Sunday, March 26, 2023

Endocannabinoids in brain and adipocytes


This is very clever stuff. It is possible to engineer in to mice the ability to induce permanent knock-out for the CB1 receptor gene, only in adipocytes and only after the whole mouse is treated with tamoxifen for a few days. So you can grow mice which are phenotypically normal on either chow or an high fat diet (circa 6% LA plus unspecified carbohydrate source) until they are 16 weeks into the study then permanently delete, using tamoxifen exposure, all CB1 receptors on all adipocytes.

Okay, so what happens to food intake if you delete the adipocyte CB1 receptor? It's interesting because some of us (myself included) feel that pathological insulin sensitivity in adipocytes is dominant over brain physiology in terms of weight gain/loss. This paper sums up isolated adipocytes and CB1 activation: 

The CB1 endocannabinoid system modulates adipocyte insulin sensitivity

Without endocannabinoid facilitation of insulin sensitivity you should stop losing calories in to adipocyte fat stores, so you should stop being hungry...

Nothing happens.

Upper line is mice fed on an high fat diet for 16 weeks and then tamoxifen treated to eliminate the adipocyte CB1 receptors in those with the tamoxifen sensitive knockout mechanism. This graph is an amalgamation of sections B and D of Figure 1. I've pulled and stretched both vertical and horizontal scales so they now match for calories and for weeks to make clear what happened. Tamoxifen exposure is circled:













I think we can conclusively say that when adipocytes can no longer listen to the insulin sensitising effects of CB1 receptor activation there is no fall in food intake. Which supports the idea that

CB1 activation -> brain -> eat

so you could say:

↑ dietary LA -> ↑ endocannabinoids -> brain -> eat -> get fat

Nice and simple. It's almost as if appetite regulation by the endocannabinoid system might be brain-centric and adipocytes might be unimportant.

Except. Here's what happens to the weights above baseline. Pulled and stretched and tidied from sections C and E of Figure 1, tamoxifen exposure circled again, as above:













So, from week 17 to week 26 the high fat fed adipocyte CB1 receptor knockout mice continued to eat as much as the high fat fed wild type mice but dropped their weight to match that of the control group.

Without dropping their food intake or linoleic acid exposure. They eat as much junk food as they like and lose weight...

Obviously they uncouple. Not just in brown adipose tissue, white adipose tissue beiges too.

Now: You could simply conclude that brain CB1 receptor activation makes you continue to eat extra and adipose tissue, now without CB1 receptor activation, becomes a calorie sink via uncoupling to dispose of those excess calories eaten under brain CB1 activation. Metabolism is hypercaloric, adipocytes off-load those excess calories. Brain first.

Or: You could conclude that when adipocytes lose their CB1 receptor with its insulin sensitising effect they become less able to store calories and, on an individual cell basis, decide to oxidise their suddenly available stored lipid. If adipocyte hypertrophy includes a lot of linoleic acid then this LA is released and it acts as the best bulk facilitator (along with some 4-HNE) of uncoupling protein activation available. So loss of calories occurs within adipocytes through uncoupling protein activation. Basal lipolysis falls with decreasing lipid droplet size and the brain senses a loss of systemically available calories so maintains food intake to maintain energy homeostasis, ie the adipocytes still control energy availability which controls the brain's action. Metabolism is hypocaloric necessitating food intake. Adipocytes first.

I was going to stop at this point and I probably should have but here's some more rambling anyway.


It has just occurred to me that we can make this comparison:

Mixed diet + LA -> ↑ insulin signal in adipocytes -> loss of calories in to fat droplets -> obesity -> obesity being due to calorie loss in to physical triglyceride storage in adipocytes -> need to eat more (brain sensing ↓ systemic available calories). Getting fat makes you hungry. Fundamental.

This is my standard view of obesity, first pointed out (in my case) via Gary Taubes, although the LA component comes from Protons.

Now we can view the situation under adipocyte CB1 receptor knockout as:

↓ insulin action in adipocytes via ↓ CB1 receptor -> ↑ lipolysis -> ↑ UCP activation -> ↑ loss of fat, but still within adipocytes, only now as CO2 and H2O eventually excreted by lungs/kidneys rather than being released as "calorie carrying FFAs" -> ↓ energy delivery to circulation -> need to eat more (brain sensing ↓ systemic available calories).



