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Sunday, 8 September 2013

The Elegant Solution

Peter D has been running a fantastic series on PUFAs and cancer. Lots of references to linoleic acid promoting the growth of hepatoma cells.

"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."

Wonderful stuff in line with all the other deleterious effects of excess (seed oil amounts) of linoleate on liver function, and with the benefits of omega 3's.

This passage also caught my eye:
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."
(or for that matter, steatosis).

This interests me because, in Hep C research, HCV can only be cultured in hepatoma cells. You can't culture it in normal hepatocytes. And this provides an answer to an old question - why do viruses cause cancer? What's the benefit, given the risk of killing the host? Because, there is something about the cancer phenotype of a cell that makes the cell a better host to the virus. Obviously it doesn't want to push carcinogenesis all the way (which is why only a small minority of chronic HCV cases end up as HCC), but it does want to tweak the cell a little in that direction. Hence activities like sequestering selenium. Better not give that virus-infected cell too much linoleate to play with.

In the middle of this discussion, Purposelessness dropped this 2008 mouse paper:

cAMP-dependent Signaling Regulates the Adipogenic Effect of n-6 Polyunsaturated Fatty Acids

This is great science thinking about the obesity epidemic. Why are high-carb diets only generally productive of obesity when linoleate is added, and not, say, in Kitava (where most fat comes from coconut and some from fish?). If it's the linoleate, how come low-carb dieters loose weight on cupfuls of nuts and olive oil - or even canola oil - with everything?

The effect of dietary fat on human health is not solely a matter of quantity but depends also on the nature of the fatty acids. The current recommendation is to replace saturated fat by polyunsaturated fatty acids (PUFAs).5 Today, more than 85% of the total dietary PUFA intake in Western diets is n-6 PUFAs, mainly linoleic acid, a precursor of arachidonic acid, whereas the consumption of n-3 PUFAs has declined (1). Since the high intake of n-6 has been associated with childhood obesity, concerns regarding this matter have been raised (2). However, animal studies have yielded conflicting results, with some studies demonstrating that a diet enriched in n-6 PUFAs decreases adipose tissue mass (34), whereas others have associated intake of n-6 PUFAs with an increased propensity for obesity (5-7).

So, we have a paradox. And a solution.

In the present study, we present data that reconcile and explain the disparate effects of n-6 PUFAs on adipocyte differentiation in vitro and in vivo. We demonstrate that cAMP signaling plays a pivotal role controlling the production of antiadipogenic prostaglandins. In vivo, the obesigenic action of n-6 PUFAs is determined by the balance between dietary carbohydrates and protein. A high carbohydrate/protein ratio translated into a high plasma insulin/glucagon ratio, and in this setting, dietary n-6 PUFAs promoted strongly adipose tissue expansion. Conversely, a high protein/carbohydrate ratio translated into a high plasma glucagon/insulin ratio and enhanced cAMP-dependent signaling. In this setting, COX-mediated prostaglandin synthesis was enhanced, and dietary n-6 PUFAs decreased white adipose tissue mass.

Don't try this last bit at home; those prostaglandins might not be liver-friendly, but you can do much the same job with omega 3s.

This bit is for all the calorie nerds:

The decreased obesigenic action ofn-6 PUFAs in mice fed a protein-rich diet did not result from increased dissipation of energy by uncoupled respiration but rather reflected increased energy expenditure in relation to gluconeogenesis and urea formation.

Phew, we didn't break the laws of thermodynamics, so the CICO police are not after us.

We observed a remarkable difference in feed efficiency between mice fed the protein-enriched versus the carbohydrate-enriched diet. In the high protein group, 467.8 kcal were needed to produce a weight gain of 1 g, whereas the high carbohydrate group only needed 67.8 kcal to produce the same weight gain, which almost exclusively represented an increase in adipose tissues. Increased cAMP signaling is known to induce adaptive thermogenesis by inducing expression of PGC-1α and UCP1 in brown adipose tissue (30), but the fact that heat production and oxygen consumption as well as expression of UCP1 in intracapular brown adipose tissue were similar in the two groups of mice indicated that decreased feed efficiency of the protein group was not due to increased uncoupled respiration. Furthermore, no increase in genes involved in fatty acid oxidation in muscle and liver was observed in the mice fed the protein-enriched diet, and the total physical activity of the carbohydrate and the protein group did not differ. Expression of UCP1 and genes involved in β-oxidation was, however, induced in the inguinal fat pad, but the relatively low expression of these genes compared with interscapular brown adipose tissue suggested that such a contribution to whole body metabolism was limited.

