Thursday, July 5, 2012

Neurobiology of Obesity (Again)

Between a quick 4th of July trip to Texas, kiddo piano lessons, and potty training, we are super busy here at Evolutionary Psychiatry.  And AHS12 is coming up at lighting speed!  I'm speaking (don't have the actual schedule yet, so no clue when!) and the paleo doctor crowd is coming for a visit, as well as the Antipodeans, and the be-yootiful Lindsay.  Maybe Evolvify will show up on his satphone, like those hapless reporters from the war zone on nightly news casts.

The new Temper Trap song is just lovely: Trembling Hands (right click to open in new tab)

All that business doesn't mean I'm not still neck-deep in interesting scientific papers.  There's a big problem, actually, in that my psychiatry practice is bursting full and the articles keep coming…if I've ignored your email, there are 10 more pressing emails in front of yours.  Sorry!

Papers that have been on the back burner for a while but deserve some attention:

Obesity is associated with high serotonin 4 receptor availabiity in the brain reward circuitry

Reward, dopamine and the control of food intake: implications for obesity (free full text)

I work a lot with addiction.  Alcohol, pot, nicotine, opiates, cocaine.  Not a lot of meth around here, but otherwise we have a fairly full spectrum.  And no one thinks cocaine addiction lives in the liver.  It's the brain.  You like something to excess, even if it stinks (nicotine, pot), makes you puke (opiates, alcohol), or makes you crazy (cocaine).  You take more and more, even if it isn't enjoyable, just to chase the anticipatory feeling of eating it.  What better describes eating a whole sleeve of Pringles?  "I was hungry." or "That was disgusting but I could eat another sleeve."

I don't think calories in and calories out is the whole story.  Otherwise we could all have just enough nicotine, or just enough cocaine.  But some of us can't, just like food.  Some of us face a world of twizzlers and Taco Bell and go "meh."  Others need a $20,000 gastric bypass to sever the hormonal feedback loops.

But I'm biased.  Some folks think the whole reward/brain/calorie thing is garbage*.  That's cool.  Everyone is entitled to an opinion.  Obese people and mice keep lighting up the reward circuitry PET scanners, with the endocannabinoids, dopamine, serotonin, opiates, GABA, cholecystokinin, neuropeptide y, and norepinephrine all playing a role, and serotonin drugs keep getting FDA approved to treat obesity.  So I suppose I am just used to thinking this way.  Leptin, insulin, orexin, ghrelin, neuropeptide y, and certain key areas of the brain (hypothalamus, hippocampus, amygdala) and regulation of endocrine systems (thyroid) and muscle systems regulating metabolism, calorie burn, fidgeting, the whole shebang.  And what I see, over and over, is neurochemistry lit up like firecrackers by highly rewarding foods.  See the definition of palatable if you are confused.

The most interesting thing about the Kitavans is that they don't exercise more than the average active American, and they have food to spare.  Piles are left for the dogs.  They are skinny, but they have easy calories available in excess.  So should we, if our brain neuroendocrine system worked properly, as it should with natural available foods and not the hyperengineered frankenfoods of the 20th and 21st centuries.  That's my opinion.

Back to the papers.  In the first, a long history of rodent papers are cited, but in this paper, actual humans were examined for the amount and receptivity of serotonin 4 receptors (5HT-4) they had in certain key reward areas of the brain.  Turns out the higher your BMI, the more active 5-HT4 receptors women had in the reward areas of the brain.  Happy and inactive 5-HT4 receptors are associated with the "fed state" and satiety.   In the reward areas, 5-HT4 transmission controls opiate and dopamine transmission.  The "neocortex" or the place of human "free conscious will" as it were is fairly light in 5-HT4 neurons.  It's the deeper areas of the brain, places of urges and impulse, that light up in PET scans of the obese.

The free full text review paper is also useful in describing the hypothalamus and how food intake is regulated (via amino acids, fats, and other signals).

(I've linked this song before, but it deserves a new listen:  Kasabian, Reason is Treason)

Based on findings from imaging studies, a model of obesity was recently proposed in which overeating reflects and imbalance between circuits that motivate behavior (because of their involvement in reward and conditioning) and circuits that control and inhibit pre-potent responses.  This model identifies four main circuits: (i) reward--saliency (ii) motivation--drive (iii) learning--conditioning and (iv) inhibitory control--emotional regulation--executive functioning.  

