Monday, April 25, 2011

A Summary of Endocannabinoids and Obesity

In my last post on endocannabinoids, I was trying to do a little too much with too little time, and I don't think the science came out too clearly.  Today I thought I would use the excellent Kim et al paper again for a quick summary of what is known about the effects of the endocannabinoids on obesity, both in the central nervous system (my usual bailiwick) and peripherally.  (Also, please check out Beth's post over at Weight Maven - she has diagrams too!)

Endocannabinoid AEA will activate the cannabis receptors in the brain and in the fat tissue and skeletal muscle.  The response is to increase food intake, possibly by increasing the appetite hormone ghrelin.  AEA is found at higher levels in obese individuals than lean individuals, and seems to promote fat storage. In the muscle, it decreases glucose uptake, which is one way to increase insulin resistance.

The other major human endocannabinoid, 2-AG, also increases food intake, and is also found at higher levels in obese individuals.  The amount of 2-AG you have circulating in your body is positively correlated with how much body fat you have, and inversely related to insulin sensitivity.  It also decreases glucose uptake in the muscle.

CCK is a hormone secreted from the intestines when we eat.  Normally it sends a signal to the brain telling us that yes, indeed, we have eaten, and we can back off with the hunger signals already.  AEA and 2-AG at higher levels seem to interfere with this whole signaling process - and, once again, higher levels of AEA and 2-AG are found in obese individuals.

Leptin is a hormone that acts in the hypothalamus of the brain.  When it is working normally, leptin sends a signal that we have fed and we need to not be hungry anymore.  However, obese individuals often have high leptin levels, suggesting that the brains of obese individuals have become resistant to leptin's effects.  Leptin-resistant mice have increased levels of endocannabinoids swimming around in their plump mouse bodies.  In mice born without the ability to make leptin, treatment with leptin will very quickly lower endocannabinoid levels.  So obviously there is cross-talk and regulation that somehow becomes broken in the case of obesity.

SO - omega 6 fatty acids become endocannabinoids, which are associated with increase fat tissue, decreased insulin sensitivity, and leptin resistance.  Oops!  (But keep in mind we only have the "associated with" there, not the smoking gun.  It's just… such a pretty theory, I can't help but squee a little.)

Kim et al. are very pro-omega 3 fatty acid, suggesting that it will help reduce obesity, reduce endocannabinoid signaling, and increase insulin sensitivity.  They do use the work of William Lands to suggest that "an increase of dietary omega 3 PUFA was more efficient in decreasing eicosanoid formation from omega-6 derivatives than decreasing omega-6 PUFA in the diet."  (Eicosanoids are the bioactive molecules, such as prostaglandins, endocannabinoids, and thromboxane, that are made from omega 3 and omega 6 fatty acids.)

I just downloaded and took a gander at the Lands paper referenced, and the whole time the good Dr. Lands talks about how the current 7% of US and Denmark diets of omega 6 PUFA is too high, and increasing the total ratio of omega 3 to omega 6 PUFA is the reasonable way to go  - it seems that in systems that are deficient in omega-3, we will hungrily gobble up the omega 3, so that is perhaps what Kim et al means by "an increase of… omega 3… was more efficient… that decreasing… omega 6 PUFAs in the diet."  But who knows what they were thinking.

Very interesting quote from the Lands article about fish, however:

"A fatal hypersensitivity to environmental stimuli ("fainting shock" syndrome) is exhibited by rainbow trout that are fed diets containing n-6 fatty acids without sufficient counterbalancing amounts of n-3 fatty acids ( 10)."

Fainting shock syndrome!  Wow.  If you are a rainbow trout, do not eat corn oil.  Enough said.


  1. Dr. Deans, thank you for emphasizing the Omega 3 again!

    If you don't mind a question, does decreasing 6 to less than 4% of total calorie intake, and eating wild salmon, mackerel/herring/sardines to increase 3, and having an evolutionary diet reverse leptin resistance?

    Thanks very much!

    Dr. Lands' talk on Omega 6 and 3, to the NIH can be watched on youtube. He emphasizes decreasing 6, as well as increasing 3. He is very engaging. It seems to be a military audience.

