Foie Gras (3) The Japanese mice

So the interesting question about the rats in the Italian study which were fed on the Safflower/linseed oil diet is:

How calorically restricted were they?

In the absence of a control group allowed ad lib high fat intake (or even one fed chow) we will have to look elsewhere to estimate this. Japan is a good start with this paper:

Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice

Just give Bl6 mice a free choice to munch chow and/or drink corn oil and they will eat/drink progressively more corn oil over 4 weeks until they are stable at ~75% of their calories from corn oil, 25% from chow. Which gives us in the region of 38% of calories from linoleic acid. They are weight comparable to chow-only fed rats throughout, maybe slightly lighter:

Under stable conditions (weeks six to eight) they feed themselves 35% extra total calories to maintain an identical bodyweight to the chow fed mice:

This is because they were uncoupling, primarily in interscapular brown adipose tissue but (from other papers, a future post) they also do so in white adipose tissue.

Back to

Fat Quality Influences the Obesogenic Effect of High Fat Diets

If we imagine the Italian rats had been offered ad-lib access to the safflower/linseed diet we could expect them to eat somewhere in the region of 380kJ x 135%, so around 500-530kJ/d.

They got fat on just 380kJ/d. Like the lard fed rats. But by two weeks they were a bit less fat (p<0.05).

How does this work?

On day one of the safflower/linseed diet there is a marked increase in insulin sensitivity, by the standard Protons/polyunsaturate mechanism, with an associated hypocaloric episode as calories poured in to adipocytes but no additional food was provided. There is no significant increase in uncoupling immediately.

But now we have an insulin sensitive liver and the standard response of the liver to ingress of excess non-carbohydrate calories is to signal, using FGF21, to BAT to induce uncoupling giving thermogenesis and calorie disposal.

The time scale for onset of uncoupling could be estimated if we had daily food intakes and body weights, but we don't, so let's just guess at around a week.

As uncoupling in white adipocytes kicks in they will become poorly able to respond to insulin with the correct ROS signal, so insulin signalling decreases and they release FFAs. At the same time as this suppressed insulin signalling occurs BAT will be disposing of bulk calories by thermogenesis and the caloric drive for the pancreas to secret insulin also drops, again assisting lipolysis.

By two weeks there is active, on going weight loss from an obese baseline. Lipid is being lost at an excessive rate accentuated by hypocaloric eating and the liver is dealing with this excess, under hypoinsuliaemia, in part via BAT and in part by the peroxisomal mechanism described in the previous post, the cost of which is, in rats (and mice), of hepatic lipid accumulation.

Would the lipid accumulation have occurred if the Italian rats had not been calorically restricted?

No.

Uncoupling made the Japanese rats hungry, they ate extra to stop pathological weight loss. The extra calories include some carbohydrate and would have slowed lipolysis by raising insulin secretion to a level where lipolysis did not overload the liver. There are several papers to cover this in future posts.

Given long term ad-lib access to an uncoupling diet based on PUFA the rats would have eventually and gradually lost weight until they matched bodyweight with their non existent control group. Assuming these mice are anything to go by, who did it over a period of 10 weeks. From here:

Prevention of diet-induced obesity by safflower oil: insights at the levels of PPARalpha, orexin, and ghrelin gene expression of adipocytes in mice

I plotted the numbers for the body weights in Table 2, by eye, in PowerPoint. The dashed lines are the ones to follow. Obese on ad-lib lard, back to control (low fat, 35% of calories from sucrose) mouse weight on ad-lib safflower oil based diet giving LA at 35% of calories:

Okay, that will do for today.

I would not, in any way, endorse drinking either varnish or safflower oil, even if they produce weigh normalisation by what are, to me, metabolically convincing/plausible mechanisms.

Better not to make your adipocytes pathologically insulin sensitive, then you wouldn't need to address the obesity with potentially pathological double bonds in your food.

Probably safflower oil and hepatic inflammation next.

Peter