so theoretically more able to bring in the right brain (though in all likelihood I am also predominantly left-brained like most of you).  I am a woman, therefore likely more balanced between dopamine and serotonin in my ponderings.  I think in collages.  In pictures.  In stories.  My influences are literature and music, the oral and written histories of our people.  For some, the structured rationality of philosophical thought creates links and certainty.  For me, that structure is an imposing irritant and a distraction from the elusive creative links.  I hope I make up in scope for what I lack in rigor.  I rely on folks like Denise and Ned to lose themselves in numbers.  I want the story behind the numbers.

In Evolutionary Psychiatry there are only a few truths that bob to the surface again and again.  Inflammation is the mediator of most evils.   Energy should be made efficiently or there will be a cost.  Fatty meat is good.  Starch is not a dirty word, but an excess sugar certainly is. Ketosis in moderation can be a powerful tool.  Plant protein should be regarded with suspicion as an inflammatory mediator.  Stress and sugar and poor sleep damage the brain.  We should probably consume a little more dirt and get a little more sunshine

But let's bring it back to energy.  Energy is everything, and the brain, for all its small size, a massive consumer of energy.  Energy for eukaryotic cells is primarily made in the mitochondria. 

Image from The Science Experts

There are a few "need to knows" about mitochondria.  Like most engines, they create waste.  However, it seems that what we want is plenty of mitochondria working at full efficiency.  If we have leftover or damaged mitochondria just hanging out, they seem to create destructive reactive oxygen species and general mischief (1).  Mischief such as dementia, premature aging, cancer, and probably autism

Things that make mitochondria happy and promote effiency and clean energy:

1) A high-fat diet and utilization of ketones
2) A ready supply of energy and mitochondrial cofactors such as the animal flesh-derived carnitine, creatine, and carnosine, and the cholesterol buddy buddy ubiquinone (CoEnzymeQ10), vitamin A, and the football crew of B vitamins are also utilized in the respiratory chain.
3) Protein and/or calorie restriction which promotes the activation of PPAR (that is peroxisome-proliferator acttivated receptors).  See, the mitochondria have two major types of garbage containment facilities, the lysosomes and the peroxisomes.  They are the waste clean-up crew, and they become more active in states of protein restriction and ketosis.  In addition, the old and inefficient mitochondria spewing more reactive oxygen species than they ought get properly decomissioned in states of protein restriction and ketosis.  This is one part of a positive clean-up process called "autophagy." 
4) Aerobic exercise seems to stimulate the creation of new, shiny, efficient mitochondria (2).

What sorts of things promote mitochondrial ineffiency and general dirty cell-killing cancer dementia promoting badness?

1) Hyperglycemia
2) Inactivity
3) Micronutrient deficiencies
4) Never dipping into ketosis

I'm guessing the mitochondrial research folks probably never heard of the paleolithic or primal style approach to diet and living.  But the common recommendations of that approach all converge to make mitochondria mighty happy.  Even the paleo conservatives with their fat phobia will be low carb and encourage intermittent fasting - which in combination should bring *some* ketones into the picture along with temporary protein restriction to promote autophagy.  Paleo/traditional foodists will be rather strident in getting plenty of micronutrients and will have the steaming plates of offal to prove it.  The special mitochondrial-loving amino acids found in meat will be, more than likely, adequately consumed by the meat-loving paleo eater.  In addition, activity is encouraged, lots of it, in realistic exertion and quantity.  The diet itself, being antinflammatory and muscle-sparing, is the perfect fuel to spur activity.

In contrast, the Standard American Diet du jour will promote inflammation ultimately resulting in hyperglycemia, weight gain, inflammation, fatigue, and sedentary living.  Micronutrient deficiencies will be the rule, unless one is exceedingly careful.  And one is told never to let 3 hours or more go by without eating lest the metabolism sputter to a halt (which I'm ashamed to admit I ever believed).  Restricting calories to the point of avoiding obesity only while eating 5-6 times a day is no picnic.  Welcome constant food with constant hunger and constant restriction.  One could hardly think of a more unnatural way to eat, or a better way to make for miserable free-radical spewing mitochondria.

Yes, more research papers, more basic science, a deeper look at a vast picture, and more of the same old answers.  If you haven't given IF a try, consider skipping breakfast every once in a while.  Or at least have some stretches of time where fat is the primary macronutrient you consume (but avoid those vegetable oils, of course).  You might be surprised how you feel - not weak, but focused, energetic, and driven.  All the better to devise a plan to bring back that large ruminant to the camp for a delicious supper.  Yum.

(Thanks once more to Jamie who sent me several of the papers and links.)