    Here is part one of four:

  2. Thank your all your articles, Dr.Dean.I think about translating some of your posts into Russian and giving it to the doctors I personally know who work in psychiatric gerontological department in a hospital (my grandma was their patient before she had to be placed into assisted living facility). I hope you don't mind.
    I have a question about the last post. You mentioned that AEA and 2-AG are correlated with the amount of the individual's fat tissue and stimulate the individual to continue to be fat and obese. However, people who are eating the LC diet seems to overcome their excessive fat tissue feeding loop in the process of loosing weight. Could you explain how it works?

  3. Hi Emily,

    I have no shares in cannabinoids of any sort but:

    Unhappy person takes iv heroin. Result is iv bliss. Heroin wears off, result is crashing depression. Probably worse than before the iv fix.

    Fat person smokes pigfood. Hits cannabinoid receptors. EATS +++++++

    What will the cannabinoid receptors then do? Downregulate?????? Depressed appetite post hit? More depressed than pre hit?????

    Just curious......


  4. Peter - I haven't looked at the objective research into that - here's my clinical experience - and let's leave out acute withdrawal and look at maybe 2 weeks to several months out of HEAVY use:

    Alcohol: moody, anxious, depressed, usually gets better on it's own, but the acute phase is very bad, lasting anxiety and insomnia.

    Opiate: generally okay, even on an opiate antagonist, once you get past the acute (sick) withdrawal, though some do better on an opiate partial agonist, and there is some lingering depression.

    Cannabis: acute phase is about the same as the next several months - irritable, moody, anxious. For some people much improvement with temporary mood stabilizers. Lasting insomnia. A TON of people self-medicate for anxiety or insomnia with cannabis - it doesn't seem to help depression all that much, though opiates seems to be a double-edged sword with respect to depression.

    nicotine: sluggishness, hunger, and lasting insomnia

    As to body habitus, there are exceptions, but heroin abusers are generally slender, cannabis abusers a little hefty (no hard data for this, just my observation), opiate pill abusers average (all sizes, I would say), nicotine abusers more slender than average, alcohol abusers typically tubby and inflamed-looking, though the heavy-heavy detox folks are often skinny fat as they drink in lieu of eating. And I'm serious on the "abusing" definition - people who use to the point where it causes significant troubles/symptoms/issues.

    And my experience with the antagonists - naltrexone, opiate antagonist - no major psychiatric issues, even long term (which is surprising). Rimonabant - cannabis receptor inverse agonist - haven't prescribed, but doubles placebo rate of anxiety, depression, can cause depression and erratic behavior.

    All very interesting. Not sure what it all means.

  5. Galina - I'm not entirely sure - people having a gastric bypass can go from diabetic to non-diabetic within an hour, so the hormonal control is significant.

  6. Close family and friends of mine are heavy marijuana users...
    inevitably all of them who are heavy daily users are skinny fat, have little appetite, and cant eat normally until they give it up or cut it back to weekend use. One uses it specifically for anxiety (doesnt work!) and for arthritis pain relief (works whilst she is high). Withdrawels - nightsweats, ongoing insomnia, irritability and aggression. A few weeks of cutting back and appetite returns with raging intensity and rapid weight gain.
    Otherwise they all have great difficulty maintaining weight. I work in a health food store, and have a lot of young guys coming in to buy 'weight gainer' powders who have been heavy marijuana users whosé appetites are diminished. Always wondered if there is a cannobinoid receptor resistance or something after such heavy use?

    More casual using friends - overweight, still get the muchies if only using a few times a week, no withdrawels, consistent increase in appetite with use.

    Just thought that may be interesting :-)

  7. Beth directed me to this blog. Thank Bets, great blog. I will eventually write abou this.

  8. "prostaglandins, endocannabinoids, and thromboxane"

    These are all made from Arachidonic acid(omega 6). Not omega 3's.

    endocannabinoids are only made during exercise.

    I would like to see a control study on individuals eating either fresh nuts(contain water) or soaked nuts. High omega 6 oils are missing valuable vitamins and minerals the body needs to process the omega 6 fats into anti-inflammatory molecules, such as DGLA.

    Ratio's dont exist out in nature. Let me know when an elephant or a monkey gets obese from eating too many nuts.

  9. To Peters question; Maybe LA and anandamide (or cannabinoids) and their effects stay with the body long enough to create self-perpetuating, CIH type hunger. The carbs finish what the oils start.
    What I said about this hypothesis being capable of reconciling food reward, CIH and CICO, as well as validating Lustig and the omega 3 crowd.
    A Unifying Theory of Obesity.


    Oh cobalamin, as long as monkeys and elephants eat their greens they get enough omega 3 to balance the ratios.


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