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marylin monroe
Showing posts with label hyperlipidemia. Show all posts
Showing posts with label hyperlipidemia. Show all posts

L-Carnitine Works! Yet, Maybe More Subtly Than Thought: 1.2-5g L-Carnitine Increase Expression of Genes Implicated in Fatty Acid Oxidation, Glucose & Lipid Metabolism.

Image 1: This is you... well, not exactly. It's rather an animal model of human carnitine metabolis ;-)
As a faithful student of the SuppVersity it stands out of question that you have read my masterpiece *rofl* on the "Purported Ergogenics" in the "Amino Acids for Super Humans Series". You will thusly be familiar with the inconsistency of the mostly disappointing results of randomized, placebo-controlled trials. Whether it was for fat-loss, for increases in exercise performance or whatever else the producers of respective supplements promise would happen, when you buy and take their oftentimes profoundly underdosed supplements, in the absence of pathological (or severe dietary) carnitine deficiency the observed effects, if there were any, were negligible.

A soon to be published paper by Janin Keller and other researchers from the Institute of Animal Nutrition and Nutrition Psychology at the Justus-Liebig-University, in Gießen, the Institute of Agricultural and Nutritional Sciences at the Martin-Luther-University, in Halle-Wittenberg, and the Hans-Knöll-Institute, Research Group Systems Biology/Bioinformatic, in Jena (all in Germany, btw.), does now shed some light onto the more subtle, epigenetic effects of l-carnitine supplementation (Keller. 2011).
Image 2: The calculation of human equivalent doses is a constant (unreliable) pain in my ass - either you don't have the adequate conversion ratio or you do not know how much an animal eats. weighs etc...
Note: While my calculation (see below) indicates that the equivalent dose of the dietary enrichment used in the study should be ~4-5g, Keller et al. use a different method to calculate dose equivalents that is based on the ~500g of feed the pigs consumed per day. According to their calculation the daily dose of l-carnitine on a per kg body weight base for the piglets (final body weight: 17kg) was 15mg/kg body weight l-carnitine. If we now take a look at our conversion table (cf. table 1), where this specific type of big obviously is not listed, we probably have to divide that by 1.1 to get the Human Equivalent Dose - but since this is for "Mini pigs", we will just leave it with 15mg/kg and would thus have a dose of only 1.2g for an 80kg human being.
Keller et al. fed a group of 16 male crossbred pigs (body weight at study begin: ~10kg) a standardized diet with a naturally occurring amount of <5mg/kg carnitine. Half of the pigs, did receive additional 500mg/kg carnitine in their feed. In view of the fact that this effectively centuplicated (x100) the carnitine content of the diet, and considering the fact that the average human dietary carnitine intake ranges from ~47mg in men to ~30mg in women (Lennon. 1986), this would translate into an additional dose of roughly 4-5g of supplemental l-carnitine per day for humans. If you buy your carnitine in bulk (currently ~5$ per 100g) mimicking the supplement regimen used in the study would cost you about 25cents a day... but I guess before you do that you will rightly want to know what the potential benefits would be.
Figure 1: Liver free and total l-carnitine levels (in nmol/g) in growing piglets after 21-days of normal or carnitine supplemented feed (data adapted from Keller. 2011)
As you can see in figure 1 the liver of the animals literally squirreled the l-carnitine away (this could also be the reason, why most of the previously cited studies saw only transient increases in serum l-carnitine levels and almost no increases in muscular carnitine stores). An increase of +915% in free and +937% in total liver l-carnitine content is - I probably don't have to mention that - more than significant and was not without consequences... consequences of which scientists probably would not have even thought about 10 or even 20 years ago - epigenetic changes of which Keller et al. write:
we observed that 563 genes were differentially expressed by L-carnitine. This shows that supplemental L-carnitine influences gene expression in the liver of piglets and indicates that at least some of the biological effects of L-carnitine are mediated by altering gene transcription. [...] Gene term enrichment analysis revealed that the most frequent biological processes associated with L- carnitine supplementation were dealing with metabolic processes. This was not surprising considering that the main function of L-carnitine is to stimulate energy metabolism by acting as shuttling molecule for long-chain fatty acids which also enhances the metabolic flux of glucose through the glycolytic chain. This was also confirmed by clustering analysis showing that 6 out of the 10 top-ranked clusters were dealing with metabolic processes. Representative genes from one of these clusters dealing with metabolic processes (carboxylic acid metabolic process, oxoacid metabolic process, organic acid metabolic process) encoded proteins or enzymes involved in cellular fatty acid uptake (SLC27A6, solute carrier family 27/fatty acid transporter, member 6), fatty acid activation (ACSL3, Long-chain-fatty-acid-CoA ligase 3) and fatty acid β-oxidation (ACADSB, Acyl-CoA dehydrogenase, short/branched chain specific), and most of these genes including SLC27A6, ACSL3 and ACADSB were found to be significantly up-regulated by L-carnitine supplementation.
Moreover, the researchers found that a whole host of genes (e.g. GLUT8, GCK and GPD1 more than 4x elevated) related to glucose metabolism (glucose transport, conversion of glucose into glucose 6-phosphate, and glycolysis, and hexose biosynthetic processes, like gluconeogenesis) and triglyceride metabolic and triglyceride biosynthetic processes were elevated, as well. Taken together this lead the scientists to conclude that the epigenetic changes that were induced by 21 days of (relatively) high-dose dietary l-carnitine supplementation suggest that the "conditionally essential" amino acid l-carnitine
  1. ... exerts its "well-known stimulatory effect [...] on fatty acid β-oxidation" at least partly by stimulating the transcription of genes involved in "cellular fatty acid uptake, fatty acid activation and β-oxidation"
  2. ... has profound beneficial effects on glucose metabolism and utilization, which are mediated "not only by [a genetically triggered] stimulation of glycolysis but also suppression of gluconeogenesis in the liver", and
  3. ... triggers genetic modifications which lead to an "inhibition of glycerolipid biosynthesis and stimulation of lipoprotein secretion and fatty acid catabolism", which contribute to its overall beneficial effects on lipid metabolism.
Now that you have all the facts, I'll leave it up to you to decide whether those "hidden" genetic changes are worth the 0.25$ (or 0.06$ if you use the 1.2g dose, cf. red box above) you would have to pay for your share of supplemental l-carnitine per day... and by the way: don't ask me if whatever other form of carnitine will do just as well, better or worse. This is a question only a separate study could answer!

    Study on Krill Powder Suggests: There is More to Seafood Than Fat - Can Krill Give You What Fish Oil Can't? Plus: Krill Protein's EAA Content More Than an Able Match to Whey

    If you listened to the SuppVersity Science News Round Up on Super Human Radio, yesterday, you may remember that the color of food can tell you something about it's antioxidant activity... well, guess what: It's the lipid-soluble pigment and potent antioxidant astaxanthin that gives krill its "healthy" orange-red color.
    In a way this post could be regarded as a follow-up on yesterday's news about the profound weight-loss effects of high dose EPA (and to a lesser degree) DHA supplementation. After all, parts of the supplement industry have been working hard on establishing krill oil as a more efficient alternative for regular fish oil (see "Neptune Krill Oil, the New or Better Fish Oil?"). And in a way, the Rossmeisel study, I had in the news back in June 2012, would support this claim, since one of the proven benefits of krill oil actually is that it contains way more of the phospholipid variety of the long-chain omega-3 fatty acids that is more readily incorporated into the cells than the triglyceride variety from cheaper fish oils (see "Only Phospholipid Based DHA+EPA Reduces Fat Cell Growth & Elevated Insulin Levels Despite Obesogenic Diet").

