Going Nuts On Berries: Ellagic Acid in Rasp- and Blueberries, Pecans, Walnut & Co Protects Against Visceral Obesity

Image 1: I hope you are not one of the guys who spits the tiny seeds of the raspberries out. That is not just disgusting, you would also spit away ~90% of their ellagic acid content.

Nuts and fruits, once hailed as healthy superfoods have been under serious scrutiny within the sometimes overtly "health-conscious" blogosphere. Yeah, consumed in excess both will make you fat; but I would venture the guess that it would be easier to kill yourself by drinking too much water, than by eating too many almonds and bananas... well, before I get derailed here, let's take a look at the data from a recently published study on the effects of ellagic acid, a dilactone of two gallic acid molecules that is found in a wide variety of - guess what? - nuts (pecans, walnuts, cashews, brazil nuts, etc.) and fruits (raspberries, pomegranates, grapes and blackcurrants, plums, grapes, cherries and the list goes on)!

Good for your heart, good for your gut, good for your metabolism, ... but bad for you belly fat

In previous studies ellagic acid has already been identified as a potential heart protectant (Kannan. 2011a, 2011b); it has been shown to ameliorate the progress of cancer (Losso. 2004), to protect from Staphylococcus aureus biofilm formation (Quave. 2012), to exert potent anti-inflammatory effects (Umesalma. 2010), to protect the gut (Gonzalez-Sariaz. 2010),... an open list of health benefits, on which the anti-visceral fat effect Panchal et al. observed in their 16-week rodent trial is probably not going to be the last health-benefit to be added.

Figure 1: Ingredient (g/kg) and macronutrient (% of total energy) composition of the control and the HCHF diet (diet according to Pudjal. 2010, which was used as a reference diet by Panchal. 2012).

In the study at hand Sunil K. Panchal, Leigh Ward and Lindsay Brown kept 8-9 week old male Wistar rats on regular (extreme high carbohydrate, cf. figure 1) or high carbohydrate + high fat (the scientists even state that explicitly and don't mislabel their diet as simply being "high fat"!) diets either with or without 0.8g ellagic acid per kg chow.

Figure 2: Ellagic acid (µg/g dry weight) content of methanol extract of selected nuts and fruits (based on Daniel. 1989)

In view of an average food intake of 30g and 22g in the control and HCHF diet groups and given an average weight of 400-450g per rodent, the animals thusly consumed roughly 40-60mg ellagic acid per kg body weight per day*:

• control: 60mg/kg per day - human equivalent ~ 10mg/kg
• HCHF: 40mg/kg per day - human equivalent ~ 6mg/kg
  
  *note: I calculated those myself, Panchal et al. provide an estimate of 50mg/kg, as a reference

If we take the data from a 1989 study by Daniel et al. as a reference (figure 2) and assume that you weigh ~80kg and that your stomach is about as effective in extracting the ellagic acid from the dry part of the fruit (it is interesting to note that in strawberries >90% of the ellagic acid is in the pulp, while in raspberries 87% is in the seeds) as the laboratory equipment of the scientists was, and if we further take into account that most fruit are ~90% water, you would have to eat ~3,200g of raspberries or blackberries to get your daily dose of 6mg of ellagic acid; or, due to the lower water content (most nuts have ~5% moisture; cf. Beuchat. 2006) 2,181g pecans or 1,220g walnuts.

Note: The above calculation is by no means scientifically valid. In addition to that, the ellagic acid content of fruits and nuts vary according to season, origin, storage, etc. So, don't blame me, if - despite adding a bag of walnuts and a huge basket full of raspberries to your pizza, cola, pasta, twinkies, hamburger, fries, etc - you still gain weight on your high fat high carbohydrate (=standard American diet), ok?

No matter how (in-)accurate the above calculations may be (as I noted, they are probably not very accurate), I am not as confident as Panchal et al. that the average diet with its ~1g of total polyphenols would more or less 'automatically' contain the required 480mg-800mg of ellagic acid, "if the majority of polyphenols in the diet are taken from the fruits and nuts containing ellagic acid".

A cup of blueberries and a handful of nuts a day keep the doctor away?

