Thursday, December 01, 2016

Inhibiting lipolysis using acipimox

Okay, time to start doing a little blogging again. I've been thinking about various aspects of free fatty acids largely derived from studies using acipimox, like this one:

Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea

I consider that one primary action of insulin is to inhibit lipolysis. Which makes it a driver of weight gain. Or, rather, it makes it a mediator of calorie trapping within adipocytes, which drives hunger (you needed those trapped calories), said hunger then gets the blame for the swollen adipocytes. You know, humans only get fat by eating too much. Ask any obesity researcher.

So what is the effect of other inhibitors of lipolysis on adipocyte size? The classic, freely available inhibitor of lipolysis is acipimox. Does acipimox make you fat? There is nothing on the patient information leaflet or data sheet about weight gain. Being hungry while you take it is only mentioned as a side effect in anecdotal reports from the poor folks taking the stuff. Of course the link between being hungry and gaining weight is easily eliminated by a simple matter of willpower. Again, ask any obesity researcher.

The published clinical research with acipimox (which is interesting) is usually of too short a duration to show weight changes, most studies usually last a few days or a couple of weeks.

So eventually I found an animal model using acipimox. It was looking at intermittent hypoxia (termed IH below) and weight loss (also very interesting, another day) but it came up with this little gem:

"Acipimox treatment [prevented IH-induced lipolysis and] increased epididymal fat mass and adipocyte size by 19% and 10%, respectively".

Acipimox, given to mice eating standard mouse crapinabag, causes weight gain, more especially fat gain. It does not cause hypoglycaemia and any appetite stimulation is likely to be because adipocytes have accepted dietary fat and are not letting it go.

Just as insulin denies lipolysis and so distends adipocytes, so too does acipimox. Acipimox, unlike insulin, does not drive potentially fatal hypoglycaemia with subsequent life saving food ingestion to explain away the weight gain.

This is where I started with acipimox: does it cause weight gain? Yes, inhibiting lipolysis, without using insulin, causes weight gain.

Of course, no one uses acipimox to cause weight gain. It is usually used to decrease plasma free fatty acids with a view to improving some aspect of metabolic function.

Which of course leads on to the monogenetic insulin resistance paper cited by Ivor on Facebook...

Peter

5 comments:

karl said...

So if we get the public to eat large amounts of purified vegetable oils containing LA thus inducing inappropriate insulin sensitivity in adipose tissue and T2D via 4-HNE :

http://press.endocrine.org/doi/full/10.1210/en.2011-1957
The Lipid Peroxidation By-Product 4-Hydroxy-2-Nonenal (4-HNE) Induces Insulin Resistance in Skeletal Muscle through Both Carbonyl and Oxidative Stress

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387404/
Skeletal Muscle Lipid Peroxidation and Insulin Resistance in Humans

https://www.ncbi.nlm.nih.gov/pubmed/21047551
Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition.

One result of T2D is elevated insulin levels. Despite what you hear - insulin is like most proteins and does more than regulate BG - it is a Swiss army knife:

- controlling storage of fat - Decreased lipolysis
- as a growth factor.
- glycogen synthesis
- Increased cellular potassium uptake
- decreases production of glucose from noncarbohydrate substrates
- Increased lipid synthesis
- Increased production of trygly from fatty acids
- decreased breakdown of proteins
- Decreased autophagy - decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.
- forces cells to absorb circulating amino acids
- forces arterial wall muscle to relax
- Increase in the secretion of hydrochloric acid in the stomach
- Decreased renal sodium excretion
- enhances learning and memory
- increased fertility

The one effect that interests me is as a growth factor. If we discount the cholesterol theory of atherosclerosis - (assuming that the recruitment of cholesterol is simply part of normal healing processes) and suspect that the initial thickening that leads to tissue damage is the real cause this is important.

What if the consumption of PUFA(mostly LA) has multiple negative effects?

What if the initial thickening is caused by elevated insulin?

What if the high PUFA diet the medical community has been pushing is actually causing TD2 and thus causative to the very thing they think they are preventing?

What if concentrated vegetable oils are considered a drug with some nasty side effects?


Now the bit I am struggling with is if LA can create inappropriate adipose insulin sensitivity and insulin resistance in other tissue at the same time?

Spittin'chips said...

Yes, yes, all very fascinating, Peter, but let's tackle the elephant - the recent dearth of new educational reading material.

I've a good mind to cancel my subscription.

Leave nasty reviews on your Amazon page about your 15 books.

And stop buying stuff from your supplement sponsors.

Seriously though, it's probably ironic that if someone were to look up CIAB, the first result is the Council of Insurance Agents and Brokers.

Have a good one.

Peter said...

Hee hee Spittin' at least I've expanded CIAB now!

Hah! Karl, yes, your last question is the one, can you have differential insulin sensitivity between muscles and adipocytes? Or is the primary defect in the adipocytes and all else follows on from that?

Peter

ItsTheWooo said...

Great entry Peter, but unfortunate obesity concept is so poor that this basic biology is required.

PhilT said...

http://press.endocrine.org/doi/full/10.1210/jc.2015-3696 is a longer human acipimox study. 6 months use showing reduction in plasma glucose and FFAs. Weight gain not observed within small sample mixed gender with fairly high variability.