Friday, 6 September 2013

Let's just summarise the role of omega 6 fats in Sauer's rat model of cancer:

In the lab situation rapid hepatoma tumour growth needs either arachidonic or linoleic acids. The acids must be taken up in to the hepatoma cells, they must be acted on by lipoxygenase to produce 13-hydroxyoctadecadienoic acid, better known as 13-HODE. 13-HODE appears to be the mitogen which promotes rapid cancer growth. 13-HODE looks like a repair signal gone wrong in cancer cells. Omega 3 fatty acids block omega 6 fatty acid uptake in to hepatoma cells. That's all well and good but the reason I got in to this paper was omega 3 PUFA signalling, rather than those omega 6 issues...

OK, Sauer starts to give some pointers on the function of omega 3 fatty acids in health. That's interesting, as I'm no great lover of any sort of PUFA when I view them from the Protons perspective, yet omega 3s seem to come out pretty well, certainly at low doses. You know my fall back, omega 3 PUFA don't always behave like omega 6 PUFA because they get used as signalling molecules blah blah blah. My own inability to tie the molecular structure of omega 3s to their clinical effects is very frustrating! That they probably act are sites "above" the ETC suggest that they act as what I view as 'high level signals".

Well they do.

The signalling appears to be through a G-protein linked receptor with all of the usual cAMP cascade that follows binding of a ligand to such a receptor. What I found particularly interesting was the effect produced on fat pads of normal rats when EPA (other papers from Sauer suggest all omega 3s act on whichever receptor is involved) was added to the perfusate.

OK, here is a neat little graph taken from here:

This is from fed rats. In the fed state the FFA uptake by the inguinal fat pad of a rat is about 6 mcg/min/gram, white open squares.

Adding EPA at 0.84mmol/l (a bit supraphysiological for EPA but let's let that ride) and FFA uptake by the fat pad drops to zero, or close to zero. Or, in fact, you could argue a suggestion of fatty acid relase, shown as a negative uptake value. Black circles. Fatty acids are not taken up, they end up in the venous effluent in the experiment, plus a little extra.

Whooooah, so do FFAs go through the roof when you take fish oil IRL??

Well no. That's because of this graph from here in the same paper:

Here we have the free fatty acid release from the inguinal fat pad of a healthy rat who has been starved for 48 hours. Fatty acid release is trundling along at about 3mcg/min/gram until EPA is added, again at around 0.8mmol/l. The release of FFAs, in the fasted state, is eliminated. Table 1 in the same paper shows you can get this effect of halting lipolysis in starved rats with under 0.3mmol/l EPA.

Both effects are mediated through a G-protein coupled receptor, ie high level signalling compared to electrons and superoxide in the electron transport chain.

Obviously there are a number of serious problems with this paper but, as a proof of concept, I buy it. I doubt DHA or alpha linolenic acid would work as well (or the group would have used them for this proof of point exercise!) and I think the levels of EPA used produce a very artefactual "switch-like" effect which is probably a graded response. I doubt 0.8mmol/l or even 0.3mmol/l of EPA is exactly physiological but...

Let's suggest that there is a progressive removal of the influence of adipocytes from the FFA flux in/out of plasma as the level of omega 3s in arterial blood increases. Omega 3 fatty acids render adipocytes irrelevant to free fatty acid levels in the plasma.

That is one hell of an idea.

Next we need a brief look at hepatoma cells, again the graph is provided by Sauer and it shows that omega 3 fatty acids, in a G-protein coupled receptor manner, completely turn off the uptake of ALL fatty acids in to hepatoma cells.

If, and it's quite a big "if", the same effects apply to hepatocytes as well as hepatoma cells, we then have a very straightforward mechanism for the protective effects of omega 3 fish oils on hepatic lipidosis. From my point of view this is quite real as there are pretty convincing papers showing that cats, in real life, can be largely protected against the potentially fatal hepatic lipidosis of rapid weight loss by modest doses of omega 3 fatty acids.