Although it would seem that Panchal et al. have not done their homework as far as the real-world implications are concerned (and as I will argue in the conclusion - mishaps like these are at the heart of the "superfood myths"), the results of their experiments suggest that ellagic acid could be one of the rare cases, where it may be worth helping nature along, by extracting and capping a polyphenol that is, at least in some cases - such as pomegranate, for example, where large amounts are contained in the leaves (Lei. 2003) - not even necessarily contained in the edible part of the fruit / plant.

Figure 3: Body weight gain, food intake, water intake and energy intake (left); body composition data (right) of rodents fed either a standard high carbohydrate (regular corn starch) or an energetically dense high carbohydrate high fat diet with or without 0.8mg/kg chow ellagic acid for 16-week (data adapted from Panchal. 2012).

If you take a look at the ameliorative effect the lower ellagic acid dosage ('lower' simply due to the lower intake of the energetically more dense high carbohydrate high fat chow) exerted you will see that its effects are surprisingly depot-specific: Contrary to the total body fat mass, which is (within the statistical margin) virtually identical in all groups, the allegedly dangerous abdominal fat was reduced by -33% and -36% by the treatment in both the control (remember >90% of the energy from cornstarch ;-) and the HCHF group, respectively (the reduction was similar in all visceral fat depots; data not shown).

Figure 4: Basal glucose, AUC glucose after 2 g/kg body weight glucose load, triglycerides, total cholesterol, non-esterified fatty acids, c-reactive protein, uric acid and urea levels in rodents fed the supplemented control and the unsupplemented and supplemented high carbohydrate high fat diets; data expressed relative to unsupplemented control diet (data calculated based on Panchal. 2012).

These profound reductions in the amount of inflammatory visceral body fat, stand in line with the statistically significant improvements in glucose and lipid metabolism (cf. figure 4). As you can see the diet-induced increases in glucose, NEFA, triglyceride, cholesterol, CRP and uric acid, as well as the reduction of its counterpart, urea were completely blunted in the high carbohydrate + high fat group that received the ellagic acid enriched chow, an effect, the researchers attribute to...

• an increase in fatty acid oxidation, indicated by increased CPT1 activity and
• reduced inflammation, indicated the reversal of diet-induced increases in Nrf2 and NF-kappaB 

... in heart and liver of the rodents. That the addition of ellagic acid to the diet also minimized the necrotic damage to the liver of the animals, is thusly not surprising.

"So, shall I embark on the fruit and nuts diet?"

Despite those scientifically 'proven' benefits I should yet not have to tell you that it would not be particularly wise to take this study as an opportunity to ransack Trader Joe's dried fruit and nuts warehouses... As unreasonable as the contemporary condemnation of real (not dried!) fruit and (non-rancid!) nuts may be, it did not come out of nowhere, but has its roots in the detrimental overconsumption of both, nuts and fruits in the media-driven believe that adding tons of those healthy "superfoods" to your diet would allow you to live into your late 90s without ever having to worry about any of the ailments of the Western society. Both, nuts and fruit are yet only two "superfoods" within a "superfood diet", ... ah pardon, a whole foods diet, where neither of them is a "treat" or "cheat", but simply nutrition!

On a side note: Can you imagine that your ancestors sprouted a handful of nuts after all the work they had to shell them? They must have been nuts, if they did - don't you think so?

 Contrary to the impression you may get, when you follow the discussion on certain bulletin boards, eating healthy does thus not imply that you have to restrict your dietary repertoire to meat, fish, butter, eggs and the occasional sweet potato; this is all the more true, since ellagic acid is only one example for the myriad of already known and still to be discovered micronutrients with beneficial health effects, of which you would be depriving yourself, if your list of "allowed foods" contains no more than 5-10 items.

Think about it: Just as the FDA-approved food additives are "harmless" if you consume only one of them and potential hazardous, when you eat the whole variety that is present in the fast-food laden SAD diet, it is the synergy of all those ellagic acids and whatever their names may be that makes a varied whole-foods diet so healthy - don't miss out on that!