Friday, February 18, 2011

Healthy Skepticism

Among the papers from the last post fell out this letter in Science, The Potential of Nutritional Therapy. (unfortunately, limited access).  However, the letter speaks to many of the shortcomings in investigating the science of nutritional cures, and has a number of important points.  Conventional adherents might find this odd, but these shortcomings are, in part, why I hold fast to a "paleolithic-style" approach (with forays into dairy fat, white rice, and neolithic vegetables that I believe are scientifically sound.)   I think the paleo fall-back is the safety zone.  Forays into modern industrial food requires a bit more careful study before we recommend it for the masses (sorry, USDA.  Grains and copious vegetable oil for my little ones?  I don't think so.)

The problem with the studies if nutritional therapies?  Often they have been poorly done, or investigated one nutrient at a time.  A "paleolithic" focus requires cutting out grains, balancing the omega 3/6 ratio, and drastically reducing fructose and eliminating processed food.  There are absolutely no randomized controlled trials for mental disorders with these criteria (unless you count the recent ADHD trial with the limited wheat and unlimited rice - which is why I post so much about the ketogenic diet trials, some omega 3 supplement trials, and the ADHD elimination diet trials - they are ALL I HAVE to truly hang my hat on.  Everything else is just vague supporting evidence and a flair for spinning a tale, and don't think I don't know that.)

The letter in Science mentions the issue with mitochondrial dysfunction that often accompanies mental issues (see Brain Efficiency and Brain Efficiency, Pediatric Edition), and notes that nutritional problems may induce mitochondrial inefficiency. 

And bless Science magazine - they discuss the problem of nutritional journalism, with the crappy headlines shadowing the misleading abstracts redoubling the worth of the Denise Mingers out there with every stupid headline:

"Medical journalism may be one important agent for spreading
information about legitimate research on nutrition and mental health,
especially in the face of the lack of profit-generated funding. This also
implies a special responsibility for medical journalists, since the dan-
ger of “pseudoscience” is close at hand."

Doctors cannot recommend therapies without evidence.  And I shake my head at (for the most part) perfectly reasonable skeptic alternative health practitioners who eschew traditional prescriptions for traditional herbals which have no more evidence (and more than likely less regulation of the actual content of the herbal formulation) than any prescription product.

"Show me the evidence" should be the rallying call of the health-conscious consumer these days.  Otherwise, I'll stick with eating nose-to-tail and seeking out seafood and going for the seasonal fruits, starchy vegetables, green leafy vegetables, and rendered fats and oils that my ancestors did. 

Tuesday, February 15, 2011

Mental Health and Omega 3/6 Ratio, A New Review

Twitter is a black hole for time spitting out information like Hawking radiation. (I may have achieved the geekiest simile ever!)  I've been a bit busy, as the applications for preschool are pretty detailed, asking for medical records, descriptions of my culture, and different ways we help the little one settle down or take her nap (bribery and threats, mostly.  Oh, wait, the correct answer is "routine.") And sure, she's allergic to sunscreen.  Well, with all that going on the blogging and reading has gone by the wayside a little.  Also, most papers come out as a preview in the last week of the month, so there tends to be a rush of exciting new information all at once.  Then a dry spell.  If I'm fired up, I'll actually look into a topic in depth and do a nearly proper literature review.  But not having had the time to do that... there's always twitter (and Jamie Scott, who is sending me a slew of papers about mitochondria, histamine, and sleep because he is awesome that way.  I'm hoping to settle down and look at them sometime over the next couple of weeks).

Twitter!  The be-ripped Martin Berkhan tweeted up a paper earlier today that is a new review of Omega 3s and 6s.  The article, Evolutionary Aspects of Diet: The Omega-6/Omega-3 Ratio and the Brain, is a tidy look at omega-3 and omega -6 biochemistry detailing all the conversions and enzymes along the way for the biochem geeks.  In the end, it describes the more interesting stuff about the evidence that omega 3s, in fact, do have an important role in the brain, and that one would be a sad and foolish monkey indeed to consume the modern 25:1 6:3 ratio (just say no to corn and safflower and soybean oil...)  Another interesting fact - the review is written by Artemis P Simopoulos, who pretty much first popularized the Mediterranean diet with her book The Omega Diet: The Lifesaving Nutritional Program Based on the Diet of the Island of Crete.  Guess she knows what she's talking about with respect to the omegas.  

Let's dig in.  Hmmm... "psychologic stress in humans induces the production of pro-inflammatory cytokines such as IFN gamma, TNF alpha, IL-6, and IL-1."  Yup.  Too much omega-6 compared to omega 3 can lead to the overproduction of inflammatory cytokines, which for various reasons is Not Good.  Theoretically, changes in PUFA ratios can alter the function and structure of the serotonin receptors (for example, essential fatty acids in the plasma predict the CSF metabolites of serotonin and dopamine)(1).  Treatment with DHA and EPA can be useful in major depressive disorder and bipolar disorder.  Other researchers note that as the dietary ratio of omega-6/omega-3 increases, depression symptoms, TNF-alpha, IL-6, and the IL-6 soluble receptor increases.  Another group studied brains of people suffering from depression when they died vs. controls.  A decrease in AA/DHA ratios were negatively correlated with age in depressed people, but not in controls.  All these lines of evidence, including the randomized controlled trials of omega-3 supplementation, seem to support the idea that our brain needs omega-3s to work well and keep the mood stable.    