Soooo while omega 3s stop the release of all FFAs from adipocytes, they simultaneously stop the uptake of all fatty acids in to the two primary storage organs for fatty acids, adipocytes and liver.

Do plasma FFAs go up or down?

They do, of course, go down. A paradox? Next paper.

Health warning: This paper is so steeped in VLDL and ApoB lipophobia that it makes difficult reading. But there is so little published on FFAs and omega 3 supplementation that it's worth the ondansetron to read it. It's looking at how omega 3 supplements might lower fasting triglycerides, which are the devil incarnate for CVD risk. A huge chunk of VLDL comes from FFAs released from adipocytes and their subsequent repackaging by the liver. Apparently, and I quote from the abstract:

"FO [fish oil] counteracts intracellular lipolysis in adipocytes by suppressing adipose tissue inflammation"

A bit like insulin resistance is caused by "inflammation". Well, maybe it's that simple. They have taken the concept of high level signalling to its 2013 pedestal without looking for basic mechanisms. They have placed the G-protein coupled receptor on to macrophages in the fat pads, which subsequently control the adipocyte lipolysis using cytokines. I haven't checked how good this concept is. Sauer never looked that deeply. Looks a bit modern to me.

Personally I would guess that there are similar receptors on both adipocytes and hepatocytes, but the review does not seem to cover the ability of omega 3s to inhibit general fatty acid uptake by these two tissues. Ah well.

What they do argue is that omega 3 fatty acids upregulate lipoprotein lipase, pretty well whole body. Of course liver and adipocytes ignore this fatty acid bonanza, as above. LPL upregulation is what I needed to know from this paper.

So where do "spare" fatty acids go to? They go to muscles. Upregulated lipoprotein lipase (heralded as the saviour from elevated fasting triglycerides) allows increased lipid release from VLDL to lower those fasting triglycerides. But it's worth bearing in mind that cells do not "see" VLDL, the LPL is on the vascular endothelium and the cells behind the vessel wall only ever receive "free" fatty acids. These are not labelled as from albumin, VLDL or chylomicrons.

Slight aside for later: It seems likely that chylomicrons are going spill their lipids via that same LPL, worth remembering.

The story in the review can be sumarised as omega 3 fatty acids block the release of FFAs from adipocytes and increase the activity of lipoprotein lipase pretty well whole body. VLDL drops, FFAs drop. All is happy in the cardiovascular system. If you believe.

Various "bits" of omega 3s, especially the lipid peroxides of DHA, are signals for mitochondrial biogenesis. I had a paper which specified which lipoxide was most effective but must have missed the "save" button. Mea culpa yet again. There are hints here.

That's a very neat story, which has more than a grain of truth to it.

Why is it like this? What does it mean, physiologcally? Speculation time:

Omega 3 fats come from plants. Mostly from chloroplasts. Where do humans get their omega 3s from? Certainly not from plants. If we did then the rabid Dr Furhman would not be (correctly) recommending DHA supplementation (along with B12) to avoid brain collapse on veg*n diets. Actually, this link is quite funny when cited by Mc-Starch-Dougall:

"There is no evidence of adverse effects on health or cognitive function with lower DHA intake in vegetarians"

Well, I found it amusing. It's almost the converse of the neurological truism which states that being concerned about having a neurodegenerative disease probably means you don't actually have one.

Anyhoo. Away from the coast we have to get our DHA from animals (or buy algae derived supplements). They get it from grass. There is DHA present in adipose tissue of herbivores just as much as it is present in lipid membranes of their cells. My suspicion is that DHA is a signal to your metabolism that you have just eaten animal fat, from an animal who's food chain starts with grass [or algae]. The more fat you eat, the stronger the signal. We do not need much DHA overall for our brains as it is well protected in this site, but we might well be using it at low levels as a [G-protein coupled receptor sensed] signal to target metabolic adaptation to process fat. So is McDougall correct that veg*n "brain" tissue is OK, despite their periphery being depleted? Shrug.

