I hope everyone has forgotten this diagram
which I simplified to this:
Well, now it's time to butcher it further, to an even simpler diagram:
And now I can get rid of the background faint image and shift things around a little to make some more space. I've also converted all "carbohydrate" pathways to blue.
which leaves room to add in mitochondrial, saturated fat derived ROS, the physiological antagonist to the ROS signal which we name as the "insulin" response, though insulin is but a partial contributor to the genuine ROS signal. We can show the blockade like this:
All very simple. Now lets look at the Surwit diet, 59% fat calories, mostly coconut oil, very low PUFA (~2% LA) and modest fructose (~6% of calories).
Aside. Oooh, look, the Surwit diet provides something very close to the 5% of calories as fructose which was used to augment glycogen formation in dogs. Neat. End aside.
I was going to get in to a deep morass at this point about why MCTs fail to generate an ROS signal in proportion to their chain length and degree of saturation. The aside became progressively larger and, not unexpectedly, more theoretical. For the sake of the discussion of the Surwit diet we just have to accept that coconut oil contains fatty acids which are dealt with differently to longer chain fatty acids and which generate a limited ROS signal.
So let's go back to the Surwit diet, 59% fat, mostly coconut, 13% sucrose, some maltodextrin and some casein.
First, at 6% fructose this will produce an insulin-augmenting level of ROS generation, solid blue arrow below. Next is the glucose from the sucrose and maltodextrin, generating a fairly low level of ROS, mostly via the insulin receptor, shown as a thin arrow because this diet is almost a low carbohydrate diet. Both the above generate ROS which signal "insulin" activation "downstream".
Next let's add in octanoate. For whatever reason this is a poor generator of ROS under physiological levels of exposure. It will do nothing to inhibit the "insulin" effector actions of the carbohydrate generated ROS:
I suppose you could even make a case that the relatively minor production of ROS from octanoate might actually produce an activation signal for the "insulin" effect. A possible explanation for this paper. Then you're really in trouble.
Or at least your liver is.
During the earlier posts on this thread about the actions of fructose I've cited papers which suggest that fructose derived ROS augment the formation of glycogen within hepatocytes. Very clever people are very welcome to look at which substrates change in which direction activating which enzyme pathways to generate this glycogen. It's complex.
To me it's much simpler. Augmented low level ROS -> "do what insulin does". One effect being glycogen accumulation.
In a Surwit type diet the directly supplied fatty acids are heavily slanted towards medium chain fatty acids. Mammals do not use MCTs for bulk caloric storage, the preference is toward a mix of palmitate +/- oleate. The liver is quite capable of converting caprylate to palmitate +/- oleate. In fact MCTs are segregated away from chylomicrons by the enterocytes in the gut and are diverted, as free fatty acids, to the portal vein and so directly to the liver for this to happen.
Given augmented hepatocyte insulin signalling combined with augmented access to free fatty acids, what is the likely effect of augmented "insulin cascade activating" ROS levels?
Could that be the accumulation of lipid in the cells subject to this combination of circumstances?
We call this fatty liver.
That's the first step of several.
Peter
19 comments:
I'm loving the doodles.
So (there are likely several examples of it) would a version of this Surwit diet in which the sucrose was competely replaced by an isocaloric amount of glucose be less obesifying? Or is it more that the coconut fat's enteric sidestep gives the un/desirable result, or the combination of just the right amounts of both?
I.e. desirable if you're the dietary scientist part of the symbiosis, undesirable for the rat part.
"I was going to get in to a deep morass at this point about why MCTs fail to generate an ROS signal in proportion to their chain length and degree of saturation. " - I am really curious about this, especially as MCT's are encouraged by the "mainstream" ketogenic diet people, and I wonder about that.
Would it be correct to say that if they don't generate a proportional ROS signal they wouldn't be as insulin de-sensitizing as they "should"?
Pass, there are problems trying to work that one out. Usually when diets switch from coconut/sucrose to just starch/maltodextrin they usually concurrently change from coconut oil to lard. They latter are much more fattening. Tab 3 in here has some data https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497000/
lapis, yes. It's also interesting from Jim Johnson's work that the MCTs + sucrose combo is excellent for increased median lifespan in mice (while making them obese and insulin resistant as well!) but has relatively little benefit in maximum lifespan. Not many of us will be part of the latter group whatever we eat. I've long wondered if the simple reduction of LA to under 4% of calories might do this.
