Protons (76) Those D12492 fed mice (Speakman and Tucker again)

For people who are thinking about re-listening to Tucker's discussion with Prof Speakman, at

Ep. 22: John Speakman—What Causes Obesity?

you could do worse than to check the section from time point of 24 minutes through to 26m 20. Speakman is describing exactly the phenomenon in the graph below, beautifully illustrated from the Schwartz laboratory. I may just have mentioned this many times in multiple blog posts:

He also describes, in brief, the concept of Reward as applied to these data.

To me, the Reward hypothesis has approximately zero explanatory power for the phenomenon in the graph and Speakman eloquently describes this deficit. He and Tucker discuss how an addictive drug drives progressively increasing consumption, but an high fat diet clearly has a decreasing drive to eat until near normal consumption resumes by about a week.

But always with residual obesity and slow, on-going weight gain.

Let's consider a better explanation for the behaviour of the mice in the Schwartz lab.

Linoleic acid in the D12492 is around 18% of total calories, according to a table I downloaded from Research Diets in 2011. This is well above the insulin sensitising dose noted for humans in the last post.

The whole argument from the Protons hypothesis is that linoleic acid has the ability to facilitate insulin signalling to a) increase post-prandial fat storage b) inhibit fasting fatty acid oxidation. That is a recipe for an acute loss of calories in to adipocytes and an hypocaloric crisis.

Which is easily corrected by eating some more. As in the above mice.

Now, before we look at the next paper, some ground rules need to be set out.

Metformin.

This is the most mis-represented drug ever investigated and almost all of the conclusions published about it are incorrect.

Metformin is an inhibitor of insulin signalling which therefore results in a decreased phosphorylation of AKT. Every time. See here here

here and many more places. It *appears* to improve insulin sensitivity, lowering the plasma level of insulin and glucose, but this is because it inhibits hepatic gluconeogenesis via inhibiting mtG3Pdh. That drops hepatic glucose output and that is what lowers the insulin level.

And don't forget SHORT syndrome, discussed here.

Having established that, let's put some ideas in to perspective. Linoleic acid is a pathological insulin sensitiser. Metformin is an insulin desensitiser.

The converse drugs to metformin are the glitazones. In vivo these *increase* the phosphorylation of AKT. What else would you expect? They really are insulin sensitisers. Their standard side effect is a worsening of obesity. Of course.

We are now in a position to explain the "hyperphagia" of mice fed high fat, high linoleic acid diets such as the D12492 used in the Schwartz lab.

We need to look at this paper:

Metformin Reduces Body Weight Gain and Improves Glucose Intolerance in High-Fat Diet-Fed C57BL/6J Mice

The mice were offered something very similar to D12451 (45% fat rather than the 60% fat of D12492)  but we don't know from which company it was purchased or even if the lard included was from Japan or America. No gas chromatography was used this time so a best guess might be around 10-15% of total calories as LA.

In the first hour of access each mouse eats roughly 5.5g of it, ie 28kcal, that's roughly a third of the 70kcal/d that the Schwartz mice would eat in a full 24h period while on a chow diet:

But the really interesting finding is what happens when you either reduce insulin signalling with metformin or increase it with pioglitazone.

Blunting insulin signalling (metformin 300mg/kg p/o) before access to the food decreases the one-hour food consumption by 80%.

That's 80 per cent.

5.5kcal in an hour to 1.0kcal in an hour.

The food is still yummy, it will still light up the endogenous opioid, endocannabinoid and serotonin systems (dopamine too I guess) of the hypothalamus but the hyperphagia essentially disappears. The hyperphagia is made worse by pioglitazone, of course.

It's simply about pathological insulin sensitivity being corrected by an insulin signalling inhibitor.

It is an energy supply problem.

So metformin is a partial rescue drug for LA toxicity. It's not perfect but it illustrates basic physiological principles. Obviously the correct solution to obesity is the reduction of linoleic acid in the diet to around or just below 2% of calories. Ruminant fat. Not metformin. Not a GLP-1 agonist.

Oh, almost forgot. Near normalisation of calorie intake: I've said it before, hyperphagia ameliorates over a week because distended adipocytes increase their basal lipolysis and will raise FFAs high enough to a) induce enough insulin *resistance* to reduce LA's lipid storage effect and b) overcome the blockade of CPT1 from malonyl-CoA. Adequate calories then become available *provided* adipocytes stay distended. Under-eating simply shrinks the adipocytes, reduces basal lipolysis mediated FFA release and re-establishes pathological insulin sensitivity. Because there is now a need to maintain adipocyte size, food intake must trickle along at levels just high enough to maintain adequate obesity for adequate caloric availability from increased basal lipolysis to resist insulin.

Peter