An Introduction: More on Endocannabinoids *cough* With a Focus on Obesity Regulation

I'm very tempted to link a Pink Floyd song here. But, truth be told, that was a little before my time. Instead we'll do some more Metric (right click in new tab - yes, it is from the movie Eclipse, which I haven't seen. Glittery vampires aren't really my thing. But the song is rather dreamy - and I had to change the original link for one with an ad as the original was removed.  Sorry 'bout that).

I took the day off today - try to do that every four months or so, but last year was mostly unable to due to growing a new business. However, I won't be missed too much for a couple of days now, and I was finally able to clean up my room after a little too long. (Working mom, two kids, not much time - and usually I spend what moments I have reading and blogging!) In amongst the stack of papers was my last lipid profile, (yes, I am going to pull a Gary Taubes here) done back in 2009, pre-paleo, when I was on what I call a "Michael Pollan" style diet. Lots of whole grains, fruits, lean meat, fish, and vegetables, avoiding vegetable oil, not too deathly afraid of butter, but most breakfasts were oatmeal + frozen fruit + skim milk nuked in the microwave. Very different from today's breakfasts of eggs or nothing. Anyway, as I was breastfeeding at the time, the nurse did not have me fast for this test (tell a breastfeeding woman to fast on a high carb diet and she will probably take off your head and eat it). It was drawn around 1:35 pm for a disability insurance physical, so probably 60 minutes after my last meal. I had trouble losing the excess baby weight before primal/paleo and weighed 25-30 pounds more then than I do now:

glucose: 91
triglycerides: 100
total cholesterol: 183
LDL: 106
HDL: 57
Chol/HDL ratio: 3.2

It's not all that terribly interesting. I imagine total cholesterol and HDL are higher now, and who knows what my fasting glucose and triglycerides were. I should add that the only one I know of in my extended family who died of heart disease was my paternal grandfather, who succumbed to a heart attack at 89 after 30 years of poorly controlled type II diabetes. That said, I think the labs do show that a high carb diet won't necessarily throw your glucose or even triglycerides "through the roof" after a meal.

Endocannabinoids are ubiquitous in the central nervous system. Pharmaceutical companies are pretty excited about them, for if they get the formula right somehow, there is the potential to throw expensive patented medicines at "food intake disorders, chronic pain, emesis, insomnia, glaucoma, motor disorders, stroke, and severe psychiatric conditions such as depression, autism, and schizophrenia." (1)

What is an endocannabinoid, to start? Well, it is a locally acting neurotransmitter. It is made nearby to where it is used, making it unlike a hormone (or the cannabis plant active component THC), which often has effects from far away. The major endocannabinoids (eCB) in the nervous system are derivatives of arachidonic acid, itself a derivative of the omega 6 linoleic acid. eCBs are a molecular key. Don't think it escaped my attention that the omega-3 derived receptor molecules could serve as a regulation system at the endocannabinoid receptor lock, as I discussed in a previous post. That tends to be how these things work. O6 is on a see-saw with O3, and the evolutionary body and brain never saw a massive imbalance of the two known as the Western Diet coming.

Because eCBs are locally acting, one has to consider their effects locally. As a psychiatrist, one of my major interests in the prefrontal cortex (PFC). That is basically the outer rind of your brain right in front. Have a thin prefrontal cortex? You are much more likely to have impulsive behaviors and get caught doing silly things and end up in jail. A thick prefrontal cortex? You probably think too much, don't take risks at all, and would make a great living in academia. A medium prefrontal cortex? Absent a conscience, you would be master criminal, never to be caught (that might be the glass half empty view of things). Otherwise, you might end up like me, with a conservative medical practice and a renegade blog.

So, at least in mice (and I don't have reason to think human prefrontal cortexes vary much except in size and complexity), eCBs are very important in regulation of all sorts of molecular systems in the prefrontal cortex. Y'all might remember that excitatory neurotransmitter, glutamate - well, turns out that eCBs will inhibit it. And, as I discussed in the previous post, they tend to turn down the volume on excessive or repetitive stimulus in the PFC via a process known as long term depression. Though that sounds bad, long term depression is good. It's your brain's way of modulating signals. Sort of like how hopefully you can tune out the jackhammer going all day across the street while at work.

In other areas of the brain, endocannabinoids regulate key positions, such as appetite and addiction. The major endocannabinoid receptor in the central nervous system, CB1, seems to have a part in emotion processing, pain perception, and motivation for food intake (2). The CB1 receptor inverse agonist (an agonist activates a receptor, an antagonist typically merely blocks a receptor from being activated, while an inverse agonist sort of reverse-activates a receptor, just so you know), rimonabant, seemed like a hopeful drug to help with weight loss, smoking cessation, and other drug dependence. Plans for investigation of this drug included uses in cardiovascular disease, shock, liver disease, gastrointestinal disease, and arthritis.