Now onto the studies of cognition and omega-3 PUFAs.  Turns out that when the neurons are stimulated with neurotransmitters, the PUFAs in the cell membrane can be released to become all sorts of different inflammatory and anti-inflammatory or signaling molecules.  The PUFAs also seem to influence cell migration and cell self-destruction (called apoptosis) - they even influence the length of telomeres, which are known to decrease with age, cancer, and cardiovascular disease.   A lot of neurochemistry has been elucidated in this area - the details are nicely summarized by Simopolous.  Suffice it to say that brain inflammation is part of the pathology of schizophrenia, dementia, and likely autism, and that omega 6/3 ratios could be important, and omega 3 supplementation (if done early on), can possibly be helpful.  There is some controversy as to the best ratio with which to supplement (2:1 EPA to DHA is recommended by Simopolous), and in these unknowns I prefer to fall back to the primary sources - fatty fish themselves.   

A study of prisoners showed many violent incarcerated young folks have deficiency ("0% intake") in omega 3 fatty acids from fish and selenium in the Table 5 of the paper, called "Diet of disaffection: nutrient intakes from a sample of disadvantaged young people."  Only 17% of them get adequate intake of magnesium too.  Interesting.

When one looks at studies of substance abusers, one also finds deficiencies of omega 3s.  Alcoholics, for example, are a known population rife with nutrient deficiencies (a med school professor used to call it the BBB diet - "beer, bread, and bologna.")  A group of researchers carried out a small double-blind randomized controlled trial of 3g EPA and DHA vs soybean oil control in substance abusers. After three months, the treatment arm had significantly reduced feelings of anger, anxiety, and cravings.  The increase in plasma EPA strongly correlated with the reduced anxiety, and the effects persisted for 3 months after the end of the treatment.

Putting it all together - the overall evidence suggests that if you want to be anxious, moody, depressed, violent, and craving addictive substances, by all means slurp down those omega 6 PUFAs. If you want more control over your brain and urges, maybe look into avoiding any extra 6 (the animal fats will have all that is necessary) and be sure to get the omega 3s you need via fish a few times a week or properly sourced beef or other grassfed ruminant meat.  This brain chemistry thing ain't so hard after all.

Thursday, February 10, 2011

The Neurobiology of Insomnia - How I Learned to *Start* Worrying and Love Orexin

The sleep and insomnia literature is vast enough to make one... well, overwhelmed.  New textbooks, then, can be a nice resource.  But textbooks are a bit of a gamble - some are fantastic, and others are disorganized and hideously boring.  Like the one I'm reading now.  But I spent some $$ and I'm powering through. (Today we're in chapter 7, pages 68-82) 

Insomnia.  There are various types.  Chronic, acute, secondary, primary.  And then there are the sub-varieties- difficulty getting to sleep, difficulty maintaining sleep, early awakening, and non-restorative sleep.  10-20% of the population has chronic insomnia, and the societal costs are huge (poor productivity, car accidents, mood disturbance, irritability, poor academic performance, tension, headaches, and GI problems, to name a few.)

A quarter of those with chronic insomnia have primary insomnia.  That is, these folks just don't sleep well for no particularly good reason.  EEG and neuroimaging findings seem to suggest a general case of hyperarousal.  Like being on cocaine without the cocaine (cocaine intoxication would be a cause of secondary insomnia).  High cortisol levels, high CRH response to stress.  Elevated alpha and beta wave "power" and diminished delta wave power.  Primary insomniacs are alert, and there's no two ways about it.

Serotonin, norepinephrine, dopamine, and histamine are all now thought to be wakefulness-promoting neurotransmitters.  These neurotransmitter concentrations will be highest while awake, low during slow wave sleep, and lowest during REM sleep. 

Sleep promoting neurotransmitters include GABA and adenosine.

Acetylcholine is seen in wakefulness, but also thought to promote REM sleep.  Activation of cholinergic neurons by GABA seems to initiate REM sleep in rats.

But now let's break up the activities of our new friend, orexin.  Orexin if you recall is a neurochemical responsible for promoting appetite and wakefulness made and released in areas in and around the hypothalamus.  Fibers from the orexin neurons reach out to innervate most brain regions, including the brainstem, cortex, and spinal cord.  Orexin neurons discharge regularly during wakefulness, and sputter to a stop when our EEGs start to slow and synchronize during sleep.  They begin to fire again in short bursts prior to waking up.  Orexin excites almost all the wakefulness-promoting neurons (acetylcholine, dopamine, norepinephrine, and serotonin neurons).  Narcoleptic dogs in research seem to lack some orexin receptors.   

