Insulin mimesis without NOX enzymes (6) MCT versus linoleic acid

I have a preference for median lifespan when thinking about the potential effect of an intervention on a population because it is looking at the population as a whole, rather than a few (quirky?) isolated individuals who make up the maximum longevity crowd. Or should I say the maximum longevity chosen few? I guess it confirms my biases too. Which I like.

Let's recap the Jim Johnson's lab findings about the Surwit diet effects described here.

Reduced Circulating Insulin Enhances InsulinSensitivity in Old Mice and Extends Lifespan

I have removed the lowest insulin gene group data and just included those with a normal insulin phenotype. A number metabolic snapshots were taken at around the 80 weeks of age mark. Surwit fed animals were heavier on the scales and fatter by DEXA compared to chow fed:

No one should be surprised that they were also hyperglycaemic and hyperinsulinaemic, ie insulin resistant:

What should be extremely surprising is that these Surwit fed mice while being obese, hyperinsulinaemic, hyperglycaemic and insulin resistant, lived over 100 days longer than their slim chow fed relatives. The data are in here:

which I can simplify down with some very crude curve fitting by eye in Powerpoint to give this:

Interesting.

Now let's look at some rats fed an obesogenic diet based on lard. There are some good data in here although it does not give us the linoleic acid content of the lard:

An isocaloric moderately high-fat diet extends lifespan in male rats and Drosophila

Oh, and their data presentation is not great.

Here we have the weights. Colour scheme is different to the first study

You can't tell if the weight loss toward the end was from the surviving rats eating less or that the fattest rats died earliest. Probably a bit of both. But the lard fed rats were fat.

They were hyperinsulinamic

and they were hyperglycamic.

and obviously they too were insulin resistant.

But this time the longevity curves are reversed and the fat rats die younger than the slim control fed rats, by about 100 days:

So we have the mice in Jim Johnson's lab and the rats in the lab in Harbin, China. Both have comparable levels of obesity and insulin resistance. Both are oxidising FFAs when insulin should be suppressing FFA availability in peripheral tissues. In both cases excess energy is being supplied from fatty acids so there is an absolutely normal physiological reduction/rejection of some of the calories which are being taken up by cells using insulin facilitation.

This normal physiological response is mediated by reverse electron transfer through complex I acting to inhibit insulin signalling at the insulin receptor/substrate level.

In animals made obese using fully hydrogenated coconut oil in a Surwit diet the mitochondria are normal and mitochondrial/cytoplasmic membranes lipids are low in linoleic acid as you would expect from 1-2% LA in the diet. So high-physiological ROS from oxidising fatty acids will inhibit the insulin cascade, as they must, but in the process will only encounter "physiological" levels of linoleic acid and only generate "physiological" levels of 4-HNE, 13-HODE, 9-HODE  etc. These lipoxides, like superoxide, are normal signalling molecules. A low level of generation is normal and generally beneficial. Probably essential.

Generating ROS via RET in the ETC is pro-survival and pro-longevity. See here, discussion on another day.

The obesity induced by increased dietary linoleic acid is different. Here the adipocytes are large because they fail to limit their insulin cascade adequately. Under these conditions adipose tissues will store an excess of lipid from all sources without insulin being elevated, indeed in the earliest stages insulin signalling will have been enhanced and IR subnormal. The core initiating problem being that linoleic acid is present in levels which generate too small an ROS signal, so fail to limit caloric ingress and storage. Also there is good evidence that linoleic acid is preferentially oxidiseg compared to saturated fats.

However excess basal lipolysis secondary to adipocyte size will release all species of FFAs, arguably with some favourites, the problem now is that adipocytes *ignore* insulin. It doesn't matter how insulin sensitised you might have been via LA in order to become obese. If basal lipolysis is up, it's up. And insulin no longer matters. The exact mix of FFAs delivered to the periphery (especially muscle) becomes less important. All cells oxidising any type of fat generate more ROS than cells oxidising glucose.

One of the secondary problems with high linoleic acid diets is that, separate from their obesogenic effects in mitochondria, the LA molecules are also present at increased levels in tissue lipids.

The problems really present when ROS are being generated on a background of an intake of (in this human observational study) of 17% of calories as linoleic acid. Apart from making you obese this provides an environment where ROS which *should* meet a "normal" level of LA (ie derived from 2% in the diet) are actually encountering an environment derived from 17% LA in the diet. Generating *physiological* levels of 4-HNE etc is out of the question when all the ROS can "see" is freely available double bonds to interact with. Lipids are converted to lipoxides in supraphysiological quantities, cellular damage ensues and this chain of redox damage manifests as what we describe as pathology.

That's what I think is happening.

I think I've said enough for one post. I'll have to write a separate post about RET and Superfly,

the fly featured in the paper nominated for the best graphical abstract of all time, ever. By me anyway.

And about ROS and mitochondrial biogenesis.

Peter