Oh no, not DNL too, I though that was all debunked, sorry folks

A hallmark of PUFA action is the ability to increase catabolism by enhancing ketogenesis and peroxisomal and mitochondrial fatty acid oxidation and to suppress expression of genes involved in lipogenesis in rodents (36). It is worth noting that the hepatic expression of rate-limiting enzymes involved in fatty acid catabolism was similar in mice fed corn oil supplemented with protein and sucrose. In contrast, expression of genes involved in lipogenesis was significantly lower in liver of mice fed corn oil and protein compared with corn oil and sucrose. Thus, despite high dietary intake of fatty acids, expression of genes involved in de novo synthesis of fatty acid continued when dietary corn oil was combined with sucrose.

In conclusion: 

In conclusion, we have shown that the adipogenic potential of n-6 PUFAs is modulated by cAMP signaling both in vivo and in vitro. Differences in culture conditions and feeding regimes affecting the glucagon/insulin ratio provide an explanation for the contradictory results published in the literature. Today's diets are abundant in n-6 fatty acids from vegetable oils (corn, sunflower, safflower, and soybeans) that are used in industrially prepared food. In addition, industrially produced animal feed is also rich in grains containing n-6 PUFAs, leading to meat enriched in n-6 PUFAs at the expense of n-3 fatty acids (39). n-6 PUFAs, predominantly linoleic acid, are now the predominant source of PUFAs in Western diets (23). PUFAs have been considered less harmful to human health than saturated fat, and substitution of saturated fat with PUFAs in general has been recommended by dieticians. If the background diet determines the adipogenic potential of n-6 PUFAs also in humans, this is of great concern, since the intake of refined sugars from sources such as soft drinks has increased dramatically during recent decades (40).
Background diet? Insulin-elevating carbohydrate. Result? Adiposity. Culprit? Linoleic acid.

I like this model because it provides a face-saving formula for many factions currently locked in bitter dispute, and because it seems to reflect the various realities we see around us. It's certainly not my job to help solve the obesity epidemic, but every now and then one can't help but take an interest, because the science gets good.
What will happen when fat, with normal protein, is substituted for carbohydrate? Less protein metabolism energy loss, different body composition, less COX-mediated prostaglandin but maybe the cAMP will still be elevated. On to the next experiment then.
Now about that proposed Kiwi saturated fat tax, supposed to increase our PUFA intake without decreasing our intake of carbs?
There's a thing called Unintended Consequences. I like this example, reminds me of the good old days:

Theobald Mathew's temperance campaign in 19th-century Ireland (in which thousands of people vowed never to drink alcohol again) led to the consumption of diethyl ether, an intoxicant much more dangerous due to its high flammability, by those seeking to become intoxicated without breaking the letter of their pledge.
(Ether in Ireland, from Psychology Today; Ether in Silesia, a fascinating J. Medical History article from PubMed)

The only thing that really worried me was the ether. There is nothing in the world more helpless and irresponsible and depraved than a man in the depths of an ether binge
    - Hunter S. Thompson


Peter said...



bella said...

could you put this laymen terms I do have hep c and would like to fully understand what this means.

George Henderson said...

Basically there are three things no-one with Hep C should eat; the first is oils and spreads made from seed oils (corn, soy, rice, canola) which are high in linoleic acid (omega 6).
Olive oil is 11% omega 6 and this is as high as you need to go; butter, dripping, coconut, and cocoa butter are lower and safe.
The second is sugar and fructose syrup. You can get away with some sugar or honey if you use it in your own cooking, but when buying say pasta sauce, choose the brand with least sugar.
The third is refined carbohydrate - cereals, bread, pasta, pastry, flour. Rice and rolled oats might be safe in small amounts. Soy might not be.
The modern diet is highly based around these three things - oil, sugars, and refined starch. In combination they produce similar effects to Hep C in non-infected individuals; fatty liver (NAFLD), cirrhosis, fatigue, increased cancer risk, autoimmune syndromes.

Whatever you eat it's important to get enough energy and enough vitamins and minerals. This means that meat, fish, green veges, fruit, nuts, fatty fruits (olives, coconut, avocado) and starchy veges (potato, sweet potato, yams) are the most essential foods. You can speed up recovery by diet by eating less of the starchy veges, more of the safe oils and fats.

The Perfect Health Diet (book) is probably the best non-technical introduction to the type of diet that minimises the dietary risk factors for Hep C.