A Double Dose of HIIT vs. Aerobics. Hazelnuts, Mushrooms, Strawberries = Polyphenol Laden Superfoods With Prebiotic, Anti-Cancer & Anti-Diabesity Effects. Plus: Backdoor to DHT

Actually the first post in today's installment of On Short Notice is a direct continuation of the SuppVersity Exercise Science Week with an intriguing novel contribution to the never-ending steady state vs. HIIT debate by scientists from the University of Birmingham (UK)

Hypothyroidism kills and therefore the SuppVersity Figure of the Week comes from a study on the effect of hypothyroidism on all-cause mortality from Denmark (Thvilum. 2013). The respective data comes from an observational cohort study and spans the years between January 1, 1978 and December 31, 2008. With an increased risk of  +52% (after stratification for the figure dropped to "only" +21%)  in the 3587 singletons, +61% in dizygotic twin pairs, but only +7% in monogyzotic twins, it's yet not quite clear, whether it's the being hypothyroid or rather having the disposition of developing respective problems is actually associated with an increased mortality. After all, you would expect similarly high levels in monogyzotic twins as in the rest of the population, if it was "only" about having a high TSH, which still is the only "official" accepted marker of clinical hypothyroidism.

Day 4 of the Exercise Science Week - A Double Dose of HIIT vs. Steady State Aerobics

(Cocks. 2012 & Shephard. 2012) -- If you ignored the titles and just read the first part of the methodological section it seems as if the two studies that were subsequently published in The Journal of Physiology late in 2012 were identical. What's identical, though is just the data set the two papers by scientists from the University of Birmingham are based on. The latter was acquired during a six-week experiment in the course of which 16 previously sedentary young men (BMI ~23kg/m²; age 21.5y) were randomized to a

• 

  34% increase in time to exhaustion, +91% increase in total work & exponentiated lean mass gains in response to HIIT + NAHCO3 (read more)

  classic steady state endurance training regimen - subjects cycled at workloads equivalent to ∼65% of their pre-established VO2peak for 40min in the first 2weeks, increasing to50min in the following 2 weeks, and 60min in the final 2 weeks; their obviously improved VO2peak was reassessed after 3weeks of training and workload adjusted accordingly

• sprint interval training  - subjects performed 30s "all out" (Wingate test) on a cycle ergometer using a load equivalent to 0.075kg per kg of body weight; each of the Wingate tests was followed by a period of 4.5 min of recoery (at 30W; <50rpm); the number of sprints increased from 4 to 6 sprints with one additional sprint every 2 weeks

As the scientists point out, all participants trained three (SIT) respectively five (ET) times a week for 6 weeks, and were excluded from the study if they were absent from more than two (SIT), respectively three (ET) sessions.

Figure 1: Overview of the relative changes of selected outcome variables measured in the "two" studies
(Cocks. 2012; Shephard. 2012)

While Cocks et al. analyzed the microvascular density and eNOS content of the muscles, the Shephard study, which was published a couple of weeks later, took a closer look at markers of intramuscular triglyceride breakdown and the expression of the anti-lipolytic lipid droplet-associated proteins perilipin 2 and 5. In previous studies, the researchers had observed that these proteins which are believed to protect the lipid droplets in adipose tissue from the "fat dissolving" lipase enzymes, appear to have a very different effect in the musculature, where PLIN2 and especially PLIN5 seem to act as key regulators of intra-muscular lipolysis and triglyceride breakdown (Shephard. 2012).

More similarities than differences?!

Figure 2: Selected parameters of body composition and blood glucose metabolism expressed relative to pre-exercise levels. (Shephard. 2012)

If we take a look at the outcomes of the studies (see figure 1, figure 2), it's not difficult to see that despite minor differences, most of the measured parameters in the Shephard study the observed differences, such as an increase of 7% in VO2Peak in the SIT vs. 15% in the ET group did not reach statistical significance. The same is true for the effect on the mitochondrial density, the insulin sensitivity, the maximal power WMax and the changes in body composition (see figure 2). Only the respiratory exchange ratio (RER), i.e. the ratio of carbohydrates to fats that were used during a 60-min endurance regimen at 65% of the VO2Peak, changed only in response to endurance training.

