Tuesday, August 21, 2012

Protons: Palmitoleate

I think we have to start with the results section of Cao et al's very interesting (and free to study if you want all the detail) paper:

Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism

As always, the paper is a superb piece of detective work featuring a superabundance of genetically engineered mice from the C57BL/6J background fed an high fat diet, the nature of which doesn't make it in to the methods, but we can just assume that it's all the usual fare. They started from the protective effect of knocking out certain fatty acid receptors in the mice, which prevented the development of metabolic syndrome, and ran with this concept for the massive project detailed in the paper. It's big. It ended up with them doing the following to confirm that they got it correct. From the very end of the results:

"To define the effects of individual fatty acids on metabolic regulation, we prepared Intralipid with triglycerides composed of a single fatty acid, either TG-palmitoleate or TG-palmitate. Infusion of either lipid resulted in a two-fold increase in total plasma FFA levels with similar dynamics (Figure S13). While TG-palmitate suppressed the entire proximal insulin-signaling pathway including activation of insulin receptor and phosphorylation of insulin receptor substrate 1, 2 and AKT in liver, TG-palmitoleate strongly potentiated these insulin actions (Figure 7A). We observed similar effects of both lipids on muscle tissue where palmitoleate enhanced and palmitate impaired insulin signaling (Figure 7B)."

It's a switch, at the crude level of Intralipid infusions. Viewed macroscopically:

Palmitoleate = insulin sensitive
Palmitate = insulin resistant

I may have mentioned this before!

If you take a light switch apart, under the plastic there are some metal parts. The metal provides a sea of probability through which electrons can flow, provided the metal is continuous from light bulb to the powerstation (pax transformers). Or not flow, if we replace a few mm of metal with a few mm of room air.

If we accept that superoxide from complex I reverse electron transport is insulin resistance, then fatty acid binding proteins are a macroscopic overlay over this process, they are part of the plastic of the switch.

Superoxide never leaves the mitochondria, it probably converts to H2O2 to talk to the nucleus or acts locally to activate transcription factors which then talk to the nucleus. Adipocytes don't talk to muscles using superoxide either. The intermediary they use appears to be palmitoleate, probably the ratio of palmitoleate to palmitic acids, once you get away from bulk Intralipid infusions.

Why is it arranged this way? The body has to know what substrates are available. Ignoring protein, carbohydrate talks to the body through insulin, and through insulin transporting glucose in to adipocytes. That's the next post.

There: Not a mention of FADH2 or NADH. Even if I'm thinking about them, as per the last post...


BTW, Charles commented on the depressing amount of superoxide associated with a high fat, low carb diet. True, but about as scary as going for a walk at the brisk-but-not-excessive pace which is reputed to burn fat best. Burning fat is what LCHF eating is all about. Useful if you don't have the hours a day to walk for health purposes. Walking seems to be quite good for you!


Bill said...

I read that paper with great interest when it was published, but I was curious about the choice of palmitate as the control for palmitoleate. I figured oleate was a better control since they’re both delta-9 unsaturated fatty acids, and “degree of unsaturation” is definitely more confounding than “chain length.” I don’t think their magical lipokine would fare so well against oleate; does this agree with your F:N analysis?

Peter said...

Oleate would be pretty much the same F:N ratio as palmitoleate. And PUFA even lower. Mice are not ruminants, so I would guess don't really do DNL to C18. The "general opinion" (FWIW) is that humans go to palmitate/palmitoleate rather than 2Cs longer.

Using the C57BL/6J mouse, when they clearly have no concept of what goes on in the VMH of these beasties under HFD (even without sucrose) was another big mistake. But informative when you realise what's happening.

But the switch concept is consistent with how control layers have been added to an underlying system.


Jill said...

Glad to see you posting regularly! I'm a big fan.

karl said...

I'm working at understanding this correctly - can someone post about the difference between palmitic and palmitate?

16:0 and 16:1? I'm thinking they are different but related?

SS Biker said...


Did you you mean palmitic and palmitoleic? then yes as these are two different fatty acids - same carbon length, one, palmitic, saturated and palmitoleic a mono-unsaturate - C16:0 and C16:1 as you say.

Otherwise the difference between palmitic and palmitate is that the -tate version is a salt or ester of palmitic acid.

In the paper Peter references the authors used Palmitate and palmitoleate triglyceride - which is the respective acid esterically linked to glycerol at all three carbons - ie 3 of each acid - hence a tri-glyceride.

There was something I wanted to ask you karl - it was a comment you made in a much earlier post - it might be around Intermittent fasting - can't remember what now I'll have to go back and look.