Fish oil supplements? Well, using our "dietary fat is here" marker to pharmacologically modify some perceived CVD risk factor, without the appropriate change in source of metabolic fuel supply, looks to me to be of very limited value. Large intervention trials do show some benefit from omega 3s provided you do your stats well enough, you have a large enough population to pick up a very small effect and you give a high enough dose. But they do not seem to be any sort of panacea. Especially of you are avoiding dietary fat while "faking" the signal that you have eaten dietary fat...

This is not exactly surprising when you try to pick the likely physiology apart. I like the concept of DHA as an animal fat signal.


Final thought: Do we need omega 3 PUFA at anything above the most minimal levels if we are in saturated fat based ketosis? Of course I don't know. But the signal to cope with starvation is palmitic acid (physiological insulin resistance), not DHA. I live in starvation mode, not on a mixed diet with only intermittent access to healthy ruminant fat. I have long wanted to look at the selective release of FFAs from adipocytes in extended starvation. My suspicion is that in the early days after glycogen depletion palmitic acid is preferentially released over other lipids, PUFA are not needed/wanted. By a few weeks all the palmitate is gone and whatever is left then gets released. People like David Blaine suddenly start to feel weak, wobbly and are probably hypoglycaemic once they run out of palmitate and have to release less saturated fats. Two to four weeks if you carry some spare weight. Sauer's rats had only ever been fed a low fat omega 6 based diet and had no serious palmitate reserves, PUFA release came early for these.

Wednesday, 20 March 2013

Let them eat fat: Ron Rosenbaum

THE SATURDAY ESSAY March 15, 2013, 9:05 p.m. ET

Let Them Eat Fat

Listening to the doctors on cable TV, you might think that it's better to cook up a batch of meth than to cook with butter. But eating basic, earthy, fatty foods isn't just a supreme experience of the senses—it can actually be good for you.


The hysterical crusade against fat has become a veritable witch hunt. With New York City Mayor Michael Bloomberg's ban on supersize sodas (now temporarily thwarted) and the first lady's campaign to push leaves and twigs (i.e., salad) on reluctant school children—all in the name of stamping out obesity—it is fat-shaming time in America. Yes, there are countertrends, like the pro-fat TV shows of Paula Deen and Guy Fieri. But in the culture at large, eating that kind of fat has become a class-based badge of shame: redneck food (which I say as someone who likes rednecks and redneck food). It isn't food for someone who drives a Prius to Pilates class.

But there's another world of fatty foods, a world beyond bacon and barbecue—not the froufrou fatty foods of foodies either, but basic, earthy, luxuriant fatty foods like roast goose, split-shank beef marrow and clotted cream. In the escalating culture war over fat, which has clothed itself in sanctity as an obesity-prevention crusade, most of these foods have somehow been left out. This makes it too easy to conflate eating fatty food with eating industrial, oil-fried junk food or even with being or becoming a fat person.

Preventing obesity is a laudable goal, but it has become the rationale for indiscriminate fat hunters. It can shade into a kind of bullying of the overweight, a badgering of anyone who likes butter or heavy cream. To the antifat crusaders, I say: Attack fatty junk food all you want. I'm with you. But you can deny me my roasted marrow bones when you pry them from my cold, dead hands.

I'm not suggesting that we embrace these life-changing food experiences just on grounds of pure pleasure (though there's much to be said for pure pleasure). As it turns out, the science on the matter is changing as well. We are discovering that fatty delights can actually be good for you: They allow Spaniards, Italians and Greeks to live longer, and they make us satisfied with eating less. I'm speaking up not for obesity-generating fat, then, but for the kind of fatty food that leads to swooning sensual satiety.

Roast goose, for instance, is a supremely succulent, mind-alteringly flavorful fatty food. In most of America, roast goose would be viewed as the raven of cardiac mortality, hoarsely honking "never more." And listening to the doctors on cable TV, you might think that it's better to cook up a batch of meth than to cook with butter.