    Moreover, the results of a 2011 study by Burri et al. (Burri. 2011), which showed that other than fish oil, krill oil with an equimolar amount of EPA and DHA in it actally decreased the expression of those hepatic genes for gluconeogenesis and glycolysis which could be responsible for the problematic increase in glucose levels Poudyal et al. observed in response to high dose omega-3 supplementation (yesterday's news). Now, these observations certainly raise the question:

    Can we ward off the negatives and maximize the benefits by using krill instead of fish?

    You can't eat krill? Fraser Lewry's recipe for krill fried rice looks very real (and delicous) to me
    The results of a very recent study from Norway appear to hold the answer to this question. Moreover, the fact that the researchers did use krill powder instead of the krill equivalent to fish oil, which was by the way regarded mostly as an unwanted waste product that was left over, when McDonald's & Iglu picked up the fish fillets for their Fish Macs and Captain Iglu (R) Fischstäbchen, actually sparks another intriguing question: Wouldn't it be more prudent to eat the whole fish, or in this case whole krill (powdered or not), anyway?

    Now, while we will come back to the question of "eating whole krill" later, let's initially take a closer look a the experiment Bjorndal et al. conducted. The scientists two groups of particularly inflammation prone transgenic male mice of a C57BL/6 strain which constitutively expresses high TNFα (tumor necrosis factor-alpha aka cachexin, or cachectin) levels iso-caloric "high fat" diets. Half of the animals were randomized to the notorious high carbohydrate + high fat diet you usually see in studies like these, the other had parts of the protein and fats replaced with the protein and fat from krill powder (see figure 1 for more details).

    Figure 1: The composition of the experimental diets (Bjørndal. 2012).
    From the "if it fits your macros" perspective, this may look like a minor, negligible change. Over the course of the six weeks the experiment lasted, it did however make a huge difference, as far as the rodents' ability to handle the lipid and energy overload was concerned. And those differences were, as the researchers had already expected, particularly pronounced in the liver:
    "The liver of mice fed the krill powder diet displayed increased β-oxidation, reduced lipogenesis, and reduced cholesterol- and glucose metabolism compared to high-fat fed mice, resulting in improved plasma and hepatic lipid levels." (Bjørndal. 2012)
    In short, the provision of the krill based lipid + protein mixture affected the lipid metabolism, the expression of genes involved in glucose metabolism and the fatty acid composition in plasma and liver of the animals, while keeping the mitochondrial respiratory electron transport chain in liver intact.
    Figure 2: Graphical illustration of statistically significant changes in hepatic gene expression (colors indicate involvement in glucose, cholesterol or fatty acid metabolism; center) and corresponding downstream effects on plasma lipids (small graphs on the right; created based on data from Bjørndal. 2012)
    However, even though we see beneficial effects on lipid metabolism, the absence of beneficial effects on blood glucose despite the presence of the previously observed (Burri. 2011) and with the study at hand now confirmed beneficial effects on the expression of respective genes in the liver makes it quite clear that krill oil, just like fish oil cannot make up for the sheer energy overload of the typical western diet (see yesterday's news).

    How come this sh*t doesn't work?

    And what about the protein in krill powder? Since we don't have a direct comparison to a krill oil only supplement it is difficult to tell, whether the protein content of the powder used in the study at hand did actually make a difference, also because we do have evidence from previous studies (e.g. Burri. 2011) that krill oil alone elicited similar beneficial effects on the hepatic gene expression. Nevertheless,the favorable amino acid profile of krill protein concentrates (see figure above; data based on Gigliotti. 2008 and Sindayikengera. 2006), alone would suggest that the powder has way more to offer than just the oil.
    With the increased energy expenditure from fat in response to both krill and fish oil, comes a lower reliance on glucose as a fuel source. Therefore, more of the sugary glue that makes an excellent fuel, but a very bad lubricant, will remain floating around in the blood, so that the unquestionably impressive >50% reduction of hepatic glyocogen breakdown and the corresponding -45% reduction in gluconeogenesis (see figure 2, green hexagons) are probably just enough to compensate the decreased glucose oxidation, so that the overall amount of glucose that's floating around freely in the blood of the krill oil / or powder supplemented animals will remain the same (with fish oil, and in the absence of these epigenetic changes, it will even go up!).

    Bottom Line: While krill powder appears to have the edge over plain fish oil, it's use is yet likewise no panacea for all the ailments of the metabolic syndrome. 

    The impressive amino acid composition of the protein fraction in krill powder (see information box on the right), as well as Yamada et al.'s 2011 observation that an obviously fat-free, since water soluble krill extract directly antagonizes triglyceride accumulation (=increase in fat content) in adipocytes by suppressing PPARγ and C/EBPα expression (Yamada . 2011), still speak in favor of my initial hypothesis that there is more healthy stuff in krill (and fish) than EPA, DHA & the rest of the omega-3 fatty acid megillah, so to say.

    References:
    • Bjørndal B, Vik R, Brattelid T, Vigerust NF, Burri L, Bohov P, Nygård O, Skorve J, Berge RK. Krill powder increases liver lipid catabolism and reduces glucose mobilization in tumor necrosis factor-alpha transgenic mice fed a high-fat diet. Metabolism. 2012 Oct;61(10):1461-72.
    • Burri L, Berge K, Wibrand K, Berge RK, Barger JL. Differential effects of krill oil and fish oil on the hepatic transcriptome in mice. Front Genet. 2011;2:45. Epub 2011 Jul 12.
    • Gigliotti JC, Jaczynski J, Tou JC.  Determination of the nutritional value, protein quality and safety of krillprotein concentrate isolated using an isoelectric solubilization/precipitation technique Food Chemistry, Volume 111, Issue 1, 1 November 2008, Pages 209–214.
    • Rossmeisl M, Macek Jilkova Z, Kuda O, Jelenik T, Medrikova D, Stankova B, Kristinsson B, Haraldsson GG, Svensen H, Stoknes I, Sjövall P, Magnusson Y, Balvers MG, Verhoeckx KC, Tvrzicka E, Bryhn M, Kopecky J. Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids. PLoS One. 2012;7(6):e38834. Epub 2012 Jun 11.  
    • Sindayikengera S, Xia WS. Nutritional evaluation of caseins and whey proteins and their hydrolysates from Protamex. J Zhejiang Univ Sci B. 2006 Feb;7(2):90-8. 
    • Yamada H, Ueda T, Yano A. Water-soluble extract of Pacific Krill prevents triglyceride accumulation in adipocytes by suppressing PPARγ and C/EBPα expression. PLoS One. 2011;6(7):e21952.

    Sucralose is for Diabetics Not, Scientists say. But How Significant is the Cholesterol Increase They Observed?