There is quite a bit of evidence that various types of stress affect orexin.  However, the effects can differ depending upon the type of stress (cold vs. immobilization, for example), or age (old vs. young rats - presumably shivering and/or tied up in these experiments).  CRH, corticosterone and the gluococortocoids seem to increase orexin.  This will increase wakefulness and increase appetite.

Whew.  I'm exhausted already.  A bit of different music today (Pixies, Where Is My Mind).

Classical depression is often linked with insomnia.  Seems that stress steroid hormones induce orexin, which induces wakefulness.  Orexin will jack up serotonin (and the other wakeful neurotransmitters), which will then (if all is going well) induce negative feedback on orexin.  But say your serotonin machinery isn't running efficiently in the first place.  So you burn it out with too much wakefulness, then you don't have the negative feedback.  So you end up awake and grumpy.  This is one theory of depression.  I'm not sure it holds water, entirely, especially as depression promotes sleepiness OR insomnia and weight gain OR weight loss.  But between the different neurotransmitters and the different negative feedback, issues with any one of those systems could cause issues with sleep, mood, and appetite.

By the time you are depressed enough to be suicidal, your orexin levels in the CSF will drop.  Maybe at this point your hypothalamus has just plumb given out.  Who knows.

Tying it all together:

Primary chronic insomnia is thought to be mediated by hyperarousal.  Stress seems to activate CRH, which activates orexin, which will leave you watching the Home Shopping Network in the wee sma's.  Over time, your entire neural network will get exhausted, and your serotonin and dopamine depleted, leaving you without negative feedback to shut down the orexin, and thus exhausted, hungry, and depressed.  Good night!

Wednesday, February 9, 2011

Some Thoughts and Some Tchaikovsky

Certain composers seem to be able to understand the music that floats in the air between molecules, the music that describes the light, wind, war, and love. Tchaikovsky can be a bit too romantic, as the Russian composers were apt to be (a writer would call it purple prose), but in my mind there are few better songs than the 1812 Overture (right click in new tab to listen without leaving this page - this is the first part). A lot of folks dig the finale with the cannons and the fireworks, but my favorite part is the beginning choral and its recapitulation in brass just before the cannons start going off. When I listen to the 1812 Choral, I feel that Tchaikovsky translated a spirit, a meme, a truth, and that when it is over, I understand something more about being human.

In some respects, that is the lofty goal of this blog. What does it mean to be homo sapiens? How do we nurture a human, how do we heal? Since I have no patience for philosophy, I work in biology and biochemistry with a hint of practical psychology thrown in.

My style is to think out loud in blog form (such a wretched word, "blog," sounds like some sort of mucousy allergy problem). Some of the ideas are early, not fermented as it were, and I will likely change my mind about some things over the months. There are so many unknowns - it can get frustrating when you realize how much money, effort, and time have been spent looking at nutrition, metabolism, and mental health in such a way as to discover nothing at all.

But there is exhilaration too, especially in the sharing of ideas, and to have (if someone wants to listen) an enhanced ability to heal. Myself, my family, my patients.

Here is the 1812 Finale.

I don't believe in magic cures. I agree wholeheartedly with this post on PaNu, about looking for that next secret, the next hack, the next way to measure your increments of success other than feeling better, lifting better, running faster or farther, and the pantsometer. Just eat well, get some sleep, play (outdoors if possible) and worry about the tablespoons of coconut oil when everything else is locked into place. Sometimes we are broken, and modern medicine can actually help with the fix. Sometimes we are broken, and there is no perfect fix.

It always settles me a bit when I find myself in agreement with Kurt Harris. Mostly because I can tell he thinks about things. He reads and sits back and asks some questions and reads some more and he thinks about it again, and then he posts. He is not as even-tempered as Stephan Guyenet, but if he jumps at being questioned, I'm pretty sure it is because he's done the time, the reading, and the thinking.

Sometimes I post first and think about it later. A different process, and in some ways a more prolific but scattershot result. And I believe the most important aspect of a "paleolithic-style" diet is the avoidance of inflammatory load. Not too much fructose, as little gluten as possible, and keep the PUFAs minimal with enough omega 3 to more or less balance the 6, and avoid all the fake food out there. My obsession is not with what exactly goes in the mouth but how the possible toxins meet the gut, the immune system, and the brain.

The audience for this blog grows and grows. It has tripled in the last three months or so, and given the growing interest and intrinsic common sense of the traditionalist/paleo diet movement, I imagine it will only get bigger. The concept is simple, the proof of concept a lot of work, especially when only a few of the researchers are asking the sorts of questions that will yield (or not) the answers we are looking for.

The picture below is of my great-grandmother, by all accounts an extraordinary woman who graduated from Vassar with a degree in Botany. She married a publisher and died at the age of 34. Her early passing I believe cast a shadow on my family that continues in some respects to my generation.

