Random musings on uncoupling (4) coconut

Feeding mice on a high sucrose, low linoleic acid diet activates FGF21 production by the liver which stimulates heat generation in brown adipose tissue, leading to a lean phenotype, marked insulin sensitivity and poor glucose tolerance secondary to down regulated glucokinase in the liver. This latter is not surprising as fructokinase has a much higher rate constant for fructose phosphorylation than glucokinase does. Use it or lose it applies, even if only temporarily, so glucokinase down regulates. A bit like eating a low carb diet also down regulates glucokinase.

This is the post and this is the paper:

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

Edit, this one too

Ingestion of a moderate high-sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon-like peptide-1 secretion

End edit

My basic feeling was that fructose generated a caloric overload in the liver. Rather than dealing with this issue using hepatocyte mitochondrial uncoupling the task of dealing with the excess was delegated to brown adipose tissue and FGF21 was the messenger. "Higher  level" signalling. BAT uncouples on behalf of the liver. 

Of course that immediately suggests that other caloric overloads, especially if uncontrolled, might do the same thing. George Henderson tweeted this paper, which I've known about for years but have never gone in to in great detail:

Long term highly saturated fat diet does not induce NASH in Wistar rats

I hadn't realised how much uncoupling these rats were doing. They all weighed pretty much the same but caloric intake was way higher in the butter fed rats and even higher still in the coconut fed rats. That's interesting compared to coconut oil used in the Surwit type diets but these current diets are low in PUFA and sucrose free. Here are the caloric intakes:

The coconut based diet was particularly interesting as the rats were consuming twice the calories of the chow fed rats and weighed exactly the same. You could argue that coconut just tastes better than chow and the rats over ate then uncoupled. Or, more interestingly, you could suggest that medium chain fatty acids enter liver mitochondria in an unregulated manner and generate large amounts of input to the electron transport chain. If hepatocytes are experiencing a caloric overload what else should they do other than generate FGF21 and sub contract a calorie disposal solution to the BAT?

This arrangement would benefit, as with fructose, from the hepatocytes being the primary cells targeted to receive the unregulated caloric supply and is a good reason for keeping MCTs out of chylomicrons and passing them directly to the liver via the portal vein. Which is what happens.

So we can look at this study (just ignore everything about stress response and how a few ketones will do horrendous things to you):

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21

Here is what gavaging a chow fed rat with MCT oil does to FGF21 an hour later

LCT stands for corn oil. The acute effect of a low dose is almost nothing. Corn oil enters the systemic circulation in chylomicrons via the thoracic duct. It will be obesogenic as per ROS/Protons and only very mildly stimulating of FGF21 generation. Long term at high dose rates it will, as we've noted, uncouple enough to offset the metabolic syndrome induced as per ROS/Protons and result in a slim rodent which needs to over eat mildly to compensate for the side effect of uncoupling.

After coconut oil the uncoupling effect via FGF21 is marked so the compensatory eating has also got to be marked because the primary source of calories floods liver mitochondria with medium chain fatty acids.

So......... Localised hepatic caloric overload is a stimulus for FGF21 production leading to BAT thermal caloric disposal. As far as the rest of the body is concerned there is just the BAT caloric loss induced deficit to be perceived. There is a hypercaloric state in hepatocytes and a hypocaloric state in other systems, hypothalmus included. Food intake rises to maintain a normal energy supply to avoid weight loss.

Note the arrow of causality. The rats/mice are not over eating and burning off the excess. They are eating extra using an appropriate appetite to cope with BAT calorie expenditure/loss. They might not want to be hot but they have no choice. They eat to make up for it.

Peter

BTW there is this:

FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway

with alcohol being another hepatocyte caloric overload source which also generates FGF21 to "dispose" of the excess hepatic calories via BAT.

Using AMPK.

Which is where things get complicated.