    This way of consuming Splenda is quite certainly going to increase your cholesterol levels ;-)
    I guess, all of you will still remember the show Carl and I did on the "Pro-Insulinogenic Effects of Artificial Sweeteners" (read more), right? The one where I tried to point out that even if there was a meager change in the insulin response, this would only be a problem if there was any truth to  narrow-minded condemnation of insulin as the deadly obesity hormone, so that, in the end, the whole hoopla turned out to be way less daunting than some scare-mongers would have it.

    Yet while something deep inside of me is telling me that the latter is probably going to be the same with the recently published study that's at the focus of today's SuppVersity article, cannot refute that the data from that very rodent study that was published in the Journal of Nutrition Sciences does clearly suggest that...

    ...sucralose increases cholesterols!

    That certainly doesn't sound so scary to you, as it does to someone who still adheres to the "cholesterol is the root cause of all evil" paradigm, yet still. The fact that the administration of  11 mg/kg body weight of SPLENDA® over the course of 6 weeks to "intensifie[d the already existing] hypercholesterolemia in STZ-induced diabetic rats" (Saada. 2013) does sound as if there must be something to the rumors about sucralose being one of the main ingredients of devil's excrements.

    Would having your coffee with Splenda instead of sugar make this cookie even more hazardous to your glucose levels and what about your waistline? Read more about the effects of artificial sweeteners on glucose-management, insulin and obesity in a previous article.
    Now 130-150mg of sucralose per day is unquestionably a whoppy dose of artificial sweeteners. After all, this stuff is approximately 600x sweeter than sugar. Sounds like a total overkill, but if you do the math, i.e. 150mg x 600 = 90,000 mg, you will realize that this is not more than the non-caloric sweetness equivalent of ~1.5 Snickers bars. And if the figures a Scivation rep mentions in a post on the most popular bodybuilding website on the planet are correct this would be exactly 10 servings of their highly popular BCAA formula. Considering the fact that for most people Xtend is probably not the only dietary source of sucralose in the diet it is thus not a totally unrealistic dose (especially for those diabetic or non-diabetic sugar addicts, who are using splenda as a means to sweeten their tea, coffee and whetever else, as well).

    Good you've made it past the introduction

    That being said the message that sucralose "intensifie[d the already existing] hypercholesterolemia in STZ-induced diabetic rats" (Saada. 2013) appears to be even more scary.

    Fortunately (or unfortunately for the "sweeteners are devil's excrements"-faction out there), this is not your average "Pubmed-Warrior blog", where the authors read a headline copy and paste the conclusion of the abstract and try to sell it as "science news" and I do not leave you hanging with the inappropriately overgeneralizing conclusion of the author's that
    "[...] diabetic people consuming high amount of sucralose must check their lipid profile to avoid diabetic complications" (Saada. 2013)
    Now, it is obviously right that diabetics should "check their lipid profile" on a regular basis, but if you look at the actual study outcomes, it is hard to argue that this would be particularly important for those of them who use SPLENDA® on a regular basis.
    Figure 1: Changes in blood glucose, insulin, triglyceride and total (TC), HDL, and LDL cholesterol, as well as the TC/HDL levels after 6 weeks on 150mg/day sucralose (Saada. 2013)
    After all, the "dangerous" increase in cholesterol the scientists observed in their lab animals (remember: we are not even 100% sure the same is going to happen in human beings) is not just accompanied by highly desirable desirable reduction in glucose (-22%) and triglycerides (-22%), it also leaves the CVD-relevant ratio of total to HDL cholesterol literally unchanged (+2%, n.s.).

    Moreover, if you look at the way statins help managing cholesterol, but increase diabetes risk, you could even speculate that there is a yin and yang connecting the two metabolic pathways, where a lower strain on the one side will precipitate a higher strain on the other. Within this paradigm, the increase in cholesterol, which is by the way something many people who are "going paleo" will see, as well, could be a totally normal part of a "balancing" process that has nothing to do with the pathological overprodcution (always remember this is not about eating too much cholesterol) of highly oxidizable small and very small density lipoproteins people fear like the plague.

    In addition to reductions in blood glucose and triglyceride compared to cornflakes & co, the regular consumption of whole eggs increases HDL's ability to carry lipids out of the macrophages. If these accumulate, they will turn the macrophage into pro-atherogenic foam cells (learn more).
    Bottom line: At least in my humble opinion, the results of this study don't imply that diabetics should stay away from sucralose. In the end, the benefits of lower glucose & triglyceride levels will outweigh the "downsides". This is all the more true, in view of the fact that we (a) the total-cholesterol-to-HDL-ratio remained essentially the same and (b) don't have data on the changes in lipoprotein particle profile. After all, improved glycemia and reduced triglyceride levels often go hand in hand with heat-healthy changes in the particle size distribution that is still totally ignored by way too many researchers.

    That being said, the reduction in 10% reduction in TBARs, a marker of oxidative damage, clearly indicates that the rats with "increased" cholesterol levels were less inflamed than their sugar guzzling peers.

    Needless to say that the same applies for the healthy rodents, where the changes in blood glucose, triglycerides and total, HDL and LDL cholesterol were much less pronounced, but the tendencies identical.

    References:
    • Saada H, Mekky N, Eldawy H, Abdelaal A. Biological Effect of Sucralose in Diabetic Rats. Food and Nutrition Sciences. 2013; 4(7a):82-89.

    Fat Content Per Energy Drink 0g, Body Fat Gain Per Energy Drink 18g! Human Trial Confirms: +1kg of Body Fat in 4 Weeks From Less than 2x Energy Drinks per Day!

    Image 1 (NYC Dept. of Health & Mental Hygiene): The words on this poster from a 2009 campaign in the NY subway must be taken literally!
    There is a reason for me to always begin my "dietary advice" with the statement "there is NO WAY that you ever again drink any soft, energy drinks or fruit juices on a daily basis". And though I would not have needed a study to confirm skipping, lemonade, coke & co is one of the simplest, for many people yet not easiest steps to a healthier and leaner physique, I must admit that I was pretty surprised how rapid both your health and body composition deteriorate, once you reintroduce this junk into your diet. +1kg of pure body fat in 4 weeks, that was the amount of weight the 11 healthy men and women in a recently published study by scientists from the UK, Italy and the US gained within just 4 weeks in the course of which they drank on average two more or less tasty Lucozade Energy drinks per day (Sartor. 2012).

    Fat content of energy drink 0g, body fat gain per energy drink 18g!

    Figure 1 (gsk): Nutritional information of the energy drink the subjects drank during the 4-week study period
    Sartor et al. about whose study on the "habituation effects" of sweet beverage you may already have read in one of the installments of the Insulin Resistance Saga (cf. "Where Has All the Sweetness Gone? Plus: Bullied to Eat Twinkies") had recruited 11 healthy young men (n=5) and women (n=6) with a mean age of 26 years, who were handed a month's supply of GlaxoSmith Kline's yummy Lucozade Energy of which they had to drink ~2 bottles per day (2x 380ml; in fact the average intake was only 760ml and was matched to deliver 2g carbohydrates per kg body weight; for detailed "nutritional" information based see figure 1) - just to make that clear, I suspect the results would not have been much different if this had not been Lucozade, but plain Coke, if the daily consumption (1.2l) had delivered the same amount of sugary carbs.