I'm tired of illness caused by bad advice, corrupt motivations, and incompetence. I love the study of medicine and the human mind. I read and I listen to find that truth, that meme, that whisper of the mathematical dance of molecules through the gut, the bloodstream, the brain. The spark of thought and what might strangle it or snuff it out. And that is the story of my blog thus far.

Saturday, February 5, 2011

Food Elimination Diet and ADHD

There is little argument that diet has a contribution in the major diseases of civilization, such as heart disease and type II diabetes.  However, the effect of diet on mental health disorders remains controversial in the conventional circles.  I'm not entirely clear why, as it has been known for a decade or more that different kinds of inflammation mediate both metabolic syndrome and the depressive disorders and schizophrenia.  It seems logical to me to look for dietary or environmental insults that would predispose one to develop these disorders, and not just in fringe journals, or Australia.

But then, I also think it is logical that our immune systems are responsible for heart disease and high cholesterol, not that our livers (in a desperate effort to do us in) release cholesterol into the bloodstream to clog our arteries like an old sock dropped into the disposal.  The reason I find the immune system to be a logical culprit is that the whole purpose of the immune system is to KILL THINGS and wreak havoc.  Sometimes your general turns tables on you.  Way of the wild.  But I'm rambling.

ADHD in children.  Controversial, of course, as stimulants are a primary treatment.  The controversy looms large in part because behavior is primarily felt to be a parental/discipline problem.  And there has always been the idea that "sugar" makes kids "hyper" - so we have this cultural meme of lazy parents and spoiled kids chowing down on skittles and garbage, driving the teachers nuts - the teachers, being lazy themselves, want the kids medicated into oblivion so that no one will have to do any work (especially, presumably, the psychiatrist, who happily prescribes addictive drugs in a 4 minute visit to keep the families coming back and to collect a large paycheck.)  Do we really live in a world where everyone entrusted to keep our kids safe and happy is hopelessly lazy and corrupt?  Because if the cultural meme is true, we are screwed.

Let's get to reality, where families really suffer with the disorder, and teachers want kids to do better, and doctors try to spend some time in multifaceted ways to help.  ADHD is a recipe list of symptoms - hyperactivity and inattentiveness being primary.  Part of the issue is the stupid recipe list - ADHD symptoms are a function of problems with the frontal lobe of the brain, and while several neurotransmitters are involved, an inefficiency of dopamine transmission may be the key player.  And, indeed, there are some families with lots of ADHD who have known genetic issues with their dopamine receptors.   There.  Simple.  It's dopamine.  A kid has the symptoms, hand them dopamine in a ritalin tablet, and call it a day. 

Not so fast.  Problem is, a lot of different issues can cause problems with the frontal lobe and other associated ADHD areas, not just genetic issues.  Depression, for one, seems to torch our ability to stay focused.  So will anxiety.   Lack of sleep (I'll be more specific about sleep and ADHD symptoms and defiant behavior in another post).  Other kinds of inflammation.  Issues with a thinning frontal cortex in development.  The vulnerability to the different insults will be genetic, and families in general face similar environments, so a family with lousy sleep or lousy eating habits might all turn up with ADHD symptoms, just like the family with the primary dopamine problem.  Stimulants will generally help perk up the frontal lobe and behavioral changes can help too, regardless of the cause - but one never wants to ignore an ongoing environmental insult that is damaging the brain while you correct the symptoms with a band-aid.

The stakes are high.  Kids with ADHD are much much more likely to grow up and get divorced, lose jobs, be in car accidents, and commit felonies.   We don't want to dismiss the problem as non-existent and focus entirely on behavioral treatments, but we also don't want to throw ritalin at every kid who spazzes out in school.  It's a complex issue, a complex and multifaceted disorder, and for a while now I have suspected dietary causes to be the problem for some kids.  I've even blogged about it a couple times - mostly reviewing the work of a British group who did a well-designed study of 300 some-odd kids in 2007 called the Southampton Study.

In short, the researchers gave kids in the community (so just a random sample of kids, not particularly any diagnosed with ADHD, though some of them may have been diagnosed with it), in blinded crossover fashion, placebo drinks or two types of food additive drinks, with washout periods in between drink trials.  Kids on the additive-laden drink were significantly more hyper in the reviews of parents, teachers, and independent observers.  It's the kind of study that should really make your ears perk up - sure, it ought to be repeated, but the results were pretty definitive.  (When I talk about conventional medicine's lack of support for the idea that diet could possibly be related to mental illness, the title of an article in Harvard's Mental Health Letter in June 2009, two years after the Southampton Study, was " "Diet and Attention Deficit Hyperactivity Disorder - Can some food additives or nutrients affect symptoms? The jury is still out.").