Eating fatty foods has become the culinary version of "Breaking Bad": a dangerous walk on the wild side for the otherwise timid consumers of tasteless butter substitutes and Lean Cuisine. Soon the fear-of-food crowd will leave us with nothing but watery prison gruel (whole grain, of course) and the nine daily servings of kale, collards, spinach and other pesticide-laced and e-coli-menaced greens and fruits on the agribusiness-promoted "food pyramid."Still worse is the ninth circle of food hell to which the fat-phobic ninnies have consigned us: egg-white omelets. Is life worth prolonging for a few (alleged) extra months if said life has been spent enduring the repellent slabs of gluey, pasty albumen that so many self-congratulatory "health conscious" types consider to be a sign of their sanity? They want to purge themselves of dietary sin. I just want to purge.

Fear of fat has become a national sickness, an all-American eating disorder: Call it fatnorexia. Where is Uncle Toby from Shakespeare's "Twelfth Night" lamenting that, under the oncoming reign of Puritan strictures, "there shall be no cakes and ale"?

Something deeper than concern for nutrition and cholesterol is going on here. You don't have to be a Freudian (I'm not) to see in the antifat crusade a cowering fear of sexuality. The evil of oral pleasure as Satan's tool of seduction, dating back to Eve, is deeply embedded in American culture. Recall Cotton Mather's denunciation of the hell-bound wickedness of the pleasures of the flesh and his call for self-mortification (anticipating today's egg-white omelets).

We live in a culture where food has become a symbol of imminent mortality, where Zagat reviews of high-end steakhouses tediously joke about the need to have "your cardiologist approve in writing," variations of which are repeated practically every time a piece of meat is mentioned anywhere ("a heart attack on a plate," "adding insult to arteries" and other super-clever jests).

In fact, some new developments have undermined antifat absolutism. Consider the recent New England Journal of Medicine report on a study of the olive-oil-heavy "Mediterranean diet," a study that included this fairly sensational revelation (as summarized by the Atlantic Online): "After five years of watching trends in heart disease and strokes among people at high risk, the researchers could not in good conscience continue to recommend a 'low-fat diet' to anyone."

Hear that, you fat-shamers? You're killing your credulous low-fat followers. Condemning high-risk people to a life that is not only dangerous but terminally boring—a terrifyingly tedious life of austere cuisine. Doctors had to intervene to save lives from your low-fat junk science!

Paradoxically, the most conclusive argument for eating sumptuously delicious fatty foods can be found in Michael Moss's well-intentioned but scarifying new book, "Salt, Sugar, Fat: How the Food Giants Hooked Us," where he uses the telling phrase "sensory-specific satiety point." As Mr. Moss defines it, this is "the tendency for big, distinct flavors to overwhelm the brain, which responds by depressing your desire to have more."

Whoa! This is big. The author, however, misses the far-reaching implications. He focuses on bashing the use of the "sensory-specific satiety" concept by the evil processed-food industry, which goes to great lengths to get you to overeat fatty fried junk by purposely avoiding the "sensory-specific satiety" point that stops the craving.

In other words, sensory satiety is our friend. VoilĂ ! The foods that best hit that sweet spot and "overwhelm the brain" with pleasure are high-quality fatty foods. They discourage us from overeating. A modest serving of short ribs or Peking duck will be both deeply pleasurable and self-limiting. As the brain swoons into insensate delight, you won't have to gorge a still-craving cortex with mediocre sensations. "Sensory-specific satiety" makes a slam-dunk case (it's science!) for eating reasonable servings of superbly satisfying fatty foods.

So, as part of my unceasing desire to serve humanity, I will offer you a few of my fattiest things—signature experiences of "sensory-specific satiety" that I've had with fat.

For me, the transformative Ur-experience of the beauty and power of fat was my late Aunt Hortense's cheesecake. Don't laugh. This was heavy duty. When I first had this as a child at a maternal family gathering, I felt transported into a realm of pleasure I had never imagined. It rearranged my brain circuits forever. She made it by supersaturating heavy, heavy cream, with heavy sour cream, creating a creamy near-thermonuclear critical mass of density and intensity.