    Apropos effects, if you take a look at the actual data in figure 2 it is quite obvious that the increase in body fat did not occur in the absence of the rise of other characteristic features of the metabolic syndrome, i.e. changes in blood glucose and lipid metabolism.
    Figure 2: Changes in body composition, HOMA markers of insulin resistance, sensitivity and pancreatic function, as well as blood lipids after 4 weeks of sugar-sweetened beverage consumption (based on Sartor. 2012)
    A particular reason of concern - at least in my humble opinion - are the rapid (remember these deteriorations occurred within only 4 weeks!) reductions in HOMA measure insulin sensitivity / increases in HOMA based insulin resistance measures. Which would only exponentiate the detrimental effects of the daily glucose overload.

    High blood glucose, high RER, high insulin, but no increase in energy intake

    Together with the significantly increased fasting glucose (+6%) and fasting insulin levels (+25%) and the accompanying reversal of the fat-to-carbohydrate oxidation rates from 2:1 to 1:3 in the fasted state this does already suggest that this is once more not solely an effect of an increase in energy intake as conventional wisdom would have it!
    Figure 3: Changes in macronutrient composition and non-existent changes in total caloric intake over the course of the 4 weeks of sugar-sweetened beverage consumption (based on Sartor. 2012)
    If you take a closer look at the data in figure 3 you can even drop the "solely" from the previous sentence and state: "the obesogenic effect of sugary beverages has no relation whatsoever to an increase in overall energy intake!"

    Its not so much about how much, its about what and which!

    It stands to reason that this increasingly accepted "violation" of the rules of thermodynamics *rofl* did not go unnoticed by Sartor et al., who had also analyzed the expression of several genes in samples of the skeletal muscle tissue of their subjects and found that there were statistically significant
    • increases in glyceraldehyde-3-phosphate dehydrogenase (GAPH), acetyl-CoA carboxylase alpha (ACC) and MonodA mRNA expression, which are indicative of increased glycolysis, decreased fatty acid oxidation and an increased cellular awareness of blood sugar abundance, respectively, as well as a significant
    • decrease in peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1a), of which you have read in relation to Irisin in "If a High Fat Diet was a Pill, the Lay Press Would Celebrate it as Exercise in a Pill!" that it is responsible for increases in mitochondrial firepower and fatty oxidation capacity
    Much more so than the 1kg of body fat, which should be relatively easy to shed by simply pouring energy-, soft-drinks & co down the sink, instead of downing them with a gulp, these transcriptional (epigenetic) changes and the previously reported deteriorations in taste perception in response to the consumption of sugar (not fructose!) sweetened beverages (Sartor. 2011), are the real alarming results of this 4-week trial. After all, they are the ones that predispose to future fat gain, diabetes and hyperlipidemia!

    So, what can be done?

    Image 2: OTC solution to the problem? Water + Workout
    Luckily there is a tried and proven non-pharmacological solution to this problem, an OTC double-whammy, if you will that is not just free, but will actually save you truckloads of money! Initially for all the energy drinks and soft-drinks you are not buying anymore and for all the medication the medical bill's and the XXL coffin for your funeral in the weeks, months, years and decades to come. What? You want to know what this OTC double-whammy is? Plain water and regular exercise! While the former is equally if not more thirst-quenching than the differently colored sugar waters, the latter will help to gradually reverse the epigenitic changes and restore a healthy glucose and fatty acid metabolism.

    References:
    1. GlaxoSmithKline (gsk). Lucozade Official Shop. Lucozade Energy - Original. 2012 < http://www.lucozadeshop.com/lucozadeenergy/lucozadeenergyoriginal > Received on June 30, 2012.
    2. Sartor F, Donaldson LF, Markland DA, Loveday H, Jackson MJ, Kubis HP. Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation. Appetite. 2011 Aug;57(1):237-46. 
    3. Sartor F, Jackson MJ, Squillace C, Shepherd A, Moore JP, Ayer DE, Kubis HP. Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes. Eur J Nutr. 2012 Jun 26.

    Spicing Up Fat Loss: Structural Similarity to Melanocortin-4 Agonists Powers Piperine's (Black Pepper Extract) Fat Loss and Lipid Lowering Effects

    Image 1: The molecular structure of
    piperine makes it a potential
    melanocortin-4 (MC4) agonist.
    Despite the fact that the American fast food mentality has long conquered the Indian subcontinent, and obesity and diabetes are on a rise, the ideal of the curry eating, spicy food loving, lean Indian still figures in the minds of people in the "old" (Europe) and "new" world (America). Maybe this is part of the reason  why many of us willingly believe(d) in the ability of black pepper and other spice extract to literally "burn away" unwanted body fat, when we read about it in the latest supplement advertisement. Other than in the cases of Goji berries, Acai and co, a recent study (Shah. 2011) coming from, you guessed it, India, was not only able to confirm the validity of these claims (at least for rodents / more on that later), it also gives a reasonable explanation for the fat-burning effect of piper nigrum.

    Using the standard rodent model of obesity-induced dyslipedemia (the high fat diet fet male Sprague Dawley rat), Shah et al. found that treatment with 40mg/kg (human equivalent dose: 6.5mg/kg)
    significantly reduced not only body weight, triglyceride, total cholesterol, LDL, VLDL, and fat mass, but also increased the HDL levels, with no change in food intake.
    In that, it is important to note, that both, weight loss, as well as the improvements in blood lipids occurred despite continuous intake of the fattening "high fat" diet (which was obviously also relatively high carb, just like the typical western diet), of which the rats kept eating about the same amount as before the initiation of treatment. A silbutramine treated control group, on the other hand, "exhibited a significant reduction in food intake as compared to the HFD-control group". In contrast to the prominent weight loss drug, piperine's effect on body weight, fat mass and blood lipids are thus not partly mediated by a simple reduction of caloric intake.
    Figure 1: Epididymal (white adipose tissue, WAT) and interscapular (brown adipose tissue, BAT) fat mass in % of unsupplemented rats on a high fat diet (HFD) after administration of either sibutramine or piperine along with HFD for 11 weeks (data adapted from Shah. 2011)
    In view of an unmistakable structural similarity of piperine to other selective melanocortin receptor agonists such as piperazine, piperidine, pyridazinone, tetrahydropyran, thiadazole, and diazole derivatives, the scientists propose direct melanocortin-4 receptor agonism at the level of the arcuate nucleus and thus "increased energy expenditure, and increased Insulin sensitivity" as an underlying mechanism for the anti-obesity, anti-hyperlipidemic effects of black pepper extract. Coupled with its thyrogenic activity, which "modulates apolipoprotein levels and insulin resistance" piperine turns out to be one of the few really promising fat loss adjuvants available on the vast supplement market.

    To all that has been said, there is however one major caveat: Humans are not rodents, and whenever you read of thermogenic effects that have been observed in rats or mice, you must remember that human beings, other than those little critters lose most of their already negligible brown fat depots (BAT) within the first month of their lives. An organism lacking this type of thermogenic fat will obviously react very differently to compounds that speficitcally target thermogenic pathways. Whether the results from this study can be transfered to humans, or in other words, whether piperine will burn your love handles away, still warrants confirmation in human studies.