Well, the British researchers continued to dig deeper into the results of the Southampton Study, and last year they published another study in The American Journal Of Psychiatry (these guys to great work, and get their stuff published in all the premier journals).  I blogged about it here - ADHD, Food Additives, and Histamine.  Again, in short, the researchers checked out the genetics of the same kids from the Southampton Study, and found that kids who were made more hyper by the food additives were significantly more likely to have certain problems with genes regulating their histamine system.  Anyone who has ever taken a benadryl for swollen eyes and a runny nose on a pollen-laden spring day will know what histamine is, more or less.  Our bodies release it in response to some sort of allergenic stimulus.  I made the point in my blog that the Southampton study seems to show us that, indeed, in some children (not all!), ADHD symptoms are a food allergy.

This week, another excellent study was published in The Lancet that took the next logical step of scientific exploration.  There is also an editorial.  (Neither are free full text, unfortunately.)  The INCA study is Belgian, and involved a randomized controlled trial with an open label phase (looks like it was single-blinded) followed by a double-blind crossover trial of an elimination diet vs. a "healthy diet" (control).  The 100 children studied were were 4-8 years old and did have a diagnosis of ADHD.

The results were pretty astonishing (well, maybe not to me, or to a lot of parents, but to the diet skeptics out there, it should be pretty darn astonishing).  Nearly two-thirds of the kids on the elimination diet for 9 weeks experienced significant reduction in ADHD symptoms and oppositional defiant behavior.  The symptoms returned when the kids went back to the "healthy" control diet.  The most up-to-date crowd of "Paleo" diet followers will grin when they hear the elimination diet - it was restricted to rice (some might avoid white rice for the excess carbohydrate with little other nutrient value, but most will agree it is essentially toxin-free and not objectionable "safe starch"), meat, vegetables, pears, and water.  There was a less strict diet where small amounts of potatoes, wheat, and other fruits were allowed but by the end of week 2 of the diet, 41% of the kids had no response to the less strict version and were placed on the stricter diet.

There were a couple of interesting wrinkles.  The kids were all tested for IgG antibodies to food, supposedly helping one sort out food intolerances.  These tests are widely used by doctors and para-professionals alike to diagnose food allergies, but when you get down to it, there is not a lot of evidence these tests tell you much about what you might actually be allergic to.  IgG antibodies simply mean that somewhere along the way your bloodstream was exposed to food allergens.  To be honest, I think people with tons of positive IgG food allergies have leaky guts, that wheat and poor gut biome are reasonably likely culprits, and the foods that show up in the IgG test are a random sampling of what happened to make it through the leaky gut.  In the INCA study, the kids were carefully rechallenged with their IgG + foods, and their symptoms of ADHD seemed to have nothing to do with the IgG test.  So I'm right ;-)  (maybe).

A quote from the Medscape article summarizing the findings and the editorial:

Dr. Pelsser's team concludes that a strictly supervised restricted elimination diet "is a valuable instrument to assess whether ADHD is induced by food, [but] the prescription of diets on the basis of IgG blood tests should be discouraged."

In her [editorial], Dr. Ghuman notes restricted elimination diet studies are "complex and challenging." The INCA study was "well-designed and carefully done, showed a benefit with a supervised elimination diet, and provides an additional treatment option for some young children with ADHD.  "For interested parents," Dr. Ghuman told Medscape Medical News, "clinicians should encourage them to seek the advice of the child's primary care provider and a nutritionist for appropriate monitoring of the child's nutritional status and needs. The parents will need appropriate guidance and supervision for a structured protocol to determine any benefit and identify incriminated foods."

So more evidence piles up.  In fact, the same researchers ran a pilot randomized controlled trial with 27 kids published in 2009 (free full text this time) and found that 11 of 15 children on the study diet improved by at least 40%, whereas none of the 12 kids on the control diet improved. 

I may not be completely off base with my basic premise after all.

(Thanks to Dr. Trevisan for alerting me to the Medscape article!)

Thursday, February 3, 2011

Sad Monkeys Hopped Up on Omega 6 PUFAs

Today, the amazing Victoria sent me a paper that is way too great to pass up: Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet*

I know, it's monkeys, not humans.  But these researchers actually took the connection between diet, cardiovascular disease, and depression seriously, and found a reasonable animal model that covered everything.  More or less.  They are lipophobes, but with a spoonful of sugar, they did eventually discover that the omega 6 fatty acids go down in the most alarming way... and couldn't find a way to directly blame the sat fat.  But that's the punch line.  Let's throw out a few facts and then get to the set-up.

First off:  Your brain is 60% fat, and, even more importantly, the important neuronal plasma membranes are 30-50% of the fish-derived (and you-are-dreaming-if-you-think-you-can-get-enough-from-flax) omega 3 DHA.  Yeah.  That much.   Arachidonic acid (AA), derived from the pro-inflammatory omega 6 fatty acids, is the other major PUFA in the brain. (DHA is widely distributed throughout the brain, AA is found primarily in the white matter - the gray matter is where a lot of the actual neuronal communication takes place.  White matter is more like wiring.)

