I've been interested in acipimox, in a round about sort of a way, for a very long time. To me, the core fascination is that it is not only an effective suppressor of lipolysis, but it is pretty well weight-neutral and it most certainly does not result in weight gain.
Which, you have to admit, is interesting.
How can this be? I feel something of a clue can be found in the studies using a similar drug, nicotinic acid. Both drugs effectively suppress plasma free fatty acids via the same receptor but the neatest study happens use nicotinic acid.
People may recall that I posted about the role of FFAs in the secretion of insulin as demonstrated by an isolated rodent pancreatic preparation, some time ago. The core concept here is that insulin secretion is dependent on the chain length and saturation of the FFAs used for perfusing the pancreas along with the glucose. This phenomenon appears to be well appreciated by the authors of this next paper (same research group):
Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans
So what happens to in-tact humans when you fast them for 24 hours (to raise FFAs) and then bolus them with intravenous glucose? Or fast them, artificially drop their FFAs with nicotinic acid, and then bolus them with glucose? This is what happens:
I think it is reasonable to state that dropping FFAs acutely, using nicotinic acid, results in a 50% drop in the area under the curve for insulin secretion over 60 minutes for a given bolus of glucose. The more speculative idea is that dropping insulin might reduce lipid uptake in to adipocytes. I don't know. It's an interesting idea.
If we simply consider acipimox to be a long acting analogue of nicotinic acid we have here a potential explanation for why it fails to induce weight gain. It might just simultaneously lower insulin levels. Understanding acipimox appears to require some insight in to the insulin hypothesis of obesity, not a notable feature in certain areas of obesity research.
Failure to appreciate the roll of insulin in obesity will limit any sort of understanding of the condition or the drugs which might or might not influence it. Seems that way to me.
Peter