    On a side note: The smaller reduction in BAT (cf. figure 1) observed in this study does not imply that the thermogenic effect of brown adipose tissue thermogenesis would not play a fundamental role in the metabolic effects of piperine. In order to raise the animal's body temperature, BAT actually uses white adipose tissue as a "fuel source".

    High Dose Caffeine + Non-Alcoholic Fatty Liver Disease = 355% Increased Very Low Density Lipoprotein (VLDL)

    Image 1: Already in "pill form" - Coffee beans
    Caffeine, the world's #1 drug certainly is a remarkable substance. It does not only have myriads of well-established physiological effects, already, but it seems that - if you wanted to - you could identify another one everyday. It is thus not really surprising that a recently published study by Abd El-Ghany, M.A., Rasha, M. Nagib and Hagar, M. El-Saiyed from the Mansoura University in Egypt casts yet another, in this case, however, pretty scary light on the lifeblood of the average Starbucks junkie (El-Ghany. 2012).

    Caffeine prevents weight gain - whohooo! Or not?

    The scientists set out to investigate the differential effects the oral administration of 10mg/day of pure caffeine, or dose-equivalents from coffee, (black) tea, cacao and Nescafe (note: this is my understanding of the somewhat sloppy English translation of the methods) would have on the lipid levels of rats who had been pretreated with a lard-based high fat diet and CCl4 for three months. This treatment had elucidated the expected inflammatory response and fatty acid deposition in the livers of the animals that were then randomly assigned to either one of the 5 treatment or a non-treated control group.
    Figure 1: Weight gain (relative to initial weight) and food intake in non-treated, caffeine, cacao, Nescafe, coffee, or black tea treated rodent model of NAFLD (data adapted from El-Ghany. 2012)
    And when you peak at the study outcome in figure 1 I would bet that your first reaction is: "Hey, cool! I must ramp up my caffeine intake even more, then!" We are in fact so conditioned to believe that weight loss, or the absence of weight gain is a "good thing" that I made the same stupid mistake, when I first looked at the (in the study) tabular data of the El-Ghany study. Then, I began to wonder: "How come that coffee and cacoa, of which I have repeatedly read that they help with weight loss, did increase the weight gain to levels that were higher than those in the non-treated control group." Finally, it dawned on me: What we are dealing with, here, is not weight loss or ameliorated weight gain, what we are seeing in all the groups is more of a special form of "failure to thrive"! After all, the non-CCL4 treated 'real' control group (data not shown in figure 1) did gain 45% of their initial body weight and thus still 15% more than the coffee group, of which I was mislead to believe that they "performed" worst.

    High dose caffeine is for NAFLD sufferers not!

    Looking at the rest of the data it became increasingly clear, the whopping dose of 10mg of caffeine per rodent per day, a dose, by the way, which happens to translates into a human equivalent dose of 10mg/kg (i.e. 800mg for an 80kg adult), did a pretty decent job in liberating fatty acids from the adipose tissue. So "decent", in fact, that the already compromised weight gain in those sick creatures was further attenuated.
    Figure 2. Lipid levels in the treatment groups expressed relative to non-treated NAFLD rodents (left); selected liver slices (right; based on El-Ghany. 2012)
    But it gets even worse, the sudden influx of fatty acids from the adipose tissue was so overwhelming that the already damaged livers of the NAFLD rodents started to spill out copious amounts of very low density lipoprotein (VLDL) - those nasty little cholesterol molecules of which researchers believe that they are the cause of cardiovascular disease. And despite the fact that we do not have any tissue images of the heart, the congested vein in the liver slice from one of the caffeine guzzling rodents appears to confirm the causal relationship of VLDL and clogging of the blood vessels; an effect, by the way, which could neither be countered by the -71% reduction in triglyceride levels, nor the -44% reduction in total lipids (compared to non-treated NAFLD control). 
    Figure 3: Total cholesterol (CHO) and LDLc to HDL-c ratios in the non-treated, as well as the treated groups expressed relative to non-NAFLD control (data calculated based on El-Ghany. 2012)
    In a 1985 letter to the editor of the Journal of the American Medical Association (Jama) William and Simpson explain the sudden occurrence of enormous amounts of VDLD in response to the lipolytic (=fat liberating) effects of caffeine as follows:
    Upon liberation from the adipocyte, fatty acids are transported to the liver, where they are reesterified and the resultant triglycerides packaged for release in very-low-density lipoprotein (VLDL), which also contains apolipoprotein B.
    If we assume that this hypothesis is correct, coffee, cacao and even Nescafe must obviously contain substances which help the liver to cope with the additional influx of fatty acids, as the animals in the respective groups do not only have significantly lower VLDL levels than the poor critters in the caffeine group, but also exhibit the most beneficial total cholesterol-to-HDL and LDL-to-HDL ratios (cf. figure 3) of all groups.

    Say no to stims, energy drinks and coke and chose natural caffeine sources

    In view of the ameliorative effects all the caffeine containing preparations had on the pathological features of NAFLD (cf. figure 2, right), and based on the results from previous studies and the assumption that the VLDL increase in the tea group was similarly well-handled in the rest of the body as it was in the liver, which did not present any of the congested veins that were so characteristic of the livers of the animals in the caffeine only group, the take home message of this study is one every SuppVersity student should be familiar with, by now: Nature knows best!
    Image 2: I don't have to tell you that the study at hand suggests that those sugary caffeine bombs people call "energy drink" could give many of their livers their quietus.
    Note: If you live in Dallas County, it does take no more than three attempts to identify a neighbor, friend, someone from your family or simply a pedestrian being in the early stages of NAFLD. And given the fact that the 33.6% NAFD rate in Dallas County was measure in 2005 already (Szczepaniak. 2005), it is almost certain that your neighbors' liver, which may still have been comparably healthy in 2005 has caught meanwhile. The results of this study could thus have greater implications on public health than you may initially have thought and it clearly suggest that the use of high dose "fat burners" and / or pre-workout supplements, as well the regular consumption of caffeine and sugar laden "energy drinks" or even coke is absolutely contra-indicated; and that not just in the obese, but also in the insulin resistant normal weight, whose liver is often similarly clogged with fat as the one of his 200lbs heavier comrade in crime.
    If the caffeine is ingested in the absence of its natural adjuvants bad things happen. If they remain where they belong, however, the same whopping dose of caffeine that makes things worse could actually turn into a decent "liver fat burner".

    While Coffee, tea and cacao drinkers can thus breathe a sigh of relieve, the average stim junkie who is already squirreling caffeine laden, geranium (DMAA) intoxicated pre-workout supplements and fat burners for the days after the DMAA ban, should better watch his liver health. Otherwise it may well be that he or she will end as a "case study" in the library of the FDA - filed under "death by fulminant liver failure induced by geranium + caffeine containing pre-workout supplement" - btw. isn't it strange that the FEDs don't have such a case study for one of the commercially available energy drinks, or even plain Coke, already?