In folks with addictions, the consumption of high quantities of "palatable" substances (or food) will result in an enhanced reinforcing value of the food and weakening of the control circuits.

The definition of a "palatable" food is anything you could eat when you are stuffed.  Like Pringles.  Or pie.  Or kraft macaroni and cheese.  Or ramen.  Anything you can eat when you are stuffed should rarely be eaten. That may be the cardinal paleo rule.

But it's only the brain.  It has little to do with macronutrients (except super low fat, super low carb, or low protein foods are likely to be highly "palatable" in our definition).  You won't get fat on garlic, or plain baked potato, butter, or even (gasp) a banana.

My opinion.  I welcome you to read others!

*The main argument here being that the nutritional transition occured with poor and crappy foods… white flour, beer, white sugar.  Have the folks arguing against this theory never tasted ramen noodles or kraft macaroni and cheese?

34 comments:

  1. J Stanton did a whole series on this. I think he said he's going to talk about it at AHS.

    I did lose fat cutting out rice over two years ago. Trying to figure out why the fat disappeared without effort is what led me down this path of nutritional and metabolic discovery. The problem with the reward theory is it doesn't explain how the body uses the energy. Energy input and output are coupled (in the mathematical sense). I'd encourage people to remember back to their differential equations courses and remember that coupled systems cannot be solved correctly by holding variables constant. So, it's "garbage" from a mathematical perspective which means it won't stand up to science.

    As a corollary to this fundamental mistake, reward theory doesn't explain on a biochemical level how the body will use the energy input. How does reward explain whether the body will store or expend energy? As a coupled system, it's likely eating more may cause you to burn more. As long as there is an imbalance between energy input and output, the the constraint of the Conservation of Energy stipulates, as a necessary effect, that weight will be gained or lost depending on the direction of the imbalance. The amount of input or output doesn't matter as long as there's an imbalance. The reward theory does not clearly explain on its own merits why the imbalance would be biased towards storage rather than expenditure.

    A scientist that doesn't understand mathematics...

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    1. Of course the default messed up will be to energy storage. If it isn't (messed up regulation swtiched to energy burning), you die in a matter of weeks or months, so that will have been heavily selected against. Clearly the brain manages energy storage via hormonal regulation via the thyroid, etc. I don't see these as fundamental problems.

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  2. I found this in the Kitavan study:

    The intake of vitamins, minerals and soluble fibre was therefore very high, while the total fat consumption was low, about 20 E% [28], as was the intake of salt (40-50 mmol Na/10 MJ compared with 100-250 in Sweden). Due to the high level of coconut consumption, saturated fat made up an equally large portion of the overall caloric intake as is the case in Sweden.

    This seems like a contradiction. Was their diet low in fat or high in fat? Or, is this saying that their diet had 20% saturated fat?

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    1. It was low fat (20% total) but a large amount of the fat was saturated, so I believe they were saying the % of calories from sat fat were the same in both cultures.

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  3. " Anything you can eat when you are stuffed should rarely be eaten. That may be the cardinal paleo rule."

    Brilliant statement, that! For me in college, that was consuming a half-box of cooked pasta drenched in tomato sauce, followed by vacuuming down an entire pint of Ben & Jerry's ice cream (Heath Bar Crunch!) in 5 minutes flat. Yikes!

    We're fervently ironing out the last kinks to the AHS12 schedule and expect to publish it ASAP (maybe even by tonight if all goes well). Apologies about the delay.

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    1. No problem! That might be the hardest part of organizing the whole thing! Also, I should give a hat tip to Anastasia of Primalmeded. I believe I saw a similar and succinct definition of palatability on her blog first.

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  4. I don't see why the reward theory and the carb/insulin theory are in conflict. They appear perfectly complementary to me. Any reason they can't both be contributing to obesity?

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    1. They really aren't in conflict, and excess insulin does lead to overeating via hypoglycemia.

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  5. This is the clearest definition of "palatable" I've seen yet.

    I think the food reward/palatability theory is easy to reject, because it's easy to mistake for several different ideas which sound superficially similar.

    Please write about this issue more, the clarity of your writing and clear organization of your thoughts can help the online evolutionary medicine community cut through the confusion and have more meaningful debates about this topic.

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  6. "The definition of a 'palatable' food is anything you could eat when you are stuffed."

    Thank you! Finally, a definition of platability that can be tested on human subjects with reproducible results. Quick, alert the obesity researchers!