Calorie loss in to storage and calorie loss in to uncoupling look the same to the brain.

One makes you fat, the other makes you hot.



Obviously today we already have research drugs to block peripheral CB1 receptors which don't cross to the brain so don't cause the suicidal ideation that central CB1 receptor blockade produces. This would allow you to eat a diet of utter crap without developing excess adipocyte size. Which might be a good thing long term, or might not. Or you could just take an uncoupler such as BAM15 or low dose/slow release DNP. Or not.

Or maybe there are other ways of reducing insulin/LA mediated "loss" of calories in to physical storage within adipocyte lipid droplets and instead activate physiological uncoupling proteins and lose fat directly as CO2 and H2O via lungs and kidneys. We all know this image of what happens when you profoundly drop systemic insulin (and associated adipocyte insulin signalling) in mice, even with continued LA exposure:

















taken from here



You can't 100% take the brain out of the framework but the brain is, fundamentally, looking at available energy, largely controlled by adipocytes and their insulin signalling.

Peter

13 comments:

water said...

So when they start using cbd to fatten livestock, we'll know for sure? I've been meaning to try ChatGPT on Hyperlipid, with the prompt, "explain it to me like I'm 11" It may be my best chance to better understand....

Peter said...

Haha. Why use CBD when you have LA? Dirt cheap and of zero recreational potential. And LA works!

Ah, ChatGPT... As we know garbage in = garbage out. I think AI would be firmly on the side of seed oils and cholesterophobia. It's only a "reading and guess the end of the sentence" app, as far as I understand (which isn't much!) it has no analysis built in.

Reminds me of SETI where perhaps STI (search for terrestrial intelligence) might be a good/better start. With apologies to Avi Loeb.

Peter

Peter said...

Or THC rather than CBD!

P

Puddleg said...

TCH and CDB are agonist-antagonists, and pot use (including moderate and intermittent and "former" smoker status) seems to reduce risk of T2D or obesity to a measurable extent, but only in those countries where LA intakes are highest. There's a meta or review of this somewhere, also good diabetes prevention in French patients with chronic Hep C.

https://hal.science/hal-03109215/file/JVH-00069-2020_HAL.pdf

cavenewt said...

I'm glad you continued rambling — that helped me quite a bit.

Peter said...

When GT wrote that getting fat makes you hungry I was initially non-comprehending/puzzled and then impressed/convinced. But I still can't accept carbs vs fats w/o the LA effect...

P

mct4health said...

Hi Peter,
I would stick with the idea that it depends on the ratio between beta-oxidation of fats in mitochondria and peroxisomes. Fats and substances that interact with CB1 receptors seem to only affect PPAR receptors and thereby activate peroxisomes at lower insulin levels than usual with meals and thus affect the switch between fat burning and fat production/storage. PUFAs activate peroxisomes more and possibly through CB1, deactivation of CB1 receptors therefore deactivates peroxisomal beta oxidation, this leads to activation of mitochondria and UCP. What do you think?
Jaromir

The Endocannabinoid System and PPARs: Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001692/

Unknown said...

That makes total sense.
LA and carbohydrate: Nuts are autumn food.
Positive hunger loop fills up the adipocytes.
When winter is coming there is need for heat and eating if food is available.

karl said...

Time - half-life of LA is likely to interfere with seeing the LA connection in human diets. Standard behavioral psychology has shown that the time to reward matters greatly in changing behaviors. A diet that takes 2 years to start to kick in is not likely to be followed - similar to long term effects of lead(Pb) exposure - cause and effect can be greatly separated in time - and thus ignored by humans.

(Speaking of LA - I was sad to learn that Ray Peat passed away last thanksgiving)

,.,.
There is a cross over between estrogen and weight balance and T2D. Many confounding bits of narratives.

I first noticed that many young women at the gym I run at when it is cold out, have exaggerated estrogen characteristics, producing a rather unattractive caricature of the female form. I'm old now - afraid that my memory might not be perfect - so I spent a night looking at old high school pictures to confirm this. I am pretty sure that this is real.