    An Old Dog Learns New Tricks: "Fatloss Fat" Tetradecylthioacetic Acid (TTA) Cardioprotective in Diabetic Rats

    Do you remember the acronym TTA? Tetradecylthioacetic Acid? No. Well, I guess then you were not into fat burners in the early 2000s. TTA, a thia-fatty acid, was all the rage back in the day: Supplement producers claimed it would literally melt fat away and it actually turned out that some users had outstanding results megadosing respective supplements. Others, however, got bloated and/or started cramping. In view of these nasty side effects, most companies decided to reformulate their products and - with the exception of a few so-called "non-thermogenic" fat burners - TTA has almost disappeared from the market.

    An international team of scientists from Norway and Canada (Khalid. 2011) has now discovered that the artificial fatty acid tetradecylthioacetic acid, which was originally intended as a drug for the treatment of the metabolic syndrome, might have the potential to protect type II diabetics from heart attacks.
    In a previous study (Hafstad. 2009) the scientists had already shown that TTA does increase myocardial fatty acid oxidation in normal mice, a finding that would generally suggest impaired cardiac efficiency and thus be considered detrimental. In the current study on hyperlipidemic [high blood lipid levels] type 2 diabetic mice, however, TTA-treatment (0.5%, 8 days) had almost opposite effects on on cardiac metabolism and function
    We found that TTA treatment increased myocardial FA oxidation, not only in non-diabetic (db/+) mice, but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. While TTA had deleterious effects in hearts from non-diabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts TTA improved ischemic tolerance, an effect that is most likely related to TTA's antioxidant property.
    Being a specifically designed (Pan-)PPAR-ligand [TTA seems to activate all PPAR-receptors] the lipid lowering effect of TTA was to be expected. The differential effect on heart function in healthy and diabetic rats, however, comes as a surprise and reminds us, again, that not all that has been shown to help sick people is beneficial - and sometimes its not even safe! - for the healthy part of the population.
    Figure 1: Myocardial fatty acid and glucose oxidation in hearts of db/+ (white  545
    bars) and db/db (gray bars) mice. Results are mean of 8-9 hearts in each group. (Khalid. 2011)
    So, regardless how promising the shift in substrate metabolism from carbohydrates to fats, as it is visualized in figure 1 may appear, if you just want to shed a few pounds of unaesthetic, but healthy subcutaneous body fat, stay away from tetradecylthioacetic acid - for your heart's sake!

    DHEA Inhibits Fat Gain More Effectively Than Testosterone. Both Work by Reducing PPAR-γ and Thusly Lipid Storage

    Image 1: This is the "Fountain of Youth" in Karlsruhe, Germany. I have never been there, but I guess I should take the next train and check whether water contains 0.4% or 0.8% DHEA ;-)
    Outside of the medical practices of some anti-aging docs nobody appears to care about the "good old" dehydroepiandrosterone (DHEA), these days. As a diligent student of the SuppVersity, you are yet well aware of the reviving effects DHEA has on the liver (cf. August, 26, 2011), pancreas & insulin sensitivity (cf. May, 15, 2011) and adipocyte metabolism (cf. April, 8, 2011) in "older" people or everyone with suboptimal DHEA levels. You will also be aware that the adrenal steroid hormone which can be converted to testosterone (and thusly DHT or estrogen) at the target tissue exerted pretty astonishing effects on body composition in a handful of initial (very) high-dose trials. Follow up studies in the late 1990s were yet mostly unable to reproduce these encouraging results and with the increasing concerns about potential side-effects and the lack of funding from the pharmaceutical industry, who did not have an interest in finding out that a non-patentable substance would ameliorate or even cure some of of the ailments they were and still are making a fortune on.

    DHEA a Weapon in the War Against Diabesity?

    The most widespread of these ailments certainly is diabetes; a pathology the management of which (not it's treatment!) has generated a $42 billion dollar market (data from 2010) that is estimated to grow to $114.3 billion dollar by 2016 (inverstorplace.com). It is thusly no wonder that the recently published study by Kei Fujioka and his colleagues from the Departments of General Internal Medicine and Parasitology at the Gifu University Graduate School of Medicine in Gifu, Japan, was not funded by a Japanese (let alone US ;-) pharmaceutical company, but by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Fujioka. 2012).
    Figure 1: Simplified illustration of the adrenal hormone production cascade
    Based on the scattered conglomerate of previous results the researchers speculated that feeding Otsuka Long-Evans Tokushima fatty rats chow with 0.4% dehydroepiandrosterone (DHEA) in it would ameliorate if not totally prevent the development of type II diabetes and / or related pathologies to which this rodent strain, which is also one of the standard models for type II diabetes, is particularly prone.
    Figure 2: Relative differences in epdidymal fat pad weights, serum glucose, triglyceride, total cholesterol and free fatty acid levels in LETO and OLETF rats after 52weeks on chow with 0.4% DHEA (=100mg/day; human equivalent: 16mg/day); data expressed relative to rats on control diet (data adapted from Fujioka. 2012)
    As you can see in figure 1 rodents don't have to be genetically disposed to get type II diabetes to benefit from a human equivalent of ~16mg/day. The ever-hungry (=polyphagic) LETO rats, the scientists put on the same 0.4% DHEA diet for 52 weeks has similarly reduced visceral fat depots (epididymal fat - LETO: -50%; OLETF: -33% vs. control), triglycerides and free fatty acids. The improved glucose levels were yet only statistically significant in the otherwise diabetic OLETF rats and the increase in total cholesterol in the LETO group is difficult to judge without at least some additional data on the ratio of "good" HDL to "bad" LDL.

    DHEA vs. Testostosterone - Who is the "King" of Metabolic Hormones

    Luckily, the Fujioka et al. were not satisfied with these results and conducted another experiment. This time with normal rats (Wistar strain) and with a second group which received 0.4% testosterone in their chow.
    Figure 3: Fat weight, triglyceride content of liver and gastrocnemius muscle, body temperature and adipocyte diameter in male wistar rats after 4 weeks on DHEA (0.4%) or testosterone (0.4%) containing chow; data expressed relative to control on standard chow (data adapted from Fujioka. 2012)
    Compared to the poor critters in the control group, who had to content themselves with the "non-anabolic" standard chow, both the rats in the DHEA and the testosterone groups had reduced body fat levels (remember the control rats were "normal", not fat!), reduced triglyceride deposition in both liver and muscle tissue, an increased body temperature and a statistically highly significantly decreased adipocyte size (cf. figure 3) - and believe it or not, all these beneficial effects were more pronounced in the DHEA group.
    Figure 4: DHEA-S (µg/dL), testosterone (ng/dL) and PPAR-γ expression in control, DHEA and testosterone group at the end of the study period (data adapted from Fujioka. 2012)
    In view of the initially mentioned role of dehydroepiandrosterone as a precursor to testosterone (cf. figure 1) and its own yet negligible ability to interact with the androgen receptor (Tan. 1997), it should not surprise you that the purported mechanism behind their beneficial effects on "all things fatty" is identical: a reduced expression of the "triglyceride storage receptor" PPAR-γ, the same receptor the smart business men from the pharmaceutical industry target with their lipid and blood glucose lowering drugs to treat high blood glucose and/or lipid levels for increased obesity, and subsequently another increase in glucose and lipid levels which will "unfortunately" require either more of the old or even better less of the more expensive "next generation" drugs... *clever, right?*