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  7. I used to be abnormally interested in food, had to carry emergency snacks in my purse, because when I was hungry, I couldn't tolerate it at all. Food itself used to taste absolutely amazing, often after eating I was planning next meal in my head. LCarbing changed all that, food is less rewarding now.

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    1. I don't tolerate super high carb/low fat (with whole grains) at all. But I think there are variations, and some people seem to thrive on low carb, while others don't. I don't bother to count macronutrients or calories, but since I don't eat grains very often (occasional rice or rice flour, or even more rarely corn tortillas), my carbs tend to come from bananas, pumpkin, squash, and potatoes. I haven't had any problems with those in any amounts, except sweet potato, which upsets the tummy in high amounts.

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    2. I totally agree about variations. I remember reading about your hypoglycemic problem in the past. Did it went away with excluding grains?

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    3. Yes, for the most part. Only recurrence was when I was too busy to eat breakfast or bring lunch one day at work, but I had been to the gym in the morning, and I was ravenous. Someone brought one of those caramel popcorn/kettle corn/ cheese corn barrels to work (it was around the holidays), and so I had several handfuls of caramel and kettle corn… a couple hours later felt absolutely horrible. Faint. Shakes. Ate some candy and it went away… repeat the same experiment with a banana, and it doesn't happen.

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  8. Wishing you godspeed with your potty training! :-)

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    1. Thanks! I think she finally has the hang of it. We've been several days without any accidents. Lots of high fives all around.

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  9. "The most interesting thing about the Kitavans is that they don't exercise more than the average active American"

    I've heard this said numerous times by several different people, but I can't seem to find any specifics. The average active american is probably the type of person who follows mainstream advice to exercise 3+ times a week (aerobic exercise is the most common). So either kitavans are also partaking in aerobic exercise, which could explain their low rates of dementia (which i'm also surprised hasn't been investigated much on this blog ;P ), or they're always (chronically) active in a more mild manner (which is also interesting and can explain things like why, if, they have lesser rates of deep vein thrombosis or other things associated with chronic inactivity). Anyways... just hoping maybe someone could fill in the blanks in regards to the type of activity they do (as well as some quantitative figures, if possible).

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    1. There is a lot of detail in Lindeberg's "Food and Western Disease." I imagine there are some marked down used copies on amazon by now. Worth the read, for sure.

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  10. One thing I know after 45 years struggling with weight and early onset depression (atypical) is that there is more to the obesity issue than the food reward and insulin hypotheses. I have lost 30 to 40 pounds three times in my life (age 26, 30, and 54) and gained it back rapidly when I went back to my standard American diet except for once (age 30) when I maintained a weight loss of 40 pounds effortlessly for about 5 years without avoiding the starchy foods and desserts I had always craved. For the first and only time in my life I ate what I wanted, when I wanted and didn‘t gain an ounce -- it was a miracle!

    The weight loss at age 30 happened as a result of a serious depression which, for the first time in my life, caused me to quit eating rather than my usual overeating and oversleeping in response to depression. After several ineffective antidepressant drug trials I hit on Nardil which literally turned my life around. I felt “normal” for the first time in my life. I continued to take Nardil/phenelzine (30mg) for the next 5 years during which time I effortlessly maintained a weight of 130 lbs.

    At 61 years of age, I now realize what an anomaly this 5 years of my life represented. The “palatability” of the food I was eating did not change nor did the foods ability to promote insulin secretion differ before and after each weight loss experience, yet for 5 years I was immune to weight gain!

    My theory is that it was due to the drug. Various studies on phenelzine have indicated that it can alter fat metabolism and circadian cycles, activate HPA activity (which is now thought to be hypoactive in atypical depression), moderate appetite and somehow affect leptin. Nardil is generally known for causing weight gain but that certainly didn’t happen to me. I believe it must have powerful and as yet largely undetermined effects on the body’s weight/metabolic/stress systems. I wonder if the drug works most effectively to prevent regain but not help to lose weight to begin with? I obviously don’t have any answers but I believe there is perhaps something there for obesity researchers to consider.

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    1. You may be interested in this informative interview where Shelley Schlender talks with Dr. Ron Rosedale about the research of Gerard Karsenty where he's discovered that serotonin created in the brain and in the gut apparently have different effects.

      "Insulin hypothesis" is a misnomer and a straw man. While insulin on its own may not explain the whole story, at least the "insulin hypothesis" gets us talking about hormonal (im)balance (or "orchestration" as Dr. Rosedale calls it) as the cause. "Food reward" observes the obvious and necessary effects of such imbalance.