And, as we mentioned in the last eCB post, even when rimonabant was used in psychiatrically healthy patients, the treated patients tended to struggle with mood symptoms, anxiety, and suicidal and aggressive tendencies. As my 2 year old would say, "Oopsie daisy!" On rimonabant, these anxious and suicidal symptoms occured 28% of the time, compared with 14% of those taking a placebo.

What is interesting to me is that psychiatrists traditionally viewed the opiate system as being more associated with reward and pleasure than the cannabinoid system. And yet a strong opiate blocker, naltrexone, can be used for a period of months in people with no seeming side effects. I've prescribed it a number of times, and no one developed anxiety or suicidal tendencies - quite the opposite, in fact. People noticed a decrease in cravings and overall discomfort. Not that naltrexone is an evolutionary answer - it is just interesting, compared to rimonabant (which I must admit, I've never prescribed.) And, indeed, the eCB system interacts only indirectly with the dopamine/opiate system. I find that quite remarkable.

But let's move on to something of interest to a more general audience - endocannabinoids and obesity, and we will refer to a neat paper Endocannabinoid signaling and energy metabolism: A target for dietary intervention (by Kim et al.)

I'm going to do a rare switch from alternative rock and classical at this point and recommend Dvorak's Serenade in E Major.

CB1 is found in the brain, but also in in muscle, the GI tract, and fat tissue. In obesity research, the focus is often turned on the hypothalamus, the brain's center of appetite and sleep and hormonal regulation. And, indeed, when we experience food deprivation, our eCBs go to work, making us hungry and interacting with some other rather famous hormones => orexin, leptin, and insulin. The endocannabinoid system in the muscles and gastrointestinal tract and fat tissue seems to communicate with the brain, directing overall energy intake in relation to expenditure. Loss of leptin and insulin regulation of the endocannabinoid system is suspected to be part of the cause of obesity and type II diabetes.

Omega 3 fatty acids are known to be satiating (3) (except, frankly, in sushi, which always makes me more hungry. Why is that?) Researchers have speculated (as I do now) that the increase in omega 3 PUFAs in the receptors leads to changes in the receptor affinity for the omega 6-derived eCBs. Interestingly, in the Kim paper, he notes omega 3 intake is associated with lower endocannabinoid levels (AEA and 2-AG) as less arachidonic acid (the eCB precursor) is incorporated into the cell membranes. The researchers go so far as to suggest that increasing the dietary ratio of omega 3 PUFAs would be a "practical approach for changing the fatty acid composition of cellular membrane phospholipids to alter membrane signaling to serve as a promising tactic to decrease the synthesis of endogenous ligands for cannabinoid receptors and minimize ECS activation."

In cows, dietary modulations of arachidonic acid and DHA (even studies using krill oil, which I would suggest is outside a cow's evolutionary experience) have been shown to change the levels of endocannabinoids in the central nervous system - AA increases eCBs, DHA seems to decrease them. This change occurs rapidly - within 2 weeks. The researchers move on to humans, discussing studies of omega 3 intake among obese and diabetic women and men, whose inflammatory markers, hunger, and body weight decreased within a few days of eating more omega 3s. Leptin is also thought to be increased by the omega 3 fatty acids (at least in rats).

There are a number of other hormonal systems involved with obesity, including regulation of the eCB system and ghrelin and CCK. In short, "the EC system works with the endocrine system and neural networks associated with the hypothalamus and the gastrointestinal tract to regulate the energy balance of the individual."

I could go on for a while, and I will have more posts on endocannabinoids and psychosis and neuroplasticity and neurotoxicity. But here we have a local neurotransmitter regulated system of addiction, pain, and appetite dependent (perhaps) upon dietary regulation of omega 3 and omega 6 fatty acids. You see why scientists suspect a multigenerational effect of the excess omega 6 in brain development and the earlier onset of fat gain and diabetes this last generation.

Scary, really. I avoided omega 6 (as much as I knew how) through both pregnancies, and then breastfed, eschewing formula (except for a small amount when the youngest was 11 months old) - both were weaned to whole cow's milk in addition to regular food around a year. My kids are very tall (99-110% of normal height for age) and average about 70% of normal weight for age. The charts are based on averages of singleton births in the US in the year 2000 or so, well into the reign of omega 6 PUFAs. I don't know how much of the kids' stats are due to genetics or food or what, but I'll leave it like my stats from my Michael Pollan diet - an interesting data point.

There is more to come with the endocannabinoids. I promise.