Next: roast goose. It's astonishing to me that so many people I know have never had the roast-goose experience. No wonder they're in a bad mood all the time. I'd always preferred duck to chicken and turkey (and still do by a miracle mile). But roast goose! The crispy, golden-hued skin, the dark meat seething with juicy, fatty, flavorsome goodness. (Don't overcook!)

Forget foie gras. (Something evil about it.) Substitute a big old goose for the dry, overcooked slabs of fibrous white meat that you get from your Thanksgiving "Butterball" turkey, with its injection of "basting material," which the Butterball people hasten to assure the fat-phobic public has nothing, but nothing, to do with butter. Too bad!

As long as we're on the subject of fowl, let us not forget Peking duck, although be sure you go to a place that doesn't serve yesterday's holdovers, as some do. Go to a place where you order it in advance. It's all about the skin, each gleaming, crisp scallop of which bears a slender, super-tender cargo of meat and fat (which shouldn't need the hyped-up hoisin sauce it's often served with).

From the fancy to the humble: lard. An ex-girlfriend from the Midwest introduced me to cookies baked with lard instead of those plastic shortenings. Though I still prefer heavy lacings of butter in my pastries, lard-infused cookies have some kind of smoky peasant savoriness. And lard is great for frying hash browns, although I prefer rendered duck or goose fat. (Ever had hash browns in cream? The old Gage & Tollner place in Brooklyn used to serve this specialty. That was living.)

And then there are steaks. I'm down with Jeffrey Steingarten, Vogue's food writer, who says that the carapace of super-fatty beef that curves around the top of most rib-eye cuts is the best there is (though a case can be made for the tender smaller side of a Porterhouse or T-bone). Still, for true beefy fattiness, slow-simmered short ribs may capture the meaty soul of beef better than most steak cuts: molten spoon-tender beef with melting fat and savory juices.

On second thought, speaking of the soul of beef, roasted marrow is its meaty essence. It looks like pure fat, but it isn't, really, just mainly, and when served in the split shank bone (as at places like the Knickerbocker or Prune in New York City), one portion will keep you in a state of sensory-specific satiety for a week.

Nut butters: One of the great scandals in American food is that when you try to talk about nut butters—some of the supreme fatty food experiences available—all that most people can say is, "Is it like peanut butter?"

This is ignorant blasphemy! Almond butter, cashew butter, pecan butter, pistachio butter, macadamia butter (!)—here is a multiflavored fat heaven that even fat-deprived vegetarians can enjoy. They are so good that you reach sensory-specific satiety after about two tablespoons. They leave peanut butter, even the unhomogenized, non-Jif-like pastes, in the dust. If you haven't had these nut butters, you truly you have not lived a full life.

I could go on about burgers, but that terrain is so well-trodden that it's pointless. When you get a chance, though, you must try lamb burgers—just plain with raw onions and spicy North African harissa sauce. You'll never go back to mere hamburgers again.

Finally, clotted cream. I've provided a good start for your fatty-food future, but clotted cream owns the scones, so to speak. I first had it in pastoral Devonshire itself, and I've never had it so good. It's cream that's thickening—on the verge of turning into sweet butter or souring into sour cream—but it has instead decided to clump together its richest essences into buttery solids in the thick, silky, creamy liquid. You can get it by mail order, but a recent trip to various expat Brit outlets in New York yielded what was to me more like a somewhat velvety cream cheese spread than the soupier, clottier Double Devonshire clotted cream of memory.

These are just a few of my favorite fattiest things. So much fat, so little time.
You watch: Once my style of luxe fatty eating catches on and people start to see that moderate portions of extreme pleasure don't make them obese, fat will become the new health food. My dream diet book: "Eat Fat, Stay Slim." I'll have my cakes and ale with a helping of roast goose, if you please.

—Mr. Rosenbaum's books include "Explaining Hitler" and "The Shakespeare Wars." He is a columnist for Slate and national correspondent for Smithsonian.