Despite this difference, the usage of intramuscular triglycerides (IMTGs) during exercise was increased after both trials:

"In comparison to pre-training, net IMTG break- down in type I fibres was significantly greater following training (training×time interaction; P<0.05), with no difference in net IMTG breakdown between groups. Both pre- and post-training, the reduction in IMTG content in type I fibres was attributed to decreases in IMTG density after SIT (pre-training, 21±13%; post-training, 38±7%) and ET (pre-training, 20±17%; post-training, 32±8%)." (Shephard. 2012)

The greater increase in IMTG response to exercise in the SIT (HIIT) group appears to be in line with the previously mentioned role of perilipin 5 (PLIN5) as a driving force of intracellular muscle triglyceride mobilization. After all, the PLIN5 expression of the interval training group increased to a significantly greater degree than the one of the endurance training group. A subsequent correlation analysis confirmed strong associations of PLIN2 und PLIN5 with IMTG breakdown and modest associations with muscular insulin sensitivity.

Para- vs. sympathetic overtraining: I would venture the guess that most of you will think of performance decrements, fatigue, depression, increased sleeping needs, constant weight or even fat gain, and lowered heart rate, i.e. the characteristic symptoms of parasympathetic (=addisonoid) overtraining, whenever they hear or read the term "overtraining". Its evil sympathetic twin, which is also known as basedowoid overtraining (named after morbus basedow) and likewise associated with performance decrements and fatigue yet in combination with an almost stimulant like restlessness, disturbed sleeping patterns, weight loss, and accelerated heart rate, is yet way less know. So, if you wake up in the middle of the night sweating like a pig and with a heart rate similar to the one you had during your last HIIT session, you better cut back on the weight lifting and HIIT side of your regimen - w/out necessary increasing the aerobics, though.

Bottom line: If you combine these mechanistic insights, with the main outcomes of the Cocks paper, which found ET and SIT "equally effective at decreasing arterial stiffness and increasing skeletal muscle capillarisation and eNOS content", even HIIT (or SIT, as it's called here) haters will be hard pressed to argue with Shephard et al.'s conclusion that..

"[d]espite the large differences in duration and energy expenditure between SIT and ET, we provide novel evidence indicating that SIT induces similar improvements [in almost all measured parameters and] provides a time-efficient exercise alternative to achieve improvements in aerobic fitness and insulin sensitivity." (Shephard. 2012)

So, now it's up to you 3x per week HIIT or 5x per week SIT? The answer appears to be clear, however, for people who are also strength training on a higher volume / density regimen, the addition of only 2-3 low(er) intensity aerobic sessions may still be the "safer" alternative in order not to overtax the sympathetic nervous system and keep a balance between sympathetic and parasympathetic activation in your routine.

More, really short news

Put introduction here

• Hazelnuts: A polyphenolic "superfood" that's prebiotic by nature (Montella. 2013) -- The skin of hazelnuts has only recently been identified as "one of the richest edible sources of polyphenolic compounds" - a polyphenol source that can compete with green tea and coffee, by the way (Clani. 2012).
  
  

  

  Hazelnut peel is laden with gut friendly prebiotics & antioxidant plyphenols

  In a paper that's soon going to be published in Food Chemistry researchers from the Italy and the United States report that the skin does also contain a whole host of potent pre-biotics:

  "Over thirty complex free oligosaccharides, composed mainly of galacturonic acid and N-acetylgalactosamine, were characterized for the first time in the present study. Their concentration ranged between 16 mg and 34 mg per g of extract." (Montella. 2013)

  And if you find that unfair, because you are allergic, you may be interested in a 2005 paper by Enrique et al. who found that their sublingual immunotherapy for hazelnut food allergy worked quite well in a first randomized, double-blind, placebo-controlled study with a standardized hazelnut extract (Enrique. 2005)

• 

  Inonotus obliquus (chaga mushroom) does actually looks like a tumor, but contains compounds that have the ability to kill prostate and breast cancer cells (photo by Tomas Čekanavičius)

  "Eat your mushrooms!" mothers are probably saying that not often enough (Kalogeropoulus. 2013; Ma. 2013) -- According to a recent study by Nick Kalogeropoulus et al. all five five wild edible mushrooms species (Lactarius deliciosus, Lactarius sanguifluus, Lactarius semisanguifluus, Russula delica, Suillus bellinii) from Lesvos Island, the researchers recently analyzed in their laboratory contained significant amounts of polyphenols, with the more abundant ones being p-OH-benzoic acid, p-OH-phenylacetic acid, o-coumaric acid, ferulic acid and chrysin. Moroever, the Greek scientists were also able to isolate the riterpenic acids oleanolic and ursolic acid (yeah, that stuff that's currently sold as test booster).
  