    Similar Effects in Healthy, Young Human Beings are Highly Questionable

    Image 2: Neither Drogba (l) nor Ronaldo (r) are candidates for DHEA supplementation (img VanityFair WC special edition).
    Assuming that you are not already on your way to your local supp store to make sure you get the last bottles of DHEA before the FDA comes up with another horror story based on which this "dangerous supplement" has to be added to the banlist, I want to caution you that a 2010 study from the PA University of Novi Sad (Ostojic. 2010), in Serbia did not find any beneficial effects on body composition in 20 young soccer players who received an oral DHEA supplement (100mg/day) for 4 weeks - and that, despite +40% increases in total testosterone (free testosterone unchanged), +27% increases in estrogen and 197% increases in DHEA. As an active non-sedentary, non-obese, non-metabolically deranged individual, like the 19-22 year old soccer players in the Ostojic study, it is unlikely that your six-pack will show overnight, just by popping grams of DHEA per day.

    Before we do not know why in some trials (rodents and humans) oral DHEA supplements yield phenomenal results (in the study at hand, both the lower dosage, as well as the "chronic" administration in very low doses spread across the day could be decisive factors), while they totally suck in others, the "specificity rule" from the Three Simple Rules of Sensible Supplementation would preclude anyone under the age of 35+ (DHEA levels begin to decline ~30y) from supplementing with DHEA, unless this someone knows (not just guesses!) from bloodwork that his/her DHEA levels are at least borderline low. And don't forget, even then DHEA or rather its downstream metabolites (estrogen in particular) can be similar suppressive on your own natural hormone production as "real gear" or the reputed OTC "pro-hormones" 90% of which are active steroids, anyway.

    It's True: Fructose Makes You Fat - In Fact, It Even Makes You Make Fat! Study Shows, HFCS Beverages Kickstart Endogenous Palmitic Acid Production, Sugary Ones Don't

    In the fashion business, "light or not light" (light=diet as in "Diet Coke" US vs Coke Light Germany) is not really a question to ask.
    Actually I have given up writing about fructose. It appears as if everyone was so bamboozled by the obvious bullsh*t you can read all over the Internet that it's useless to tell them that you are not going to get obese from eating one, two or even ten apples a day! In view of the fact that today's SuppVersity article is about the negative effects of fructose, I am yet quite confident that more than the few enlightened SuppVersity regulars will read it.

    I mean, who would not want to know whether moderate amounts of various sugars (including fructose, sucrose, and glucose) in sugar-sweetened beverages (SSBs) will have differential effects on fatty acid synthesis and degradation in healthy young men?

    Now that I'd probably even have Dr. Lustig attention, let's first take a look at what exactly Michel Hochuli and his colleagues from the University Hospital Zurich did to answer this question.

    The study we are dealing with is a randomized controlled crossover trial with a total of four different dietary interventions. During each of these, subjects were supplied with SSBs containing various sugars in different concentrations in random order during 3 weeks:
    • 40 g fructose per day [medium fructose (MF)]
    • 80 g fructose per day [high fructose (HF)]
    • 80 g glucose per day [high glucose (HG)]
    • 80 g sucrose per day [high sucrose (HS)]
    In the second part of the study, in addition, hyperinsulinemic euglycemic clamps were performed with nine participants after each intervention to assess glucose metabolism and the dynamics of acylcarnitines. What adds to the significance of the data is the fact that the subjects were 34 healthy, normal-weight men - no rats, or type II diabetics and thus a study population of which you can expect that the things that happen to them, after the ingestion of the differently sweetened SSBs could happen to you, as well.
    Figure 1: Relative levels of palmitate to linoleic acid ratio (left) and palmitoylcarnitine (right) after the ingestion of the four test-SSBs; values expressed rel. to baseline (Hochuli. 2014)
    Apropos "things that can happen, when you consume too much SSBs", as you can see in Figure 1 the things that did happen were (a) a significant increase in fatty acid synthesis as it can be seen from the relative abundance of palmitate (16:0) and the molar fatty acid ratio of palmitate to linoleic acid (16:0 to 18:2; Figure 1, left) in the high fructose (HF) and medium fructose groups (MF).

    These changes went hand in hand with increases in fasting palmitoylcarnitine (=palmitic acid that's "carried" by carnitine to the mitochondria for oxidation) that signifies impaired or at least insufficient fatty acid oxidation  and, last but not least, a decreased inhibition of lipolysis by insulin in the clamp condition.

    Now, this is what happens next...

    In a lab setting and after the consumption of an isolated test beverage this obviously isn't much of a problem, but if you think of a real-life SSB-consumption scenario, you will have to agree that people tend to use their fructose sweetened beverage to wash down a greasy piece of pizza ... and, believe it or not, this is where the whole fructose problem begins.
    Learn more about EVOO
    Tip - Use Extra Virgin Olive Oil to minimize hepatic lipid production: The results will obviously still have to be confirmed in a human study, but based on the effects scientists from the University of Salentoobserved in the petri dish it would appear that the inhibition of hepatic fatty acid production, ie. exactly what happened in the study at hand, is yet another feature on the list of beneficial health effects of the polyphenols in extra virgin olive oil (Priore. 2014). In that, hydroxytyrosol (-41%) and oleuropein (−38%) are the most, tyrosol (−17%) the least potent polyphenol.
    It's the combination of sugar (➲ insulin), fructose (➲ palmitic acid production + blockade of the inhibitory effect of insulin on the former) and fat from your delicious piece of pro-obesogenic Americanized and super-sized Italian cuisine (➲ influx of free fatty acids via the portal vein) that will elevate their blood lipids to a degree which impairs their glucose metabolism (Roden. 1996). This, in turn will keep the insulin up, the palmitic acid production running (remember, fructose reduced the ability of insulin to blunt this process) and the free fatty acids (in this case palmitic acid) accumulating.

    Now even that wouldn't be a problem. People could, after all, burn the fat off by fasting. Unfortunately, the combination of insulin resistance and impaired fatty acid oxidation leaves them starving in abundance. What nutrients are their cells supposed to use? Glucose? Doesn't work, because of the insulin resistance. Fats? Can't be oxidized because of the elevated insulin levels. The consequence? Well, if we are talking about the average overweight inhabitant of the Western obesity belt, he will find himself sneaking through the kitchen, opening the fridge and annihilating a family packet of ice-cream only 30 minutes after his 1,500kcal+ "all American" version of the Italian way of making use of leftovers... eventually al this takes us - you won't believe it - back to the simple but undeniable truth that eating processed foods promotes overeating and overeating promotes obesity, hyperlipidemia and diabetes. My gosh! Who would have thought that?
    Figure from " 6x Bananas a Day!? Meta-Analysis: Lower Glucose, Insulin and HbA1c Levels From 'Catalytic' Dose of 36g Fructose" | read more
    Is all this going to happen if you have an apple with a meal? NO! It isn't. And that's exactly, why I hate news like these. It is true: We are not made to handle the sudden influx of several grams of fructose and I am all for avoiding fructose sweetened beverages, fruit juices and other processed foods for this reason. What I am not willing to accept, though, is that the overgeneralizing anti-fructose propaganda-machinery scares people away from eating whole, fresh fruit... and yes(!), when I am talking about "fruit" I am not referring to berries, only.
    References: 
    • Hochuli, et al. "Sugar-Sweetened Beverages With Moderate Amounts of Fructose, but Not Sucrose, Induce Fatty Acid Synthesis in Healthy Young Men: A Randomized Crossover Study."  J Clin Endocrinol Metab (2014). Early Release.
    • Priore, Paola, et al. "Extra virgin olive oil phenols down-regulate lipid synthesis in primary-cultured rat- hepatocytes." The Journal of Nutritional Biochemistry (2014). Accepted Manuscript.
    • Roden, Michael, et al. "Mechanism of free fatty acid-induced insulin resistance in humans." Journal of Clinical Investigation 97.12 (1996): 2859.