Peter
Pass, I was just looking at Jim Johnsons work for non related reasons and checked out the D12330 they used. This is a Surwit family coconut diet *w/o* the sucrose. Still fattening but it alters the potential longevity benefits of MCT induced obesity. Whether these apply with sucrose is now an unknown. As are the relative obesity effects, though both are obesogenic. ie, it's the MCTs.
P
That is a hard paper to parse but the bottom line might be : C57BL6
Apart from wondering how FFAs could be transported like that - if not via some lipoprotein relative are they otherwise emulsified? Anyway aside from that, I was thinking that with fructose and with those fats which head straight for the liver you have two types of involuntary calories. Put them both together and, not so good, and without the very tight calorie control in those experiments, even worse.
(I need to do some of my own doodles.)
On albumin, same as those released by adipocytes...
P
"Not many of us will be part of the latter group whatever we eat. I've long wondered if the simple reduction of LA to under 4% of calories might do this." - I wouldn't be at all surprised... >.> Just negating the deleterious LA effects, but what with obesity - not actually increasing lifespan. Super interesting, I didn't know that.
I wonder if we as humanity didn't stumble upon coconut fat as a not-ideal, but doable substitute for fatty ruminant meat, but being not ideal it doesn't make for maximal lifespan. Just better than other alternatives. I think I'll stick with beef :D
Peter re:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497000/
Maybe I'm stoopidly missing something but it seems to me that table 1 and table 2 in that paper are irreconcilable when it comes to wt% pufa vs kcal% pufa.
DoesNotCompute. Outofcheeseerror.
Also I assume that cellulose in a mouse diet is a cryptic glucose source so the total sugars are pretty similar for HFD and HFHS diets.
Yes, uergghh, but yes:
"Rodents have a large cecum where bacteria digest cellulose into useable carbohydrates. After this plant material has been processed in the cecum the animal eats it again to use as energy. This behavior is known as coprophagy."
Thanks for that mental image, Ponder Stibbons.
Rodents are exquisitely efficient.
"Also I assume that cellulose in a mouse diet is a cryptic glucose source so the total sugars are pretty similar for HFD and HFHS diets."
That would depend on the design of the cages, and whether the mice had access to their...output.
Well they did count the cellulose in the total carbs ....
I rewired the stoopid a little. Table 2 is a red herring. Table 1 and Table 3 tell us that even if you drop carbs a few % and cut saturated fat by 35% but increase the heart healthy fats by 37% to make up for it you will gain 25% more weight, so just don't.
What would be nice to see would be another group like Surwit but where all the mcfa was replaced by lcfa.
The metabolic efficiency figures are curious???
So let's up the fructose. D12329 is the Surwit 'control' diet. What mice he thinks eat 60% sucrose, I don't know, but that's the control for D12330 or D12331.
Non-obesogenic, natch. Sorry, Gary.
But it does lower the insulin requirement for a given glucose load in an IVGTT.
"Differential Development of Glucose Intolerance and Pancreatic Islet Adaptation in Multiple Diet Induced Obesity Models"
Tucker that's the paper which I was puzzling over the abstract of up above, an algebraic vortex that will suck you in. It is useful to nut through the summary tables to work out what total amount of fructose vs sucrose in each arm, and what level of pufa vs mcfa. Then notice that there were more kcal in the fat arms etc. It's a work of art.
Plus, these are c57bl6 mice. Do c57bl6 do carbosis?
Just as a throw-in, Surwit himself did some publication re sucrose vs starch in the 1990s which I'm looking at alongside your paper, Pass and Tucker. I've also blogged about fructose (and MCTs and ethanol) on hepatic FGF21 output in the past. Oddly enough I'd forgotten about this and it was only a couple of years ago!
I think I might blog too much!!!!!!
P
Oh, Surwit paper https://pubmed.ncbi.nlm.nih.gov/7752914/
"I think I might blog too much!!!!!!"
Nooooooo.
Btw I meant total fructose vs total glucose above.
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