  If you add to that the not even published results of Ma, Chen, Dong and Lu, who fount that the ergosterol, ergosterol peroxide and trametenolic acid in Inonotus obliquus (chaga mushroom), another mushroom that has been used in TCM for centuries, do not only have potent anti-oxidant activity, but can also kill human prostate and breast cancer cells, the initially raised question, why your mother never told you to "eat your mushrooms" suddenly appears in a very different light, doesn't it?

• Did you know that the aggregate-accessory fruit (with the green dots on its flesh being its "nuts") has the highest total antioxidant capacity, when it's still green (see facebook news), can contain up to 160mg/g of fisetin (Kimira. 1998) and that the latter has been shown to reduce thyroid peroxidase activity (Divi. 1996) and thus to protect against thyroid cancer? Fisetin is also supposed to have anti-allergic and anti-angiogenic (pro - cardiovascular health) effects.
  Strawberry polyphenol fisetin ameliorates hepatic steatosis and lowers circulating glucose concentrations (Cho. 2013) -- While it's still a couple of days until the Strawberry season will begin it's still good to know in time that the fisetin content in strawberries can ameliorate hepatic steatosis and decrease blood glucose levels by increasing GLUT-4 (glucose transporter 4) expression in a rodent model of diet induced obesity.
  
  Unfortunately, the changes the Korean scientists observed in response to a human equivalent dose of 130mg/day was statistically significant yet not uniquely impressive and "thanks" to the increase in PPAR-gamma and the non-selective increase in GLUT-4 receptor expression (measured only on adipocytes), the rodents in the supplemented group got exactly as obese as their unsupplemented pears. Nevertheless, better "weighty" and healthy than skinny fat and sick, right? 

• Scientists find alternative androgen pathway - DHT synthesis from progestorone more effective than from testosterone (Kamrath. 2013) -- Usually it's my friend Carl Lanore who says that he, respectively Super Human Radio has the smartest listeners. I would hovewer argue that listening is easier than reading the stuff I produce (including sentences that are longer than the paragraphs of most other bloggers) and therefore it's no wonder that SuppVersity readers must be at least as smart ;-)
  
  

  

  The alternative pathway to androgen (DHT) synthesis as proposed by Kamrath et al.

  That being said, I just received a facebook message from Rob, who pointed me towards a very recent paper claiming that there was an "alternative androgen synthesis pathway" in human beings. "Alternative pathway?" Sounds like the adrenal gland and the DHEA => Testosterone => DHT pathway, right? That's what I thought, as well, but actually this one is different. As the pediatric scientists from the JLU Gießen (Germany) point out in their review of the literature, there is a hitherto largely overlooked "backdoor" by the means of which 17α-hydroxyprogesteron instead of it's 12,30 lyase product androstendione is 5α-reduced to 17α-hydroxy-dihydroprogesteron, which is then, in a 4-step process converted to 17α-hydroxyallopregnanolon (2α-HSD), Androsteron (12,20-Lyase), androstandiol (17b-HSD) and finally DHT (3α-HSD).

  "This so-called "backdoor" synthesis pathway appears to play an important role especially during the development of male fetuses, since respective defects will result in a suppressed virilization in boys." (Kamrath. 2013)

  Another context that's probably more important for most of you is the role of the "backdoor" in castrate (and probably also androgen suppression) resistant prostate cancer, where this alternative pathway jumps in, when the regulate substrate for DHT synthesis by a mere change in the specific 5α-reductase subtypes.

Now don't tell me you still haven't had enough for today? I mean, with the long article on the sprint vs. endurance study you've just gotten day 4 of the SuppVersity Exercise Science Week, and with the other short notice items, even those of you who have been missing nutrition and other news within the past couple of days should have gotten way more than your money's worth - after all, the SuppVersity is still free!

