Wednesday, January 12, 2022

Rimonabant and adipocytes

Okay. I hope everyone has heard this podcast with Raphi chatting to Tucker and Amber:

I feel Amber articulated the adipo-centric view rather well. The whole podcast reminded me of a few ideas I've had kicking around for ages and it might now be time to do a bit more posting.

I was taken back to good old Rimonabant by some of Tucker's points. It got a passing mention in an old blog post back in 2010. I may not have been terribly impressed at the time.

Rimonabant and hemopressin

For those of us with an adipocentric/insulin based outlook on life Rimonabant is interesting. It takes about 30 seconds on PubMed to pull out

CB1 agonists make adipocytes insulin sensitive. Rimonabant blocks this effect, which made me feel good about Protons/insulin/obesity and I left the subject alone in a nice glow of confirmation bias for a few months.

But these are isolated cells, does anything like this happen in real life? I would expect Rimonabant -> adipocytes -> reduced insulin signalling   -> release of free fatty acids -> weight loss -> reduced appetite. 

In that order.

Central to this is that the brain senses energy availability (Amber cited work I'd never heard of, my own ideas are just ideas. I felt it was self evident. You could say I just made it up) and reduces appetite when energy availability is good. Rimonabant frees up calories from adipocytes. But it is nasty stuff in the brain.

Developing drugs which do not pass the blood brain barrier is old hat in anaesthesia. Doing the same for CB1 receptor blockers seems pretty simple too. Just imagine, all the weight loss, none of the suicidal ideation. There are several under development.

But peripheral CB1 blocking drugs hit all sorts of targets ranging from the gut through the liver to the vagus nerve. And adipocytes.

What would an adipo-centrist look for?

Obviously we want an adipocyte specific CB1 receptor knockout mouse. It just has to dawn on you that that is what you want. Which took a while in my case.

So another 30 seconds on PubMed gave me this one:

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

and a little wander to the Place-which-shall-not-be-named gets you the full text.

They built a mouse model with a tamoxifen trigger-able deletion of the CB1 gene, specifically in adipocytes. How the hell they do that I can't follow but it's in the methods with links (not followed by me this time I'm afraid). I just have to accept that they can do it and that the technique is very, very clever. Then they fed a German high fat, high linoleic acid diet (around 10% calories from LA, ballpark) to make the mice fat over several months, leading to the start point at week 17 of graph E below. Then they injected tamoxifen daily for 10 days to induce permanent deletion of the CB1 receptor gene in adipocytes only. Here's what happened to the weights.

Black squares are fat mice which keep their CB1 receptors. Open squares are fat mice which lose them. D Both diamonds are controls:

Nothing changes in the gut. Nothing changes in the liver. Nothing changes in the brain. The hypothalamic Reward dopaminergic neurons are left untouched. All that happens is that adipocytes lose (at least) the insulin sensitising effect of CB1 receptor activation. Weight completely normalises in less than a month. It's also worth noting that in control mice adipocyte CB1 gene deletion does nothing.

Ultimately the adipo-centric view has phenomenal explanatory power when backed up by the insulin ROS concept. Everything else is higher level signalling and unexciting to me.

There are other interesting things in the paper relating to food intake and uncoupling (ie the rapid weight normalisation occurred without reduction in food intake) but I'll call it a day for now. Except to mention that in human victims of Rimonabant it is well recognised weight loss is greater than can be accounted for by reduction in food intake. Fascinating.

At some time I'll drag myself back to working out the F:N ratio of mixed fats. Two different butters, two lards, one plus 5% soybean oil, done so far. Still got coconut oil and fully hydrogenated coconut oil to go. Losing the will to live.

Perhaps I should ask my son to write me a bit of software to do this!



Frank Wierzbicki said...

Hi Peter,

I'm an interested reader that also happens to be a programmer. If you'll let me know what kind of program you are looking for I could likely whip something up in Python - or what might be better depending on what you need: Google Spreadsheets are a pretty good format for sharing some kinds of programs. Let me know, I'm a huge fan of your work!

Passthecream said...

Peter, thanks for pointing out that podcast. The last 15 minutes or so are particularly fascinating in the issues they raise and the contrasting viewpoints. Amber's quietly and clearly stated views are extremely compelling. The concept of addictive food reward is weird, I think it describes a situation where some higher level signalling leads to chaotic situations when an underlying tightly regulated process is thrown out of whack. I suspect the mixed time delays involved in this although quite short are part of the chaotic dynamic. Rimonanbant sounds like the unfortunately-sliced cold turkey drug. But perhaps possible to see that apart from its unfortunate side effects it does effectively remove an inapropriate high level (ie the endocannabinoid) behaviour generating stimulus and allow the more important lower level regulatory process to reassert itself.

Malcolm said...

Frank, yes, sounds like Peter needs a spreadsheet to me, surely one of us can do that :)

Maybe one sheet with base data (F/N for each specific fat?), a second sheet with the list of fats and proportions in a product, and the answer ... wherever.

If that works then Peter could just copy the spreadsheet, update sheet 2, and read off the answer. Of course, copying the sheet is only necessary if he wants to keep his working, otherwise he could just change the recipe, note the answer ... change the recipe, note the answer, ... :D

Frank Wierzbicki said...
This comment has been removed by the author.
Frank Wierzbicki said...

Peter and Malcolm:

It looks like Alex Joseph has done the spreadsheet work already:

I found this via reddit:

Peter said...

Hi all, re spreadsheets, yes. Thanks for the input. Alex (assuming he is Sabram on twitter) and Tucker have both spoken to me about these and Alex does appear to have already done the work. Now to integrate Alex's numbers in to a post which has been languishing for weeks...

Pass, I have no problem with the concept of "addictive" food. The problem I have is that I think such addiction has nothing intrinsically to do with obesity. For that you need foods which are "addictive" and which also cause pathological fat storage. Both criteria must be met (in my mind). Linoleic acid is highly "rewarding" for rodents. At 10% of calories it is obesogenic. At 50% of calories it is not. Nor at 80% either. Sucrose can be manipulated similarly but, as I keep finding, sucrose is very complicated.


Tim said...

Unfortunately, those spreadsheets use the old formula for calculating ROS. Also, they take into minuscule amounts of very long chain fatty acids which are processed by the peroxisomes.

Tim said...

Peter, made you a spreadsheet take will calculate the F/N ratios based on the updated formula of (n-1-db)/(2n-1-db). In order to save a copy, click the link, hit file in the upper left corner and then download as excel.

Once you have it saved, you could be able to open it, input triglycerides as either percentages or grams (doesn't matter which), and it will provide you with a calculation based on a weighted average F/N ratio calculation once every value has been entered.

If you have any issues or suggestions for improvements, let me know and I'll do the best that I can. I've omitted less common fats, but if you need any others, please let me know and I can add them in!

I've also left instructions in the spreadsheet. I hope this helps.

karl said...

Interesting how people have developed and shared the spreadsheet work - of course the public should be banned from doing anything like this or talking about medical interventions - only politically appointed 'experts' should be allowed to say anything.

Peter said...

Hi Tim, many thanks. For odd practical reasons IRL I've been neglecting the blog for this last week but am now starting to look at the spreadsheets provided by yourself and by Tucker. Looks excellent and I now have no excuse for delaying getting the next Protons thread post accurately written and posted. IRL is intruding in the way of work for two more days but I'm hoping to get some time at the weekend.

Off to do some cutting and stitching today!

Many thanks again