One of the best suppressors of basal lipolysis is the nicotinic acid derivative acipimox.
which has a nice diagram like this, slightly edited:
The process is quite simple. Acipimox, a nicotinic acid derivative (NA), interacts with a cell surface receptor (here HM74A but it has many, many names) which is coupled to a signaling G protein (G) which inhibits adenyl cyclase (AC), lowering cellular cyclic AMP so deactivating a cAMP dependent protein kinase (PKA) which does something magical to all lipases to shut down lipolysis.
Despite the fact that acipimox can reverse diabetes overnight it has been a clinical complete flop and is nowadays only used to improved a few lab numbers of people eating a diet of complete crap.
I woke up this morning thinking about why "Magic happens" in the above diagram. Not how, but why.
Niacin is a drug acting on the ketone body receptor of adipocytes. The endogenous activator is shown as beta-hydroxy butyrate:
The obvious explanation for ketone bodies inhibiting lipolysis is that this is a negative feedback loop. The original diagram also had FFAs inhibiting lipolysis too.
There are upper limits to the body's tolerance of elevated FFAs and ketosis is a marker that decreasing the FFA supply to the liver might be a good idea.
The most obvious inhibitor of lipolysis via hormone sensitive lipase is insulin. Under ketosis (ignoring MCT exposure) insulin is at absolutely rock bottom levels and if you want something to limit lipolysis under hypoinsulinaemia you had better develop a system which does so independent of insulin's action.
Ketones do that (pax hyperglucagonaemia and ketoacidosis, there are limits).
So if a cell has elevated basal lipolysis (which cannot be shut down by insulin) choosing an alternative mechanism, insulin independent, for suppressing lipolysis is effective stratagem.
Acipimox activates this process in the absence of the normal physiological ligand, ie ketones.
ATGL is key to mediating lipolysis triggered by increased adipocyte lipid droplet size where as elevated insulin exposure cannot do this. You can shut down this elevated basal lipolysis with a "ketone mimetic".
Which reverses type two diabetes. Until the drug wears off.
Peter
Oh, another thought: Is this how exogenous ketones improve insulin sensitivity? Never mind all those complicated intracellular switches (I told you I was lazy). The "problem" is that adipocytes are leaking FFAs. Acipimox fixes this problem. Acipimox is a ketone mimetic. Do exogenous ketones "mimic" acipimox? Amusing thought for the day!