I was talking to a relative that drives bus the other day. He was telling me about young girls in 2nd-3rd grade that he drives that have to wear brassieres! I mentioned this to my wife and she is telling me about young boys in the Philippines that are now growing breasts. Couple that with the reports of falling testosterone and sperm counts and I think there is something of a endocrine poisoning pandemic going on. These endocrines don't just change bodies - but effect the brain as well and may well explain some of the current bizarre social changes?

Of course this might be an example of my own confirmation bias (once I learned about confirmation bias I started seeing it everywhere ). Could it be possible that the T2D is the cause of endocrine problems?

There is a rather long list of possible substances that might be causing endocrine problems.. (perfluorocarbons, polychlorinated biphenyls, phthalates, bisphenol-A etc etc (but what is not on the list yet?) - I don't think we know at this point what it is. I've heard some points that suggest that there is a correlation with packaged foods - not sure. I think it would be a bad idea to trust any official narrative coming from captured institutions.

The other possibility is the endocrine effects might be connected to the T2D pandemic?

One other thing happening is large changes in the excess death rates - Dowd thinks it is related to an experimental medical treatment - but in the back of my head I've been thinking that the public has been getting sicker and sicker for a long time.
https://phinancetechnologies.com/HumanityProjects/Projects.htm#Nav_ExcessDeaths

So I'm left with the possibility that we have up to 3 concurrent pandemics - T2D, endocrine disruptors, LARGE scale latrogenic harm. Much of this can be grouped into effects of what Bret Weinstein calls hyper novelty. Throwing wrenches into complex systems..

It bothers me that the research is all about potential drug targets instead of helping identify and limiting exposures.

I'm finding about zero information of the mechanism of action or how antibiotics induce weight gain in livestock - I'm assuming it is not yet known. ( and we might want to reframe preservatives and call them food-storage-antibiotics for a bit of fun).



https://www.nejm.org/doi/full/10.1056/nejmoa064725

cavenewt said...

karl—my potential comment was headed off at the pass when you said:

"So I'm left with the possibility that we have up to 3 concurrent pandemics - T2D, endocrine disruptors, LARGE scale [iatrogenic] harm. Much of this can be grouped into effects of what Bret Weinstein calls hyper novelty. Throwing wrenches into complex systems.."

That's exactly my feeling. All of these pandemics are a result of our evolutionarily-inappropriate lifestyles, and when looked at that broadly, are all symptoms on the same spectrum. And because of financial incentives there is absolutely no interest in prevention, just potential drug targets.

Our habit of reductionism blinds us to the big picture. Reductionism can be useful, for example in recognizing the dangers of linoleic acid and its prevalence in modern food, even meat, thereby giving us strategies for avoiding it. So even while appreciating individual trees, I think it's really important to keep our eye on the forest at the same time.

I'm not going to hold my breath hoping the global bureaucracy will change its focus anytime soon. (Everything is global these days, so I don't think it's very useful focusing only on one's own country). In that vein, here's a fascinating article about "Spontaneous Order in Complex Systems" https://www.eugyppius.com/p/spontaneous-order-in-complex-systems.

The illustration is of an ant mill, a.k.a. ant wheel. Which is a fascinating concept in itself https://en.wikipedia.org/wiki/Ant_mill

Peter said...

karl, I had an injury at work which required a week on flucloxacillin. I gained a kilo. It melted away at the end of the course. I wonder about FIAF. This is produced by gut bacteria to ensure storage of "their" excess available calories in the adipocytes of their host mammal. If we wipe out n% of gut bacteria, do we leave a glut of food for the remaining bacteria/yeasts which have the correct plasmid or intrinsic immunity to the ab? Giving the gut microbiota ++++calories -> store fat ++++. Just an idea, no data.

Peter

JustPeachy said...

water, pot has the interesting reputation of being an appetite stimulant, but it is also possible to smoke so much of it that you lose weight, like to the point of being malnourished, because you lose the ability to be hungry normally-- you can only even contemplate food if you're completely baked, and it's hard to afford that for enough meals to stay reasonably healthy.

Knew a guy, rail-thin, quit smoking to join the military. Gained over 20 pounds in basic training, because it was the first time in years that he'd been hungry, and also suddenly had access to all the food he wanted to eat. Cannabis is weird. Not sure it'd work for making cattle fat. Plus we already use antibiotics for that, and they're cheap.

Gyan said...

Not in Africa, they aren't, I assume.