Insulin resistance (16) Yes. Vitamin E can cause weight loss

Part 3

It's time to set out a logical explanation for this graph:

taken from 

Ability of high fat diet to induce liver pathology correlates with the level of linoleic acid and Vitamin E in the diet

The first thing we have to do is to ask the correct question:

To me the correct question which has to be answered is why an high fat diet (35% of calories) with only 1% of calories from LA is obesogenic, at all. If you come from the point of view that the mechanism of obesity is down to LA alone, irrespective of macros, you need to be teasing this paper apart in great detail.

We know from

Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice

that a mouse eating an high fat diet based on D14521, if you choose your fat correctly, will not become obese at all provided LA is limited to 1.4% of energy intake. We can simplify Figure 1 from the paper:

to this:

This makes it abundantly clear that if you hold one variable constant, that is the percentage of energy supplied by linoleic acid, the nature of the rest of the fat in the diet is not insignificant.

Okay.

Here is the fat used in Graham's study, which is obesogenic with fat at 35% of calories:

and here is the non obesogenic diet with 45% of calories from fat in the D12451 study. I've combined the saturated fats together and expressed all as percent of total energy to allow easy comparison with the obesogenic diet from Graham's study:

They are identical in composition, the only difference is between 35% and 45% of energy from fat causing an absolute difference in overall calories from fat. A complete coincidence, but still very neat. Both studies look like they could have used the same jar of fat to make up the two diets. Except...

Those 27% of calories from saturated fat in Graham's study were largely from hydrogenated coconut oil. In total, hydrogenated coconut oil supplied 89.1g/kg of saturated fat to the diet.

We can ignore all fatty acids of C16 or greater as they are, as always, completely absorbed as chylomicrons through the thoracic duct and in to the systemic circulation, bypassing the liver completely.

For the shorter chain fatty acids I think we can ignore the myristic acid (~17% of the coconut oil) as it too is mostly carried in chylomicrons and treated much like palmitic acid. Only around 5% of it goes directly to the liver as FFAs.

The lauric acid which makes around 45% of coconut oil is partly packaged in to chylomicrons but something around 30% is delivered directly to the liver as FFAs.

Capric acid (C10) and caprylic (C8) (~15% combined in coconut oil) are completely transported directly to the liver as FFAs and do not enter the systemic circulation.

This medium chain triglyceride inclusion is the major difference between the 35% fat obesogenic diet used by Graham et al and the non obesogenic diet based on the stearate/palmitate/oleate mix in the cocoa butter D12451 study.

This matters.

To get some idea of what is happening we have to go somewhat in to reductio as absurdum and use pure MCT oil with a splash of soybean oil giving 50% of calories as fat in this study

A rich medium-chain triacylglycerol diet benefits adiposity but has adverse effects on the markers of hepatic lipogenesis and beta-oxidation

and look at this, Figure 1:

from which we can extract the relevant lines like this:

Here we can see that, on 4% of linoleic acid, MCT oil at 45% (no lard in this group) of energy intake is obesogenic when compared to 5% LA on a low fat background ie without the MCTs.

MCTs, in any significant amount, are obesogenic in their own right.

In this last study the obesity is made much worse by adding lard containing significant LA, that's what the faded-out lines on the unaltered graph show. I'll just add in the all-lard fed group as we need it when we look at pAKT levels:

So now we can look at the degree of insulin signalling present in hepatocytes at the time of euthanasia after a six hour fast. The full panel C from Figure two looks like this:

which we can simplify down to the interesting bits like this:

Clearly there is a marked reduction of insulin signalling in the lard fed mice. They are the most obese and are providing long chain fatty acids to the fasting liver, some LA but also palmitate and oleate. This is the normal physiological insulin resistance of fasting augmented by elevated basal lipolysis.

The lard-free highest MCT oil fed mice also demonstrate hepatic insulin resistance but far less than the lard fed mice. Which looks like a paradox.

The main problem with interpreting the pAKT signal is timing. The levels were measured in liver tissue after a six hour fast, which is quite a long time for a mouse. If you feed an MCT rich meal you would expect to flood hepatocytes with FFAs via the portal vein during the peak absorptive phase, probably around 1-2h post intake.