One of the main differences between traditional and ancestral diets and our Western diet is the vast excess of omega 6 PUFAs, primarily in the form of Doritos and Hidden Valley Ranch and Hellmans Real (ahem) Mayonnaise, I mean stuff fried in and composed primarily of vegetable seed oils such as corn or safflower or soybean oil.

I'll quote the article here:

Several studies suggest that patients with clinical depression have either an elevated ratio of circulating long chain ω6:ω3 PUFAs, or just low circulating long chain ω3 PUFAs. There is a 60-fold variation across countries in annual fish consumption and a strong inverse relationship between national per capita fish consumption and the prevalence of depression. Early clinical trials suggest that dietary fish oils reduce signs and symptoms of depression in some, but not all patient populations 
And just to reinforce the fact that these monkeys are rather reasonable models of human-like depression - these female monkeys respond to stress via depressive-behaviors (certain depressed postures, decreased movement) which is accompanied by changes in the hypothalamic-pituitary adrenal axis in a similar way to humans experiencing depression.  They also show decreased hippocampal volumes, ovarian function changes, serotonergic system changes, and changes in serum cholesterol similar to humans with depression.  Depressed female cynomolgus monkeys also develop four times the coronary atherosclerosis as their non-depressed counterparts.

So, the actual experiment.  32 monkeys were placed on an "atherogenic Western diet."  (I'm sure they meant the crystalline cholesterol + butter, beef tallow, and lard.  I'm a bit suspicious of the sucrose and the safflower oil, myself.  And was there any choline?)

Diet composition was the following:

Alphacel (this is "non-nutrative bulk" otherwise known as "fiber")
Beef tallow
Butter, lightly salted (guessing this was not Kerrygold ;-)
Safflower oil (linoleic)
Crystalline cholesterol (yum!)
Complete vitamin mix
Mineral mix
Calcium carbonate
Calcium phosphate

Diet composition (% of calories): 38.3% carbohydrate, 42.4% fat, and 19.4% protein
with 0.28 mg/cal cholesterol.  I'm not sure what sort of "Western" diet this is supposed to mimic - it looks a lot like milky sugar in animal fat and vegetable oil sprinkled with cholesterol to me.  Where are the grains?  But that's okay, I suppose.  Adding the grains might add an extra variable that we would have to parse out, and now we don't have to. 

When you get to the actual fat content, it was about 60% saturated, 30% monounsaturated, and 10% PUFA.  But the PUFA omega 6-3 ratio was a whopping 25:1, and to add insult to injury, there was 0.00 DHA or EPA. 

So what happened?  The monkeys were put on this diet for a total of about two years and observed for signs of depression, and several body and serum measurements were taken. 

Interesting and significant developments - a whopping 42% of the monkeys developed depressive behavior.  The depressed monkeys tended to eat less and have a lower BMI (this is actually typical for a classic depression and more short-term severe depressive episodes - people tend to gain weight over the long term or in atypical depression).

The researchers compared fasting lipids of the 6 saddest monkeys compared to the 6 happiest ones.  (Measures of depression included the amount of time spent in depressed postures and pretty objective signs of depression.  They did not have the monkeys fill out the depression scales we tend to use for humans).  The sad monkeys had higher total cholesterol, but lower HDL (I would call this a cholesterol pattern consistent with inflammation).  The happier monkeys had lower total cholesterol and a higher HDL.

The researchers also broke down the fatty acid composition of the monkeys' plasma - there was no correlation between saturated fats and the amount of depression (which does not surprise me or the readers of Evolutionary Psychiatry, I would hope).  However, the depressed monkeys had significantly (42%) higher circulating omega 6 fatty acid (which would also mean that the higher circulating omega 6 fatty acids would match up with those monkeys with higher total cholesterol and lower HDL.  Hmmmmmm) than the nondepressed monkeys.  Omega 3 fatty acids were not much different between the two groups (possibly because they got so little omega 3 anyway).

So there you have it.  There was no control, which is problematic.  It would be nice to know how much depressive behavior these monkeys have in the wild, and in a similar captive situation but with their Indonesian forest diet flown in.  But I think that if you are a female cynomolgus monkey who is apt to be in a stressful subservient social position, you ought not to eat a diet of omega 6:3 PUFA in a ratio of 25:1.  I'm guessing that a moratorium on soybean oil mayonnaise for the human animals out there might be a good idea too. 

*Chilton FH, et al, Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet, Physiol Behav (2010), doi:10.1016/j.physbeh.2011.01.013

Wednesday, February 2, 2011

Appetite Regulation and the Brain

Before we get back to sleeping, there's a bit of brain signaling that it is important to get a handle on.  Most of this information is derived from rodent studies, but I have no reason to believe their brain signaling about appetite and whatnot would be much different from our own.  I want to go over this bit about satiety and hunger pathways in the brain because they overlap with the sleep pathways that we will cover next. 