CharlesVegas said...

I hate to hijack the thread, but Michael Eades has a post up on a new paper he's pretty excited about:


It relates to upregulation of AMPK on a low-carb/high-fat diet.

Here is the paper:

Draznin B, et al. Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. Horm Metab Res. 2012 Aug;44(9):650-5.


karl said...

O Numnos said...
...the difference between palmitic and palmitate is that the -tate version is a salt or ester of palmitic acid.

Ok I'm not sure there is a connection - I remember seeing this paper:

Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells

LOX-1 is one of the effects of statins - they block LOX-1 and may be one of the good things that statins do ( not all the effects are positive ). oxLDL - ( not LDL) appears to be the real buggy man in CAD - and oxLDL appears to be, at least in part, the product of elevated BG.

There might be a possible tie in here?

donny said...

I was reading a few years ago about the effect of the ability to synthesize oleic acid and its effect on some rodent model of obesity. This might be it;
Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver

Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids. Mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased energy expenditure, and up-regulated expression of several genes encoding enzymes of fatty acid β-oxidation in liver. The mechanisms by which SCD deficiency leads to these metabolic changes are presently unknown. Here we show that the phosphorylation and activity of AMP-activated protein kinase (AMPK), a metabolic sensor that regulates lipid metabolism during increased energy expenditure is significantly increased (≈40%, P < 0.01) in liver of SCD1 knockout mice (SCD1-/-). In parallel with the activation of AMPK, the phosphorylation of acetyl-CoA carboxylase at Ser-79 was increased and enzymatic activity was decreased (≈35%, P < 0.001), resulting in decreased intracellular levels of malonyl-CoA (≈47%, P < 0.001). An SCD1 mutation also increased AMPK phosphorylation and activity and increased acetyl-CoA carboxylase phosphorylation in leptin-deficient ob/ob mice. Lower malonyl-CoA concentrations are known to derepress carnitine palmitoyltransferase 1 (CPT1). In SCD1-/- mice, CPT1 and CPT2 activities were significantly increased (in both cases ≈60%, P < 0.001) thereby stimulating the oxidation of mitochondrial palmitoyl-CoA. Our results identify AMPK as a mediator of increased fatty acid oxidation in liver of SCD1-deficient mice.

Not explicitly stated there, but Stearoyl-CoA desaturase 1 is needed to synthesize oleic acid and palmitoleic acid.

If I was really silly, I might think there was some kind of a tie-in here between palmitoleic acid, insulin signaling and obesity.

It even ties in with Michael Eades post, look at that.

Peter said...

Hi all, there is also this:


Making the body run on palmitate is a good thing (unless you are an ob/ob mouse of course).

Now palmitate makes you thin, palmitoleate makes you fat. Linoleic acid, from the F:N ratio point of view, is like super palmitoleate. If you pour lipid in to cells using a fat which still allows glucose in, you are not exactly going to put AMKP in to overdrive. And if you don't drive through complex II you are not exactly going to generate the physiological signal which does all the good stuff, superoxide.

PUFA are like sugar, from the F:N point of view...

This is where the tread has been heading for weeks now. Great to see Mike Eades posting again (funny how stuff slots togther), and Garry Taubes too.


David Leitner said...

Thanks for the interesting post. I apologize for the dumb question. Clearly I am missing something. In the post Peter says

"Palmitoleate = insulin sensitive
Palmitate = insulin resistant"

But in the comments he said

"Now palmitate makes you thin, palmitoleate makes you fat."

These seem to be contradictory statements. Doesn't being insulin sensitive make you less likely to be fat?

Peter said...

David, does the next post explain things better? Some of the steps are small in the series but I'm trying not to make posts 20 pages long...


George Adventures In Health said...

Thanks for this Peter, I think I need to read both forward from this and backward, to get the full picture. I'm endlessly impressed by your understanding of this stuff, and your continued writing to uncover these issues.

Onto the next post!


David Leitner said...

I think so. Basically Palmitoleate is saying the adipocytes are ready to store fat?

Like some of the other readers I think I need to go back and forth through the posts a bit more.

Puddleg said...
This comment has been removed by the author.
Puddleg said...

Palmitic acid = free fatty acid purified in a test tube
Palmitate = state of said FFA under normal physiological conditions, or as a salt or ester in a test tube.

The difference in a diagram is
palmitic acid (etc) = HOOC-R
palmitate (etc) = -OOC-R

They are exactly the same thing to most of us, I think.
I use "palmitate", "ascorbate" etc. when I get sick of tagging on the word "acid".