Insulin resistance (02) those Rhesus monkeys

I wrote this post several months ago but never got round to publishing it. Here we go.

I don't like this paper.

Targeting LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques

and I am very grateful to Tucker for posting it on X and also for sending me a copy when I lost both the paper and the tweet.

Ignoring everything apart from the results section it has to be said that it does pose some interesting findings from the ROS hypothesis perspective.

Here we go.

They made rhesus monkeys fat using some unspecified "high fat" diet plus some fructose in their drinking water. This generated a model of metabolic syndrome without diabetes. The monkeys had normal glucose tolerance test results but at the cost of marked hyperinsulinaemia.

Next they developed/bought an antibody against highly oxidised LDL.

This significantly reduced the degree of insulin resistance and subsequent withdrawal of the antibody injections allowed a return of the insulin resistance. Like this:

The two upper lines are pre and post treatment and the lower small-dash line is while under treatment with the oxLDL binding antibody. If anyone would like to see how a slim monkey fed standard chow would respond to an IV glucose bolus, it's approximately the blue line which I've extrapolated from the data in panel G of the same figure to give this:

which makes the result slightly less impressive but still very real.

Some of us view the development of insulin resistance as an adaptive and an absolutely correct response to calories being supplied to a cell (or population of cells) without the mediation of insulin, with the result that insulin facilitated calories need to be rejected on a pro rata basis. This is the fundamental message from this paper:

Insulin resistance is a cellular antioxidant defense mechanism

which sets out that case and also integrates ROS as the oxidant stress signal which mediates it. Pure Protons.

So the obvious explanation for the improvement from scavenging highly oxidised LDL particles from the blood stream is that this, mechanistically, *must* be reducing the delivery of lipid to somatic cells, so reducing the necessity to resist insulin's signal. Which could be simply explained if oxLDL itself was a lipolytic agent in much the same way as fructose is lipolytic

Metabolic fate of fructose in human adipocytes: a targeted 13C tracer fate association study

and 4-HNE is lipolytic

Prevention of 4-hydroxynonenal-induced lipolytic activation by carnosic acid is related to the induction of glutathione S-transferase in 3T3-L1 adipocytes

Aside: while I would in no way suggest people prioritise oxidised frying oil (group HO) as a source of calories, it's one hell of a weight loss intervention:

A high oxidised frying oil content diet is less adipogenic, but induces glucose intolerance in rodents

The insulin sensitivity of these rats and mice is worth discussing separately but IMNSVHO they are exquisitely insulin sensitive but cannot secrete adequate insulin. Not good but absolutely NOT obesogenic. An insulin tolerance test would be fascinating and probably fatal. End aside.

So I spent some time down this lipolysis rabbit hole on PubMed and I might even be correct, there is certainly a hint that oxLDL is an ROS generator in an "adipocyte-like" cell model, bearing in mind you can show just about whatever you like in 3T3-L1 adipocyte models (caveat, I've not read the full paper):

Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression through reactive oxygen species generation and ERK1/2 activation in 3T3-L1 adipocytes

so maybe it's that simple, but probably not. More likely is that oxLDL delivers 4-HNE to adipocytes and the ROS developed in response to 4-HNE triggers the lipolysis cited above.

Here's what the Rhesus monkey researchers think is going on based on their very clever experiments:

There are essentially two processes going on in this macrophage. Everything down the left side of the image is pro-inflammatory and, if these are detected, the macrophage activates NF-kB mediated inflammatory cytokine release and associated insulin resistance, shown on the right. Down the (right hand brach of the) central section is the oxLDL/antibody complex activating a negative feed back mechanism to inhibit NF-kB activation and subsequent cytokine mediated insulin resistance.

This looks quite simple. In the presence of an acute infection cells of the white blood lines (mostly macrophages and polymorphonucleocytes) will attack the invader using a respiratory burst of extracellular ROS from NADPH oxidase and produce a localised soup of dead organisms (lipoplysaccharide), damaged local lipids (oxLDL) and secreted long distance danger signals (ILs) to get the body in to peak defence mode. All activate the innate immune system. You can't afford to wait around for the 10 days it takes for the adaptive immune system to generate the antibodies needed to take over.

Indeed, once the cavalry arrive in the form of effective antibodies, it is actually time to turn down or off the innate immune response. So, while oxLDL floating around as a free entity indicates the need to get in to fight mode, when oxLDL is bound to an antibody this complex signals that the adaptive (antibody based) immune system, finally, has the situation under control. Innate immunity, ie inflammatory cytokines and insulin resistance, is no longer needed. There is negative feedback and NF-kB calms down.

Which is all well and good.

It just leaves open the question as to why an acute inflammatory response should generate insulin resistance. The trite answer that failure of an organism to develop insulin resistance during a severe infection could be serious. What happened to those organisms which, in the past, didn't do this? As Holly once said 

Why insulin resistance is essential to survival during an inflammatory process is a whole other question. Equally interesting, and related, is why corticosteroids, the most potent anti-inflammatory agents we have, also induce (equally essential) insulin resistance. Mediated by ROS.

It all goes back to Hoehn's paper

Insulin resistance is a cellular antioxidant defense mechanism

and the Protons view of fatty acid oxidation automatically generating ROS.

Nothing makes sense without it.

Peter