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    2. Of course they have different effects. But I'm confused… do you believe carbohydrates, as a macronutrient, will kill you faster than eating only protein and fat?

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    3. I think dietary glucose is unnecessary and likely suboptimal. It produces less ATP than fatty acids and doesn't produce ketone body byproducts like fatty acids.

      Will it kill us faster? That depends on a lot of confounding variables. But, maybe... http://www.youtube.com/watch?v=WUlE1VHGA40

      Though, I do enjoy buttery mash potatoes. :-)

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  11. Dear Emily, I stumbled on your blog a few days ago, following a link in another blog I follow. I am so very grateful for that link now!

    I, too, am a psychiatrist, working in a CMHC in rural central Kentucky. After reading your most recent couple of posts, I became so enthused that I dove back into your 2010 archives, and have nearly finished that whole year's material. (By the way, yes, your views have 'evolved' a bit since then, but I love the continuing emphasis on inflammation as one of the core etiologies of so much of psychiatric illness!)

    Today I am choosing to send a note to you ... I want to thank you so much for the work you are doing here! If I knew a way to do this: http://www.youtube.com/watch?v=Vh78T--ZUxY for you in person, I would!!

    I have ordered a copy of 'The Primal Blueprint', and next I think I shall order 'It Starts With Food'. I am very eager to learn more, and to follow through on 1) making real change in my own lifestyle, and 2) helping in whatever ways I can to begin helping my own patients make some basic nutritional changes for themselves.

    There is so much to do! And it's hard to stay in the present and not jump 8 moves ahead!

    Anyway, I am now your earnest follower. You have a brilliant mind, a wonderful writing style, and you're a true human. A very nice triad of qualities. Thank you.

    Craig Meek

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    1. Thanks! "Brilliant" is stretching it… I just got bored with basic psychopharm which is a lot of big words, handwaving and guessing, and I'm not really that deep into the theories of therapy, which is the other route a curious psychiatrist can take, so I kinda picked my own way.

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  12. Dear Emily, I stumbled on your blog a few days ago, following a link in another blog I follow. I am so very grateful for that link now!

    I, too, am a psychiatrist, working in a CMHC in rural central Kentucky. After reading your most recent couple of posts, I became so enthused that I dove back into your 2010 archives, and have nearly finished that whole year's material. (By the way, yes, your views have 'evolved' a bit since then, but I love the continuing emphasis on inflammation as one of the core etiologies of so much of psychiatric illness!)

    Today I am choosing to send a note to you ... I want to thank you so much for the work you are doing here! If I knew a way to do this: http://www.youtube.com/watch?v=Vh78T--ZUxY for you in person, I would!!

    I have ordered a copy of 'The Primal Blueprint', and next I think I shall order 'It Starts With Food'. I am very eager to learn more, and to follow through on 1) making real change in my own lifestyle, and 2) helping in whatever ways I can to begin helping my own patients make some basic nutritional changes for themselves.

    There is so much to do! And it's hard to stay in the present and not jump 8 moves ahead!

    Anyway, I am now your earnest follower. You have a brilliant mind, a wonderful writing style, and you're a true human. A very nice triad of qualities. Thank you.

    Craig Meek

    ReplyDelete
  13. Dear Emily, I stumbled on your blog a few days ago, following a link in another blog I follow. I am so very grateful for that link now!

    I, too, am a psychiatrist, working in a CMHC in rural central Kentucky. After reading your most recent couple of posts, I became so enthused that I dove back into your 2010 archives, and have nearly finished that whole year's material. (By the way, yes, your views have 'evolved' a bit since then, but I love the continuing emphasis on inflammation as one of the core etiologies of so much of psychiatric illness!)

    Today I am choosing to send a note to you ... I want to thank you so much for the work you are doing here! If I knew a way to do this: http://www.youtube.com/watch?v=Vh78T--ZUxY for you in person, I would!!

    I have ordered a copy of 'The Primal Blueprint', and next I think I shall order 'It Starts With Food'. I am very eager to learn more, and to follow through on 1) making real change in my own lifestyle, and 2) helping in whatever ways I can to begin helping my own patients make some basic nutritional changes for themselves.

    There is so much to do! And it's hard to stay in the present and not jump 8 moves ahead!

    Anyway, I am now your earnest follower. You have a brilliant mind, a wonderful writing style, and you're a true human. A very nice triad of qualities. Thank you.