It is this flood of MCTs, which enter hepatocyte mitochondria with minimal restriction, which necessitates the resistance to insulin. Never forget that insulin resistance, at it's core, protects against the damaging levels of ROS generated by unrestrained elevation of delta psi. Insulin resistance automatically reduces insulin catabolism.

MCTs are not stored, so the excess lipid within the liver or exogenous lipid from the systemic circulation by six hours post intake will reflect the highly controlled oxidation of longer chain FFAs, not the un-restrained catabolism of MCTs at peak nutrient absorption. As the mice consuming MCTs are less obese than those on lard, it is reasonable for the level of insulin resistance to be lower because basal lipolysis is also lower.

In fact there are various influences on the high MCT fed hepatocytes pushing insulin sensitivity in conflicting directions, especially under fasting. But we can tease out what matters, and when, from a few extra studies. 

The Protons prediction from hepatic insulin resistance with associated reduced hepatic insulin extraction is the facilitation of elevated systemic plasma insulin, primarily at the time of peak delivery of MCTs to the liver via the portal vein circulation.

We can get an idea of whether this genuinely happens from this human intervention study here:

Thermic effect of medium-chain and long-chain triglycerides in man

which gives us this graph:

There is a small but significant rise in systemic insulin after MCT ingestion. It was triggered by 400kcal of MCT oil. You can enhance the effect in rats, who can't object to the GI distress caused, by giving them close to half a full day's calorie intake as a gavage. That's in this paper

Relation of ketosis to metabolic changes induced by acute medium-chain triglyceride feeding in rats

including this effect on systemic insulin

which we can tidy up like this:

It's also quite simple to ask how much insulin is extracted by the liver from the portal vein before being passed out through the hepatic vein and in to the general circulation. All you have to do is compare systemic insulin levels after an MCT bolus in a normal person with those generated by people with severe cirrhosis and multiple porto-systemic shunts, which by-pass whatever dysfunctional liver tissue they have remaining in-situ. That will be this study:

Stimulation of Insulin Secretion in Manby Medium Chain Triglycerides

After just 30ml (270kcal) of MCT oil we get this doubling in systemic insulin in cirrhotic patients during the time of peak MCT absorption, but the effect is gone by three hours post ingestion:

This effect is only present under MCT ingestion. Neither corn oil nor other LCFA containing fat sources do the same. My expectation is that, at peak MCT absorption times, flooding hepatocytes with MCTs will generate an high ROS signal, confined to those hepatocytes. This ROS generation can be dealt with by storing the acetyl-CoA as intra-hepatocyte LCFAs derived from acetyl-CoA (to be later exported as VLDLs), by off-loading acetyl-CoA indirectly as ketone bodies and, finally, by simply resisting insulin.

Which allows systemic hyperinsulinaemia.

The action of insulin is the inhibition of lipolysis.

Which is obesogenic.

The Surwit diet does this.

Here we have a fundamentally different form of obesity compared to linoleic acid induced obesity. In LA obesity the fundamental problem is at adipocyte level and here *inadequate* FADH2 driven ROS generation allows excess insulin signalling to distend those adipocytes.

In Surwit's hydrogenated coconut oil diet derived obesity, the fundamental problem is an *excess* of ROS from the MCTs in coconut oil, delivered in high levels to the liver only, allowing passage of insulin through the liver to give systemic hyperinsulinaemia which acts directly to cause simple obesity.

I suppose that the addition to this is that the lauric acid which reaches the systemic circulation might be a factor in the obesity, the shorter chain length gives poorer ROS generation compared to palmitate or stearate. 

MCT obesity is the only form of obesity which should be *reduced* by limiting ROS signalling.

Drop the ROS, restore hepatic insulin sensitivity, allow the liver to extract insulin, so shrink peripheral adipocytes via normalisation of peripheral insulin levels. *Hepatic* ROS scavenging does this:

and the converse is ROS scavenging does this:

Or, more relevantly

Or, with a minor change of one arrow's colour:

I'll leave it at that for the time being. There are, as far as I can find, no studies looking at the effect of vitamin E on Surwit-like diets. That's understandable. Why should vitamin E, considered to stabilise PUFA, have any effect on saturated fat induced obesity? So why bother looking at this?

But, given the ROS hypothesis of obesity, a plausible mechanism for the action of Surwit like diets is clear.

Peter