Before I get to talk about this (highly recommended) paper:
which came up in a discussion between Tucker and Brad a few months ago, I have to clarify as well as I can how fully hydrogenated coconut oil, one of the most saturated fat sources on the planet, is obesogenic, even under low linoleic acid conditions. The post is already part written but I want to get the MCT mechanism down here as clearly as possible using one of my long term doodles.
Apologies if it's getting repetitive, this is really an executive summary. Here we go.
One basic concept of the Protons hypothesis is that saturated fats shut down insulin signalling when fatty acids are freely available and glucose is scarce. Classically this is under fasting conditions where allowing glucose in to muscles etc would rapidly deplete the body of glucose stores which are helpful to maintain brain function under fasting conditions. It applies whole-body. Like this:
Under high fatty acid availability the ROS derived from reverse electron transfer through complex I of the mitochondrial electron transport chain inhibit insulin signalling at the insulin receptor/receptor substrate level, ie at the cell surface. Simple and obviously adaptive. This is also the system which fails when linoleic acid in bulk is introduced to the diet.
The next concept is that metabolic substrates which do not cause insulin secretion from beta cells will generate their own insulin-mimicking ROS signal using NADPH oxidases, also at the cell surface of nutrient recipient cells. At low levels these ROS inhibit the "insulin signalling suppression system" and allow the insulin signalling to take off, in the absence of insulin per se:
Mostly this happens in the liver because that's where most of the fructose/ethanol/acetate ends up. High doses are a separate story.
Aside: An high concentration of these substrates, ie two cans of cola giving >17mmol/l fructose in the systemic circulation or doing ethanol shots, will generate severe inhibition of the insulin cascade at the insulin receptor/insulin receptor substrate level whole-body, via NOX hyperactivation. And cellular damage from ROS spilling everywhere will result, ie Badness. Back to low level discussions. End aside.
The situation with MCTs is different from both of the above. They too are delivered primarily to the liver, not to the systemic circulation, and taken up rapidly by the mitochondria. All undergo beta oxidation to acetyl-CoA but only some of this acetyl-CoA will enter the Krebs cycle to provide FADH2 and NADH to the electron transport chain. The rest will be diverted to ketone bodies without providing any input to the ETC, and so without generating the inhibitory ROS you would expect from a saturated fat. I consider this is what happens, almost only in hepatocytes:
Low levels of MCTs (in this doodle I've suggested 50micromol/l, this is just for a thought experiment, not data based) arrive at the liver and have absolutely nothing to do with NADPH oxidase enzymes while generating low levels of ROS via mitochondria. These "low" levels are high enough to disable the "insulin signalling inhibitory system" and allow the insulin cascade to be activated but not high enough to directly inhibit the insulin receptor/substrate complex. This activation is insulin "mimesis" without substrate going anywhere near NOXs 1,2, 4 etc. But only in hepatocytes because that's where MCTs are diverted to.
The result is to sequester glucose in to hepatocytes so reduce penetration of glucose past the liver and in to the systemic circulation. The pancreas sees reduced glucose, so secretes less insulin. Lipolysis increases, you might lose weight.
Under Surwit-like diet conditions with coconut oil at 35-60% of calories things are different. Here large amounts of MCTs are delivered to the liver, I've suggested 600micromol/l but who knows what the portal vein concentrations really are? These MCTs still "waste" acetyl-CoA to produce ketones but the increased bulk supply means more acetyl-CoA can enter the Krebs cycle/ETC. Enough to generate ROS at levels which will inhibit activation of the insulin cascade at the insulin receptor/substrate level:
Under conditions of suppressed hepatocyte insulin signalling dietary derived glucose will penetrate past the liver and in to the systemic circulation. This will require the pancreas to crank out more insulin. And so inhibit lipolysis. As in the obesogenic Surwit diet.
That is all for now.
Peter
