Endocannabinoids in brain and adipocytes

Well, these are interesting:

Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages

Adipocyte cannabinoid CB1 receptor deficiency alleviates high fat diet induced memory deficit, depressive-like behavior, neuroinflammation and impairment in adult neurogenesis

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

A high-fat, ketogenic diet induces a unique metabolic state in mice

with a little support from here 

The ketogenic diet increases mitochondrial uncoupling protein levels and activity

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