I have read Mary Rogge's paper on the concept that impaired fatty acid oxidation leads to obesity. This post is not aimed as a criticism of her ideas but modifies them somewhat, simply by following references she cites in her text and maintaining an insulocentric viewpoint. Obviously the failure of beta oxidation is strongly challenged by the success of low carbohydrate dieting and supported by the success of (extremely) low fat dieting. Is it correct?
There are a fantastic number of pieces to the jigsaw puzzle of obesity in this paper, many of which are probably very important and I'll run through them as soon as I can get my head around which ones matter most.
The basic concept is that there are excessive fatty acid derivatives in the cytosol of muscle cells (and probably other tissues, the main thrust of the paper is toward muscle metabolism). Why I view this as supportive of the carbohydrate/insulin hypothesis of obesity is yet another post. This particular post is on some of the problems I have with the concept of a simple defect in fat metabolism as the cause of the accumulated fatty acid derivatives.
As so often there will be a series of stolen diagrams, scribbled over using Powerpoint, which probably break every copyright rule in the book... Oops. Here we go.
Okay, here is the basic concept as a straight copy-paste:
Uptake of long chain fatty acids in to the mitochondria is mediated through carnitine palmitoyltransferase 1 (CPT1, green box upper left hand side). This is suggested as the failed step.
But there are problems with the diagram. Look here:
Here we have citrate being exported from the mitochondria and converted to malonyl-CoA via "fatty acyl-CoA". I think it would have been much better to actually specify acetyl-CoA at this point rather than "fatty acyl-CoA", but that may be nit picking on my part. But it is ONLY acetyl-CoA which is liberated by the citrate shuttle. The function of the citrate shuttle is to get acetyl-CoA out of the mitochondria and in to the cytosol for fatty acid production...
Next we have this feature:
I'm not sure whether this arrow suggests that fatty acyl-CoA, straight from triglycerides, facilitates or activates the citrate shuttle (I can't find any suggestion of this being the case) or is being cited as a source of citrate, which it is not. For fatty acids to form citrate they have to under-go beta oxidation:
And this is not supposed to be happening because the malonyl-CoA is inhibiting CPT1 mediated transport of fatty acyl-CoA to the site of beta oxidation. Hmmmmm.
So where might the cytosolic malonyl-CoA be coming from? Is glucose supplying so much citrate that the obese can use it for malonyl-CoA production?
If we flick to this fascinating reference we can look at the TCA cycle itself, to see whether glucose is producing enough citrate to export for conversion to malonyl-CoA as the spanner in the works.
From the paper we can see that if you have a very complex magnetic resonance spectroscopy machine, which you are willing and able to home-modify (read the methods text!), some exceedingly complex computer models and a supply of carbon 13 labelled acetate tracer you can actually work out how active the TCA cycle is in normal vs insulin resistant muscle tissue. This paper is so cool.
The offspring of diabetic parents have crap TCA cycle activity in their muscle tissue. It will not be producing the amounts of citrate which might be exported for fatty acid synthesis. This is not a failure of beta oxidation. It is a failure of the TCA cycle in its entirety. The fact that obese people run their metabolism on glucose does not mean that they run it well on glucose.
Why is the TCA cycle so compromised?
This study has some excellent pointers. Look at this picture, it could be from an obese or diabetic individual:
These folks have odd muscle tissue.
a) They don't have many mitochondria, b) many of their mitochondria look crap and c) many of their mitochondria are dying.
They don't have a simple failure of fat oxidation, they have a failure of mitochondria full stop. It simply shows most clearly in the failure of beta oxidation.
I'll take a break now and put this post up. There are, of course, a whole stack of follow-ons to this. If you have duff mitochondria you accumulate fatty acid derivatives in your cytoplasm. They cause insulin resistance. Once you have insulin resistance you will be chronically hyperinsulinaemic and, in all probability, go on to develop obesity as a direct consequence of that hyperinsulinaemia. Let's make this plain. Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss.
Over eating is not causal. Whatever anyone tells you.
If you are an undamaged human being and you force overfeed yourself with FOOD, say in some tribal ritual, I would suggest that you will not do this to your mitochondria. You will continue to burn fat easily. You will not develop chronic hyperinsulinaemia. You will lose weight automatically after that cultural binge is, thankfully, finished and you can get back to life within your normal appetite.
Humans do such weird things to themselves! Culturally and accidentally.