Since the same also goes for the facebook news, I'd suggest you head over to the SuppVersity Facebook Wall, where you will find roughly half a dozen of additional short news items every day. Examples? This is a selection of what you could already have known if you were already a friend, fan or whatever you call that on facebook, when you click on the "like button" at www.facebook.com/SuppVersity:

Just out: Part II of my interview with Sean Casey. This time about the A-Z of supplements for strength, endurance and all other trainees who want to boost their health and performance (read more)

• Skin protection from within - Orally ingested green tea or rather respective catechin metabolites end up in your skin and protects it from UV radiation (read more)
• Iron deficiency starts in the gut - Epidemiological findings confirm: Even people with mild gastrointestinal inflammatory bowel disease need more iron and co-factors in their diet to prevent deficiency than healthy individuals (read more)
• Hormonal contraception increases risk of HIV infection - Medroxyprogesterone acetate (MPA) suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens (read more)
• Grape seed and peel extracts stop working, when they are "purified" - Another case where man shalt not isolate what nature put together, if he wants to have the active ingredients survive the digestive process (read more)

And when you are done with those and i have not yet posted another handful of news, head over to Part II of my interview on CasePerfomance.com. Afterwards, you hit the power button switch off this damn machine and have a nice weekend with family and/or friends. 

References:

• Calani L, Dall'Asta M, Derlindati E, Scazzina F, Bruni R, Del Rio D. Colonic metabolism of polyphenols from coffee, green tea, and hazelnut skins. J Clin Gastroenterol. 2012 Oct;46 Suppl:S95-9.
• Cocks M, Shaw CS, Shepherd SO, Fisher J, Ranasinghe AM, Barker TA, Tipton KD, Wagenmakers AJ. High intensity interval and endurance training are equally effective in increasing muscle microvascular density and eNOS content in sedentary males. J Physiol. 2012 Sep 3.
• Divi RL, Doerge DR. Inhibition of thyroid peroxidase by dietary flavonoids. Chem Res Toxicol. 1996 Jan-Feb;9(1):16-23.
• Enrique E, Pineda F, Malek T, Bartra J, Basagaña M, Tella R, Castelló JV, Alonso R, de Mateo JA, Cerdá-Trias T, San Miguel-Moncín Mdel M, Monzón S, García M, Palacios R, Cisteró-Bahíma A. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005 Nov;116(5):1073-9.
• Kalogeropoulos N, Yanni AE, Koutrotsios G, Aloupi M. Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. Food Chem Toxicol. 2013 Jan 24. 
• Kamrath C, Hartmann MF, Wudy S. The alternative androgen synthesis pathway in humans. Klin Padiatr. 2013 Jan;225(1):3-7. [Article in German]
• Kimira M, Arai Y, Shimoi K, Watanabe S. Japanese Intake of flavonoids and isoflavonoids from foods Journal of Epidemiology. 1998; 8:168–175.
• Ma L, Chen H, Dong P, Lu X. Anti-inflammatory and anticancer activities of extracts and compounds from the mushroom Inonotus obliquus Food Chemistry. Feb 2013 [in press]
• Montella R, Coïsson JD, Travaglia F, Locatelli M, Bordiga M, Meyrand M, Barile D, Arlorio M.dentification and Characterization of Water and Alkali Soluble Oligosaccharides from Hazelnut Skin (Corylus avellana L.) Food Chemistry. Feb 2013 [in press]
• Shepherd SO, Cocks M, Tipton KD, Ranasinghe AM, Barker TA, Burniston JG, Wagenmakers AJ, Shaw CS. Sprint interval and traditional endurance training increase net intramuscular triglyceride breakdown and expression of perilipin 2 and 5. J Physiol. 2012 Dec 17.
• Thvilum M, Brandt F, Almind D, Christensen K, Hegedüs L, Brix TH. Excess Mortality in Patients Diagnosed With Hypothyroidism: A Nationwide Cohort Study of Singletons and Twins. J Clin Endocrinol Metab. 2013 Jan 30.