Some of the links in this post might be helpful,

Purposelessness said...

Sugar is more rewarding than protein. :-/

I like to drop the study in random comments every now and then, but until now I apparently was the only one who thought it was very interesting. I enjoyed reading your take on it.

Kindke said...

I dont know, I mean I can gain large amounts of weight without excess omega6 in my diet. plain boiled potato's will pile on the fat no problem.

Then again, I am post obese.

George Henderson said...

I read somewhere that the combination of linoelate and sugar is especially rewarding. This is what I mean by the face-saving formula;
people who like carbs can blame linoleate, people who eat nuts and oils on protein-sparing low carb diets can justify that, and people who lower both oils and carbs and protein (a la PHD, or optimal diet) have their rationale too.
Meanwhile, SAD comes off worst, paleo low-carb best, which is as it should be.
It seems to explain a lot of the variation in results.

George Henderson said...

@ Kindke,
Yes, there was obesity pre-seed oil days, just at a significantly lower frequency. So for these old-school gainers, Brillat-Savarin's advice (basically the same as Taubes') still applies. And there are other causes of adpipocyte expansion - viruses, hormonal imbalances.
Still I wonder, if someone had a history of seed oil use, how long would it be before adipocytes stopped releasing linoleate? What about linoleate in bacon, pork, and chicken - quite a lot (Paul Jaminet's stats show chicken contributes most of the LA to the SAD, though I'm not sure some of that isn't fried in oil) or even grain-fed beef, and are some people more sensitive than others?

Not a sole cause surely, but linoleate is the nutrient that has increased most, proportionately, in the NHANES data during the rise in obesity.

I saw a good stand-up joke on TV: In America, we keep animals as pets that in other countries end up in meals.
Like fish.

Bill said...

I also like your "face-saving" formula, it's PC and makes sense --> ie, linoleate is probably safe in a proper low carb whole food setting.


While the CICO police might not be after you, the ELMM ones certainly might (and I think they're the of the same kilt IRL).

George Henderson said...

We still need to move; I imagine that vigorous exercise depletes excess linoleic acid fairly well. It should switch up the cAMP. So maybe exercise doesn't burn up lots of calories, but if it can be focused to burn the right ones - a calorie not being a calorie - it can potentially do a disproportionate amount of good.

George Henderson said...

this is the sort of thing I mean:

"These data support an association of vigorous but not moderate or total exercise with the severity of NAFLD."

NAFLD being a classic example of linoleate overload.

ItsTheWooo said...

As with virtually all adipogenic factors, o6 only is so when fertilized by insulin q.e.d.

in trying to understand my work related wt gain I realize more frequently occurring meal times are significant more conducive to signsof new adipogenesis likely because of greater insulin bias through out the day.

great post George :)

George Henderson said...

Thanks. Fertilized by insulin is good.

Here is a perfect illustration of this principle, from "Behavioral risk factors for obesity during health transition in Vanuatu, South Pacific"

"Heavier reliance on animal protein and incorporation of Western foods in the diet – specifically, tinned fish and instant noodles – was significantly associated with increased obesity risk.
Risk factors included consuming tinned fish (ORs from 1.92–2.91) and consuming multiple fish/meat dishes (ORs from 2.10–4.85) in 24-hour dietary recall. Protective factors included hours of TV/video/radio per day (ORs from 0.70–0.80) and gardening and housekeeping as the primary occupation (ORs from 0.28–0.49)."
(This probably just means that, as everywhere, women get less to eat)

Well the noodles are obvious, but why the tinned fish? Why isn't the protein and omega 3 protective (as fresh meat seems to have been)?

If these researchers had READ THE LABEL BETTER they would know the answer. The tinned fish, mostly mackerel and tuna, sold in the islands is packed in soy oil (sometimes deceptively labelled "natural oil"). The same fish is sold in stores here (Auckland, New Zealand) in stores that cater to Pacific Island migrants. If the fish isn't drained, but is cooked with its oil - which is what you'd do if you were poor and hungry - that adds up to a lot of linoleate. If it is drained, there's still probably enough oil in it to counter former benefits of omega 3.
Notice that sugar is not necessary to produce this effect.

