Let's peep inside an adipocyte belonging to a mouse which has had its stearoyl-CoA desaturase gene deleted.
It's busy making lipid, being an adipocyte. Two carbons, four carbons, six, eight, ten, twelve, fourteen and hey, there's the sixteen for palmitic acid. Now, how much glucose and insulin is there around? Ah, lots. Need to signal this with palmitoleate. In goes the double bond to prove it... Oops. No SCD1. Hmmmm. We now have a ton of palmitic acid and no chance to convert any of it to palmitoleic acid. Tricky.
Is the adipocyte going to become insulin resistant? Unless it runs on glucose and never uses any lipid this seems likely. Will the adipocyte stay small? It should do, it's insulin resistant, so won't store fat. Should it export saturated fat as FFAs? Yes. Should we have a slim but insulin resistant mouse? On chow it should become hyperinsulinaemic. Well, you might expect so.
But that's not what happens. The mice stay slim alright, but have excellent insulin sensitivity. Like really, really good insulin sensitivity. You can even feed them on toffee fudge cheesecake and they stay fairly slim and very insulin sensitive.
The SCD1 deleted mice also eat more despite being slimmer than WT mice when on chow, ie they are in CICO-denial:
"On average, the SCD1−/− mice consumed 25% more food than wild-type mice (4.1 g/day vs. 5.6 g/day; n = 9, P < 0.05). Nonetheless, they were leaner and accumulated less fat in their adipose tissue"
Huh. Bloody gym sneaks again. Even while they are asleep:
"The SCD1−/− mice exhibited consistently higher rates of oxygen consumption (had higher metabolic rates) than their wild-type littermates throughout the day and night (Fig. 3A). After adjusting for allometric scaling and gender, the effect of the knockout allele was highly significant (P = 0.00019, multiple ANOVA, Fig. 3B)."
These animals have a hugely increased metabolic rate. The brown adipose tissue "looks normal". That's not the answer.
They are also ketogenic during fasting (daytime is sleep time but they don't really go to the gym while they are asleep). Fasting BHB was 4.4mg/dl. For those watching their ketone meter at home, eat your heart out. They do this even when living on toffee fudge cheesecake.
OK. Utter basics:
What is the F:N ratio within the mitochondria of these mice? Is it:
g) >0.48 (trick answer, don't choose this one!)
The mice are insulin sensitive. They do not have undiluted palmitic acid oxidation going on in their mitochondria. This would produce a ton of superoxide and severe insulin resistance. We know that their mitochondrial F:N ratio must be low. Their metabolism is ketogenic. What fats produce ketones on a high carbohydrate diet? Those MCTs from coconuts and breast milk do. Where do you get C8 caprylic acid from if you are an SCD1 knockout mouse on a low fat diet?
From your peroxisiomes.
Mice with palmitic acid on tap and no ability to lower the F:N ratio by desaturation simply oxidise it in peroxisiomes, FADH2 free, to C8 which is ketogenic, has a low F:N ratio and they produce a lot of heat in the process.
In the words of the paper:
"Northern blot analysis also supports changes in fatty acid oxidation and lipid biosynthesis. Probes for acyl–CoA oxidase (ACO), very long chain acyl–CoA dehydrogenase (VLCAD), and carnitine palmitoyltransferase-1 (CPT-1) indicate increases in β-oxidation"
My emphasis. VLCAD is the main one in peroxisomes, as well as being present in mitochondria. The authors do not come up with any comprehensive explanation of what is going on. The F:N ratio delivers.
I think I mentioned some time ago the explanatory ability of the F:N ratio is awesome. It just goes on.
I was going to leave it there, back to work next week so blogging will diminish, but here is some idle rambling which followed on from this post.
Now here's the question. If some guy like me set out to maintain the lowest practical insulin level (which will minimise SCD1 activation) and bases his diet on the very longest chain, most fully saturated fat practical, would you expect me to activate my peroxisomes? Might the result be that I might stay slim and be cold tolerant?
When we moved in to our current house I unpacked the scales after they had spent nearly a year in a box provided by Pickfords. I was 63.8kg after a year of not checking anything, down by about a kilo from Glasgow. But I was getting a great deal of hill walking in Scotland and probably had more muscle. I forgot about the scales for another year but dug them out recently. Down to 62.8kgs. I eat a huge amount of palmitic acid. I generate enough superoxide to maintain the needed physiological insulin resistance to eat LCHF and I suspect I might have quite active peroxisomes.
I still run a dawn phenomemon FBG of around 5.5mmol/l, if I get up early enough to check it beforehand it's about 4.3mmol/l, once 3.9mmol/l. Random BG through the day vary from 3.3mmol/l after a half day of walking to and from the beach while the car was being MOTed to 6ishmmol/l post prandial if I had parsnip chips (yum) with my high fat beef burgers. Yes, I pour the cooking fat over the chips. A big carb load will get me above 7.0mmol/l easily but only for a couple of hours. I try not to do this too often.
Posting-wise I have no idea what time will allow next week but beta cell failure in SCD1 knockout ob/ob-ve mice tells us interesting things about cells which have minimal antioxidant defences and are deprived of palmitoleic and oleic acids.