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!
8 comments:
Interesting bit. I once dug into niacin in connection with CVD - never felt that there was any clear understanding to how it worked - it mucks with lots of systems - immune, lipids hormonal - later research seems to suggest that it might move lab numbers, but didn't improve CVD. Arginine pops up here, also has a connection with CVD - thought to help relax arteries via NO.
OT:
I think the excess deaths phenomena is real. The evidence of the timing suggests that it is due to the novel intervention. The quants expected to see a regression to the mean by now - but so far, we are NOT seeing this. I think that they are pushing what is the most likely explanation, but there is also the effect of the T2D pandemic.
https://www.phinancetechnologies.com/HumanityProjects/Humanity%20projects.asp Scroll down to "our projects" to follow the links to the reports.
There is something real here - jobs not getting filled, people missing more work. It is human nature is to respond to immediate threats and ignore the long term ones, I think the public gravely underestimates the risks of T2D. Couple this with a grossly mismanaged economic policy (a result of again ignoring other long term risks) and it appears we are in the midst of a paradigm shift. Consider the number of young people that are not healthy enough to reproduce - or simply feel lethargic, not wanting or able to work - and we have some sort of collapse - both economic and cultural.
@karl, interesting comments in light of the fact that I just read 1177 BC and am now diving into Jared Diamond.
karl, I guess I’d expect niacin to be neutral from my acipimox reading. Obviously it acutely decreases RET through complex I due to lack of FFAs. ROS from RET are pro-longevity (drosophila). ROS from NOX are thought to be Bad, but eliminating NOX4 (alone) doesn’t extend lifespan (mice, I think). The rebound increase in lipolysis will facilitate ROS from RET is why I think niacin might be neutral…
I suspect the current increase in all cause mortality is quite serious. During the first wave of covid we lost the vast majority of our elderly-infirm due to gross governmental mismanagement, so the following winter (at the very least) should have been an especially low all cause mortality season. Instead it’s up, by quite a lot. I’m attending my third funeral in under a year the day after tomorrow. It might be just that my cohort is ageing and three cardiac related losses are to be expected. But I can’t help but wonder.
cave, yes, Sumption may be on to something. Ultimately some sort of civilisation *will* continue. Perhaps just not ours.
Peter
@Petro ..
What I'm hearing is yes some increase in cardio deaths - but what is mostly pushing the numbers appears to actually be an increase in cancer. Similar patterns in several countries. What is the root cause of the increase in cancer? Many in our institutions have too much invested in things they emotionally promoted to ask hard questions.
,.,.
I've seen a huge number of papers pushing the narrative that ROS is bad, but I think they are amplifying ungrounded narratives by missing the fact that they are looking at a nonlinear feedback loop nested in other overlapping feedback loops. So most of the anti-ox supplements are poorly absorbed and the few that are absorbed seem to have negative effects (vit-E).
Our immune system needs ROS to function - I think the ROS signal is ancient - perhaps the first system? Inappropriate inflammation is bad - but inflammation is really good if it saves your life.
The key is to have a ROS system that works - No ROS is bad - too much ROS is bad. If one eats things that mess up the balance. If ROS controls insulin sensitivity, mitochondria replication etc in a system that evolved over millions of years and suddenly the population is eating stuff that disrupts the system - bad things happen.
So my take is ROS is good when appropriate - ROS is bad if it is always on. Taking drugs that modulate ROS might well have serious unintended long term consequences. Much better to remove the original cause of the imbalance.
@karl
the excess deaths thing is already getting harder to trace in the official statistics, though. Post-event elevated numbers of deaths are starting to get rolled into the five-year averages, so the "excess" numbers look smaller than they ought.
karl, one of the first signals to come out of the vaccine roll-out was an increased risk of shingles. That speaks of suppression of a long term immune response. Obviously the increase in cancer deaths can be attributed to loss of health care access but healthcare is not particularly effective at extending life in cancer patients...
JustPeachy (apologies), yes the UK Office of National Statistics is doing everything it can to bury the reality. I have a lot of time for Norman Fenton.
P
@karl "So my take is ROS is good when appropriate - ROS is bad if it is always on. Taking drugs that modulate ROS might well have serious unintended long term consequences. Much better to remove the original cause of the imbalance." This is an excellent general principle, which runs counter to most of modern medicine, as well as the interests of the entire pharmaceutical industry.
The idea of ROS = evil parallels what I am noticing with the whole subject of vaccines. I read a lot of historical fiction as well as fiction and nonfiction. Thanks to my heightened awareness from the Covid episode, it's obvious that the cultural acceptance and even deification of vaccines, historically and currently, is just assumed. The more recent trend of antioxidant-fetish is similar.
As for the suspected recent trend of increased and sudden cancers, I have a personal interest, because my brother is one of those cases. He died from a "sudden malignancy" after only a few weeks of illness.
Sorry to hear that cave. Been to too many funerals recently myself.
Peter
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