    Craig Meek

    ReplyDelete
  14. Some say "meh"...
    True story; I used to chain-smoke. Only when drinking or high on opiates or speed, which was most of the time.
    But any day I didn't have my drugs of choice, or they weren't working right, I couldn't stand to be near a cigarette.
    I know people get badly addicted to nicotine, and I definitely craved it at times - but a withdrawal symptom from nicotine?
    I can't imagine what that's like.
    Apparently 1 in 5 can't get addicted to nicotine.
    I imagine most of us never smoke.
    It's a long time since I've felt like it.
    Feeling like I would really enjoy a cigarette; that was the reason to smoke.

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  15. I accidently deleted this comment from my phone rather than "publish" (sorry)

    George Henderson has left a new comment on your post "Neurobiology of Obesity (Again)":

    Nice. Metabolism (CIH) and behaviour (FRH) ought not to be impossible to reconcile.
    I hypothesize that in some people carbohydrate restriction works because exposure to ketone bodies restores function to damaged neurons that regulate appetite.
    In others, because insulin resistance was the problem after all.
    As Paul Jaminet says (after Tolstoy), all healthy people are healthy in the same way, but each unhealthy person is unhealthy after their own fashion.

    Another IF study
    http://www.fasebj.org/content/early/2012/05/16/fj.12-208868.abstract

    Although timed HF-diet-fed mice consumed the same amount of calories as ad libitum low-fat diet-fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4-fold increased insulin sensitivity. Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF-α levels, and 3.7-fold improved insulin sensitivity. Timed HF-diet-fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low-fat diet.

    Wouldn't sensibly scheduled eating help explain the Kitavans?

    Small island populations that subsist by fishing are characterized by anthropologists as "sedentary". When they are hit by western diets, they get the highest obesity rates in the world (Nauru, Cook islands, Tonga - ahead of larger islands like Fiji, Tahiti, or Papua-New Guinea).

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  16. Wouldn't sensibly scheduled eating help explain the Kitavans?

    Nice observation. Input and output are coupled. And, maybe the Kitavan energy input (along with other lifestyle factors) may not adversely affect their metabolic flexibility.

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  17. excellent post! Im a Portuguese psychiatrist and I´m currently interested in the paleo lifestyle and neuro - inflammation. I´m following your blog and I´d like to keep in touch.
    Rita Barandas

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  18. I am interested in how heart rate variability graphs in the food side of this. It would seem it would mirror the drug aspect if what you are saying is accurate?

    In my own body and dealing with some of the above as well as heavy anxiety, HRV is a massive tale-tale sign. Though meditation/breathing can increase my HRV in the moment I find eating a whole food diet (starch included) prevents low hrv moments to a large degree. However, dose me with sugar/ethanol or flour and it is very evident on my HRV readings.

    Interestingly, I have tracked HRV in response to pictures and even writing invoking the thoughts about sugar/junkfood/alcohol and they send my hrv to 'dangerous' territory.

    I am rambling.

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  19. Look at the psychology of meal timing in a traditional society; if you "raid the icebox" and eat alone you are acting antisocially. If you dig up the communal garden because you feel peckish, you still need to cook the food, and everyone will want some - so you might as well prepare a satisfying meal at a time when there are people who want to help you.
    People who ate alone too often might be killed off.
    People who felt guilty about eating alone would have passed on their genes.
    Hence the guilt complexes around eating today, when our social groups are disrupted and people sometimes have to eat alone.

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  20. Ok, of all i enjoyed the Temper Trap song..thanks for the share! Obesity

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  21. Ah, I was confused as to "palatability" which is used here and in the nutrition community in a technical sense. Normally I think of palatability as depending on my state. Triple fat blue cheese is palatable when I am hungry, when not it is not very palatable.

    I don't consider Kraft Macaroni and Cheese to be palatable, except when I am extremely hungry very bland. And ramen I ate because it was *cheep* and I thought I need carbs with my meal, but I always added vegetables or meat to give it substance.

    Palatability is sort of dependent on the person even in the technical sense above, so it's hard to predict or measure. For each person you have to run a trial feeding them ad libitum and see what they gorge on if anything, and you can't be certain the palatability of any food will not change with time, or that the people didn't self restrict on danger foods.

    In short palatability theory reduces to "People eat too much of the foods they eat to much of." , and hence has poor predictive value. It seems it might better be called food addiction.

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