"Our findings are similar to those of the Vanuatu Ministry of Health 1998 NCD survey, which highlighted associations among obesity and daily consumption of nontraditional fat sources (OR=2.19), including oil, margarine/butter, milk, fresh meat, poultry, tinned meat, and tinned fish (11). However, our analyses suggest that tinned fish might contribute more to the risk of nontraditional fats compared to fresh meat (including poultry). In fact, including fresh meat in the nontraditional fats category might actually weaken the observed association, since this emerged as a protective factor in linear regression models, perhaps because fresh meat displaces other less healthy options in the diet. While fresh fish remains a major part of the diet in Vanuatu, it is not available in all areas and only seasonally in others. In this case, fresh meat might be a better dietary option than tinned fish.

Refined carbohydrates might also contribute to increased obesity risk. Packaged “2-minute” noodles are popular in Vanuatu and were associated with increased risk of obesity based on %BF among the whole sample, and with overweight/obesity based on BMI and obesity based on %BF among men."

Also see the story linked in this blog:

Purposelessness said...

By the same author, depending on the full text it might also be interesting. If there is any new information in it I mean:

George Henderson said...

Thanks! So far it has led to this find:
"Central obesity was positively associated with n-6 polyunsaturated fatty acids and inversely associated with monounsaturated fatty acids and n-3 polyunsaturated fatty acids in adipose tissue (P < 0.05)."
In humans. With adipose tissue biopsy.

And, (also by Lise Madsen)
Sucrose Counteracts the Anti-Inflammatory Effect of Fish Oil in Adipose Tissue and Increases Obesity Development in Mice

- Which is like an inverse corroboration of our original paper

We fed C57BL/6J mice a protein- (casein) or sucrose-based high fat diet supplemented with fish oil or corn oil for 9 weeks. Irrespective of the fatty acid source, mice fed diets rich in sucrose became obese whereas mice fed high protein diets remained lean. Inclusion of sucrose in the diet also counteracted the well-known anti-inflammatory effect of fish oil in adipose tissue, but did not impair the ability of fish oil to prevent accumulation of fat in the liver.

More Madsen:
Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity

Last but not least:
Of mice and men: Factors abrogating the antiobesity effect of omega-3 fatty acids
Which is the 2012 review of all her papers on n-3, n-6, sucrose, protein and carnbohydrate.

This is a real gem from it:
"It is important to note that there is a large variability not only in intake of n-3 PUFAs but also in LA between different countries, and thus, the omega-3 index is highly variable.23 Accordingly, the amount of n-3 PUFAs required to meet 50% n-3 PUFAs in tissue is also highly variable. For instance, the average amount to meet this 50% in the Philippines, Denmark and US, is 133, 578 and 2,178 mg per day, respectively.23 In this respect it is worth noting that we found a strong positive correlation between obesity development and consumption of LA and soybean oil.6 Also, intake of sugar was positively correlated with obesity, whereas changes in total energy consumption were not.6 Moreover, intake of calories from poultry, a major source of LA in the US diet,22 correlated with obesity development, unlike intake of grains, beef, fish and seafood, eggs, dairy or vegetables.6 In this context, it is worth mentioning that the women in the Nurses' Health Study cohort, who frequently consumed fish and were likely to be obese, also had a high intake of poultry."

George Henderson said...

See figure 5.

George Henderson said...

More from Lise Madsen's group: it's the glucose, not the fructose, in sugar that lessens fish oil's effect on besity.

A major difference between proteins and sucrose is the ability of sucrose to elicit a rise in blood glucose and stimulate insulin secretion. Insulin is a powerful anabolic hormone that stimulates adipocyte differentiation and adipose tissue expansion (41), and activation of insulin signaling is crucial for the development of obesity (9). Moreover, increased insulin signaling by transgenic expression of insulin receptor substrate-1 is sufficient to induce obesity (52). Thus, it is possible that increased insulin signaling and glucose uptake in adipose tissue in sucrose-fed mice may override the anti-inflammatory and antiobesity effects of fish oil.

The glucose moiety of sucrose is responsible for the rise in blood insulin upon intake of sucrose because fructose, unlike glucose, is unable to stimulate insulin secretion (16). This in part relates to the very low levels of Slc2a5 [solute carrier family 2 (facilitated glucose transporter), member 5, GLUT5] in pancreatic β-cells (64). Furthermore, fructose does not stimulate the release of gastric inhibitory peptide, which stimulates insulin secretion indirectly (27, 67). Thus, the ability of sucrose to counteract the beneficial effects of fish oil seems to relate to a glucose-dependent stimulation of insulin secretion. The fructose moiety of sucrose may further modulate the effect of fish oil on the development of obesity. Thus, the increased consumption of fructose over the past decades has been linked to development of metabolic disorders (59), and fructose is routinely used to induce glucose intolerance in rats (70).