Protons: Physiological insulin resistance, addendum two

George put up the link to this paper, which allows you to tease information out about omega-3 PUFA as bulk calories vs lard as bulk calories. We are not talking about essential supplies of essential lipids here. We are looking at serious bulk calorie supply. This is quite, quite different.

Aside: The basic conclusion that FO is protective against endotoxin shock is fascinating but may be restricted to C57BL/6 mice. Pity everyone uses them. But it's interesting, and on file, never the less. End aside.

Here's the composition of the diets:



Fairly typical research diets, a little more sucrose than I would like but, well, everyone does it.

What about weight gains? Here they are:



Although body weights, at all time point, are not significantly different between groups this is just due to the initial group weights being different. If you look at weight gain rather than absolute weights, the lard group gains more weight than the fish oil group.

The insulin and glucose levels do support the idea that insulin sensitivity is controlled by the degree of unsaturation of the bulk lipid in the diet, ie PUFA diets increase insulin sensitivity. But there is no excess weight gain in the fish oil group. Why not?

C57BL/6 mice suffer an injury to their hypothalamus on exposure to a saturated fat based diet, especially if combined with sucrose. Omega-6 PUFA do not seem do this and I doubt omega-3 PUFA do either. I considered this back here.

So we are comparing obesity in an un-injured group carrying omega-3 enhanced insulin sensitive adipocytes versus a hypothalamic injured group carrying adipocytes which are partially resistant to insulin due to dietary palmitic acid and partially sensitive to insulin due to decreased sympathetic outflow from the hypothalamus to adipocytes. C57BL/6 mice are very special in their response to saturated fats.

This is a knotty problem to try and untangle. This paper helps a lot.

I just want to look at two of the control groups, both of which are C57BL/6 mice, both of which are exposed to a high palmtic acid diet and so both will have an hypothalamic injuy.

So we can have, among many, two groups of C57BL/6 mice, one fed a high fat diet to make it fat and the next fed a high fat diet to make it fat, but then add in a significant dose of omega-3 PUFA. Just to add some insult to injury. The first group gets a whammy. The second group gets a double whammy. Want to see the graph? Ok, ok, here it is:



First, strain your eyes to follow the open triangles. This is the high fat only control group. These are C57BL/6 freak mice with a brain injury triggered by palmitic acid. They have limited weight gain but, as they store palmitate without DNL, hence without desaturase activation, hence without palmitoleate generation, they develop metabolic syndrome. Visceral fat, fatty liver. Of course the group didn't measure either insulin or glucose (they are in obesity drug development), but these mice have metabolic syndrome and have lost the ability to get any fatter. They are in trouble. They don't actually weigh any more than un-injured C57BL/6 mice fed traditional crapinabag.

Now look at the open circles of ever increasing obesity. Fatties or fatties? This is what happens when you add fish oil to the diet of a palmitic acid injured C57BL/6 freak mouse. Impressive waistlines huh? Of course we don't get the insulin or glucose levels here either, but these mice do not have metabolic syndrome. They maintain the insulin sensitivity of their adipocytes, especially peripherally, and continue to become obese with sustained metabolic health. They will stay healthy until their adipocyte distension induced insulin resistance eventually over rides the insulin sensitising effects of the bulk fish oil.

We have a pair of models. Skinny-fat and obese-but-metabolically-slim. Both are explicable by looking at the basic effects of bulk lipid supply from the diet acting on the insulin signalling system within mitochondria.

Summary: These are palmitic acid injured C57BL/6 freak mice which have the added insult of having their adipocytes rendered extra insulin sensitive by the F:N ratio of a significant percentage of the fatty acids in the fish oil of their experimental diet. This postpones metabolic syndrome until they have become fat enough to develop it.

The F:N ratio concept delivers again.

Peter

BTW no one knows the omega-6 content of the fish oil is in this second study! The discussion mentions that there is zero omega-6 in the basic high fat diet, which has no added fish oil. Imagine running a Rimonabant study when you don't know the omega-6 content of the (high fat) diets. But this becomes irrelevant if you look at the basic metabolism at the molecular level. Either family of low F:N ratio PUFA will delay metabolic syndrome, while ever they assist weight gain. And you have to remember that C57BL/6 mice break by eating butter.