The center of appetite is in the hypothalamus of the brain.  The most important part of the hypothalamus with respect to appetite is the arcuate nucleus.  (When we talk about neurons, a nucleus is generally a collection of neuron cell bodies with long branches called axons that spread out to different brain regions, spreading signals along the way).

Now it is time to introduce some players.  Bear with me, as there are a few too many.  Within the arcuate nucleus,  one set of neurons makes CART and POMC.  POMC is cut up into a neurotransmitter called alpha melanocyte-stimulating hormone.  This critter acts on various areas of the hypothalamus to reduce appetite.  Another set of neurons in the arcuate nucleus makes appetite-increasing neurotransmitters and sends axons to the same areas of the brain as the POMC (appetite reducing) neurons.  The appetite increasing chemicals are AgRP and neuropeptide Y.

Quick recap - arcuate nucleus of the hypothalamus is the nerve center for appetite regulation.  It is responsible for sending out appetite reducing neurotransmitters (alpha melanocyte-stimulating hormone) and appetite increasing neurotransmitters (AgRP and neuropeptide Y).

Now, these things are always beautifully regulated via negative feedback loops.  The POMC neurons and the AgRP and neuropeptide Y neurons project signal to an area of the brain called the paraventricular nucleus.  (Don't let all the long names blow your mind.  They are just names.  Maybe we should rename them Robb Wolf, Mark Sisson, Melissa McEwen, or Richard Nikoley to make them more friendly.)

The paraventricular nucleus synthesizes and secretes two appetite-reducing neuropeptides (corticotropin-releasing hormone - yes, that corticotropin releasing hormone - and oxytocin) in response to the stimulus by the appetite increasing neurotransmitters.  The arcuate nucleus also sends projections to the lateral hypothalamus to stimulate the appetite increasing hormones melanin-concentrating hormone (MCH) and the orexins.  It is these last two appetite-increasing hormones that have a lot of overlap with sleep regulation, and even mood.  I'll get to them in a few days.

Phew.  Now let's get a bit more big picture.  The arcuate nucleus is the epicenter of appetite control and receives a lot of signals from outside players.  The presence of glucose, and also long chain fatty acids such as oleic acid (the primary component of olive oil, but also a major component of most animal fats) in the arcuate nucleus will inhibit feeding behavior and peripheral glucose production.

And remember those CART/POMC (appetite reducing) and AgRP/neuropeptide Y (appetite increasing) cell bodies in the arcuate nucleus?  Turns out they are the major site of action in the hypothalamus of the hormones leptin and insulin.  Both those hormones will tend to reduce appetite by suppressing the AgRP/neuropeptide Y neurons. 

Have I lost everyone yet?  There is a slew of wondrous basic science research into appetite regulation in the hypothalamus.  One of the cooler things to do is to infect the hypothalamus with various genetically modified adenoviruses* (I know, it does sound like the first act of a zombie movie).  If the adenovirus carries a gene that activates the signal of "low energy availability" (for biochem geeks, this is AMP kinase), the mice increase food intake and gain weight (maybe they will be hungry for BRAINS).  If the virus signal suppresses the low energy signal, the mice will stop eating and get a bit too slender.  Our "food is aplenty" hormones insulin and leptin will decrease the "low energy available - so EAT" signal, whereas known bingey hormones cannabis and ghrelin will increase the appetite signal and lead you to eat. 

So for many, many years, researchers have known that glucose and insulin seem to decrease appetite.  (BUT BUT BUT what about diabetes and gaining weight and too much insulin and glucose!!!!  Yes, in that case the negative feedback is broken, likely through inflammation and damage in the hypothalamus - so you need more and more glucose and more and more insulin to give the signal to cut off the appetite, and protuberant bellies and sales of "Sweatin' to the Oldies" increase accordingly).  I think this basic science, in combination with a false sense of security about high carb diets causing increased insulin sensitivity in the periphery (as opposed to low carb diets, which will physiologically increase insulin resistance in the skeletal muscle), is what led to the misguided advice for diabetics to consume carbohydrate-rich diets all these years.  It was only recently (well, 2002) that oleic acid, for example, was found to significantly reduce appetite also.  (And that basic science finding pretty much coincides with the massive enthusiasm for olive oil and the Mediterranean Diet).

Um, I hope I still have a few readers by the end of this post!  Go out there and eat healthy and get some sleep.  Your hypothalamus will thank you, as will your less protuberant belly.

As always, a big thanks to Jamie Scott, who has sent me the major reference article for today's post.

*there was a recent study showing that kids who had previous infection with adenovirus-36 were much more likely to obese than kids with no previous infection.  No, I doubt it is the mutant strain that escaped the lab.  Antibodies to adenovirus-36 are also found in 30% of obese adults.**

**get some sunshine to boost your vitamin D to ramp up antiviral immunity.