Preamble/caveat. You have to be careful with Astrup's work over the years. When you get in to the fine print some of his control groups are perhaps not quite as normal as you might like and some of the post weight loss subjects might not be quite as slim as you might like. His work spans many years and what the subject might have been eating when free living will have changed and the lead-in food served from the hospital kitchens may well have changed too. So caution. Having said that several of his papers have picked out various features of the pre/post obese. This is one such.
I wrote this post about a year ago but never hit publish. Here we go.
Insulin sensitivity in post-obese women
and in particular I'd like to reconstruct this part of figure 2. It illustrates nicely what happens when you track the FFA levels under an hyperinsulinaemic euglycaemic clamp:
Astrup discussed the right hand data points at 105 minutes, as below, with their statistically significant difference in free fatty acid levels, lower in the post-obese, whom I identify as identical to pre-obese, if they were to eat to satiety using the food choices which made them obese in the first place.
Astrup talks, correctly, about how we know nothing about what factors are influencing the FFA levels to produce this difference. This would need tracer studies which do not appear to have been done, certainly not by Astrup's group. So I am going to speculate, as I do, about how much explanatory power the Protons hypothesis has in this situation.
The first thing to do is to remove the lines for both groups from time -15m to time +45m. This is valid because Astrup's diagonal hash mark indicates that these lines were never intended to indicate what the FFA levels were while the clamp was being set up and started. I've also stuck in a line for time zero. So now we have:
I'm going to assume that FFA levels from time -15m to time zero didn't change by enough for me to bother about, giving this:
which is non controversial. What is more dubious is that I'm now going to guesstimate what the FFA levels did between time zero and time +45m. I'm going to suggest that the lines follow some sort of exponential decay. Like this for the control group in red:
Next I want to torture my scarce data points in to a slightly different curve, which accepts that FFA levels have probably plateaued out at ~300μmol/l, like this:
Now let's do the same for the post-obese group. The initial curve in blue looks like this:
and it takes only a minimalist eye of faith to extend it to this longer line:
We can now remove Astrup's hard data points and just look at a concept of what might actually be happening in the both groups, as viewed from the Protons perspective. Like this:
In the control group being exposed to insulin at just over 1000pmol/l with glucose clamped at 5.0mmol/l the FFAs bottom out at 300μmol/l. In the post-obese they are down to ~100μmol/l and are still dropping at the 105 minute time point.
Insulin at 1000pmol/l is around the peak level experienced transiently by normal humans at 30 minutes after a modern low fat, high carbohydrate meal.
I'm now going to assume that the fall in FFAs under the clamp is from insulin mediated suppression of FFA release from adipocytes. There will also be enhanced uptake but never mind that.
Following the red line of the control group we have, by 30 minutes, a state where adipocytes are exposed to 1000pmol/l of insulin, which will have translocated way more GLUT4s to the cell membrane than exposure to 5mmol/l of glucose would normally generate. So glucose pours in to cells, adipocytes included. There is no fall in glucose because, well, it's a clamp. By 30 minutes the control subjects' adipocytes are getting a large amount of glucose from the insulin/glucose infusion superimposed on lipid oxidation derived from a plasma concentration of ~300μmol/l of FFAs.
The adipocytes are generating 300μmol/l of FFA derived ROS. They are receiving enough glucose in addition that that their energy needs are met completely, there is a physiologically appropriate rise in delta psi and a completely appropriate rise in overall ROS which is the actual signal to limit insulin signalling, ie demonstrate cellular "fullness". Insulin's action is inhibited.
Inhibiting insulin's action inhibits insulin's inhibition of lipolysis.
FFAs stop dropping, the adipocytes stop taking up and storing lipid, the VMH feels full and the subject stays slim.
The blue line representing the post-obese shows the same initial fall but for these people the oxidation of a significant amount of linoleic acid means that, by 30 minutes, the adipocytes and VMH cells are ATP replete but are only generating sub-physiological levels of ROS, so there is no sense of cellular "fullness" in adipocyes (or the VMH cells) so no rejection of insulin signalling.
Insulin signals, lipolysis continues to be inhibited, plasma FFAs continue to fall. In real life, outside of the clamp situation, you now have to eat. Now.
You have to eat because the cells in the VMH fail to generate an adequate ROS "fullness" signal from their linoleic acid oxidation and also because adipocytes have "stolen" and retained FFAs which the VMH now never gets to see. Both happen, plus other effects, for other posts.
Hunger is no fun.
Peter
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