Satiety (02) TD.130051

One of the reasons that I'm excited about Shulman's description of Thr¹¹⁶⁰ is that it provides us with a very simple way of assessing or quantifying insulin resistance without all of the problems of hyperinsulinaemic euglycaemic clamps, and there are a lot of problems with those.

It doesn't even seem beyond the realms of possibility that Shulman's lab might develop yet another NMR protocol to track this phosphorylation in vivo. That would be very cool.

On a very simple basis I'd like to make some suggestions about what the phosphorylation of Thr¹¹⁶⁰ might mean from the Protons perspective.

This is the Shulman paper

Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation

Shulman has a pathway from the accumulation of diacyl glycerols (DAGs) in the cell surface membrane to the activation of phosphokinase C ε (PKCε) which, along with many other targets, phosphorylates Thr¹¹⁶⁰ and so induces insulin resistance.

So this particular pathway to insulin resistance looks like a sensor built around the accumulation of the penultimate molecule in triglyceride synthesis and could be viewed as a marker of supply of lipid. My own ideas are rooted in the ability of fatty acids to generate ROS mediated insulin resistance as a physiological function. We are looking at a different level of the same signal. It would be very interesting to look at the ability of differing DAGs to activate PCKε. I would predict that saturated fatty acids are better activators than PUFA, following the ROS pattern the sensor is built around. This would be very cool and could be really useful for "blaming" saturated fats for the "defect" of insulin resistance.

Anyway, I am going to consider insulin resistance, aka phosphorylation of Thr¹¹⁶⁰, under various circumstances

I've taken the Schwartz lab graph yet again, which we now all know,

blotted out the food intakes and put an hypothetical scale of percentage phosphorylation level of Thr¹¹⁶⁰. We can put four clear cut data points on such a chart from Shulman's work

Chow is easy because it shouldn't change much in a week. Fasting is easy too because, if we fasted a human for a week they would clearly develop insulin resistance in order to spare glucose for brain usage, as observed by Shulman in the video. A mouse would die in less than a week of fasting.

We know D12942 produces higher insulin resistance than chow but lower than fasting. The paradox being that the D12492 fed rats are moving towards the fasting value despite having over-eaten for a week.

Before we go on to consider this we need to think about the custom diet made by Harlan for this perviously discussed (not very good) study

A High Linoleic Acid Diet does not Induce Inflammation in Mouse Liver or Adipose Tissue

where TD.130051, with 50% of calories as fat, produced zero weight gain in excess of that of mice on chow. So here we have an high fat diet which does not produce "hyperphagia" or, as Shulman phrases it in the title of his paper, "overnutrition". Mice eat enough to grow, no more, no less. At 50% fat.

Where would we pin the donkey tail for TD.130051 on the red line which marks the level of insulin resistance on day seven?

If we ignore D12492 and simply think of the phosphorylation of Thr¹¹⁶⁰ as being a surrogate for how much of the adipocyte (in this study) metabolism is being based on lipid oxidation, and so generating ROS, we can assume it will come somewhere between the value for chow (18% fat) and fasting (virtually 100% of calories from fat derived from adipose tissue). This is very simple, though impossible to specify numerically. I would expect something like this:

For fasting there should be a delay while liver and muscle glycogen is depleted then a rapid rise in insulin resistance to the fasting level.

For TD.130051 there would also be a delay but we are not expecting any need for glycogen depletion, all we need is for the adipocytes to adapt from the level of ROS production associated with 18% fat to that associated with 50% fat. I've assumed this is a couple of days too, pale blue line. Or you could, in Shulman-speak, assume this is the timescale for a 50% fat diet to increase the level of DAGs in the cell membrane so activates PCKε and so generate Thr¹¹⁶⁰ phosphorylation mediated insulin resistance.

Not that Shulman views a rise in insulin resistance as a simple adaptation to an high fat diet, be that exogenous fat or secondary to fasting. It's a defect to be corrected, unless it's from fasting. And I would expect TD.130051 to be *worse* than D12492 in this respect. This is obvious because you have to resist insulin if you want to stay slim. Saturated fat does this. TD.130051 is very high in saturates and only around 6% linoleic acid.

So in the case of TD.130051 there is absolutely no suggestion of "overnutrition" as a Shulman-esque explanation for the insulin resistance. Normal weight, normal calorie intake, normal growth but with 50% fat. I predict it will still lead to insulin resistance. This is to limit glucose ingress to offset the calories from fat so that an adipocyte, and the whole organism, would have an RQ or RER (to use the horrible but correct new terms) which matches the food quotient (FQ). And not get fat.

That's how it works, using ROS/DAGs, whichever you prefer. Although the ROS signal is far more fundamental than the DAG signal, it's probably much more labile too (but also capable of a rapid response) and there is clearly some advantage in smoothing it out with an overlay (slower but more even response). The DAG signal will be a derivative of the ROS signal. It will concur with it. In both cases the insulin resistance is utterly physiological.

D12492 is more complicated.

Peter