    Selenium, the Fertility Mineral!? Organic and Inorganic Selenium Ameliorate Reductions in Testosterone, Testicular Damage and Abnormalities in Sperm Quality in Obese Mice

    Image 1: With enough selenium in vivo, "in vitro" (-fertilization) may not be necessary.
    If you have not heard about it in one of my previous blogposts, you may probably heard about the antioxidant, pro-fertility effects of selenium in the context of Tim Ferris' "selenium experiment" in the 4-Hour-Body. Ferris claimed that by just eating a handful of Brazil nuts (544µg selenium per ounce) every day shot his testosterone levels and libido through the roof. Now, what most people probably overheard, though, was that Ferris was selenium deficient to begin with. Just as every bodybuilder's holy grail, zinc, selenium won't help up your testosterone or fertility if you have already plenty of the potentially toxic trace mineral in your diet. In view of its central role in the antioxidant defense system of our bodies, it is however likely that selenium requirements increase, whenever our bodies are exposed to increasing amounts of oxidative stress.

    When your body fat sets your testicles on fire, selenium may come to a rescue...

    One of the most common causes of increased oxidative stress, these days, are the increased levels in highly oxidizable very-low density cholesterol and triglyceride levels which appear to be an almost inevitable consequence of the "modern" lifestyle (=sitting on the couch and washing down your fast-food, as well as your low-fat "healthy" cereals, pasta and rice with soda). A recent study from scientists from the Institute of Nutritional and Metabolic Disorders of Domestic in China does now show that an adequate amount of dietary or supplemental selenium, which is, as you may gather from the data in table 1, pretty scarce in everything that was not grown or raised on selenium-rich soil, may not be able to reverse all negative side-effects, but could ameliorate them so that reproduction would still be possible (Ibrahim. 2011).

    Table 1: Selenium content of common foods (based on data from the NIS. 2011)
    While the basal diet, which had been enriched with cholesterol, lard and cholic acid, so that it would mimic the obesogenic high carb + high fat diet, researchers love to mislabel HFD (high fat diet), contained only 0.04 µg/g of selenium (without the addition the lard, i.e. for the control group, the se-content was 0.05µg/g), both the inorganic selenium HF-diet and the diet of the animals that received a combination of (organic) selenium (75% selenium-methionine) and probiotics (C. utilis and S. thermophilus strains) contained ~6x the amount of selenium (0.3µg/g chow). For humans this would translate to ~1.2µg/kg and 7µg/kg, respectively (since the scientists did not report food intake and body weight of the animals, I based this calculation on the respective data from other HFD feeding studies with mice).

    Amelioration? Yes! Reversal / complete prevention? No!

    After 75 days on control, high fat, high fat + probiotic only, high fat + inorganic selenium only, and high fat + 90% organic selenium + probiotic diets, the testis of the mice showed histopathological changes even a non-expert as I am one would identify as "probably not healthy" (cf. illustration 1):
    Illustration 1: Compilation of the histopathological examination of murine testes (H & E, ×400; based on Ibrahim. 2011)
    The evident degenerations, decreases in cell population, and irregularities went hand in hand with a pretty profound changes in the quality of sperm (cf. figure 1), which were ameliorated, yet not prevented in the selenium and selenium + probiotic groups.
    Figure 1: Measures of sperm quality - sperm count and motility (left); relative incidence of sperm with abnormal heads and tails (right; data based on Ibrahim. 2011)
    In that, it is noteworthy that the selenium + probiotic (SePro) group had an only 1.5x increased amount of sperm with abnormal tails. The latter can thusly hardly be the reason for the -20% reduction in overall sperm motility.
    Figure 2: Lipid (left axes) and testosterone (right axes) levels in the different groups (left); HDL to total cholesterol ratio and change in testosterone levels compared to control (right; data calculated based on Ibrahim. 2011)
    In view of the fact that the male gonads do not only produce sperm, but also testosterone, it is not surprising that selenium and selenium + probiotic supplementation had a similar ameliorative effect on the diet induced reduction -47% reduction in testosterone (cf. figure 2). The +3% increase in serum testosterone (over the obesogenic diet group) in the probiotic only group, on the other hand, lacked statistical significance.
    Image 2: The importance of selenium for thyroid function, specifically the local conversion of the "inactive" T4 to the "active" T3 is not the only reason why women should try to achieve adequate selenium intakes, as well.
    Selenium for women? While it appears that research has hitherto focused on the role selenium plays in male health, there is a handful of studies which suggest that adequate levels are just as important for women, as they are for men. The results of a Polish study from 2006, for example, stand in line with the, as of late, controversial anti-carcinogenic effect selenium is supposed to have on prostate cancer. According to the authors, the provision of selenium supplements to women with a genetic disposition for breast and ovarian cancer led to a small, but statistical significant reduction in cancer rates (Huzarski. 2006). In 2009, Hermsdorff et al. observed a statistical significant inverse correlation between selenium intake and serum levels of retinol-binding-protein 4, a marker of whole body inflammation and purported contributer to insulin resistance and diabetes (Yang. 2005), in 74 young (~20y) healthy women (Hermsdorff. 2009). In post-menopausal women, Llaneza et al. found a non-negligible association of low-serum selenium levels and higher LDLc and triglyceride levels (Llaneza. 2009). A 2007 study by Negro et al. underlines the particular importance of adequate selenium levels for thyroid health during and immediately after pregnancy (Negro. 2007). And according to a recent review of the role of selenium in reproductive health, low selenium levels in the follicular fluid are a characteristic feature of "unexplained infertility" in women.
    As far as the "potency" of the probiotics is concerned, the study was thusly quite disappointing. That the scientists who were proud to have developed a "Se-enriched probiotic as a new feed additive product for promoting animal industries" do not explicitly state that, is understandable, but won't stop me to repeat my previous recommendation to just add a handful of brazil nuts to your diet on a regular basis to make sure you satisfy your selenium requirements.

    Selenium intoxication from Brazil nuts? I don't think so...

    Image 3: Eating lots of brazil nuts and other selenium rich foods until they achieve what the US consider "toxic" serum and plasma levels does not seem to impair the health of the inhabitants of the regions around the Tapajós River in Brazil - on the contrary, their cardiovascular health is outstanding (Lemire. 2011)
    That this practice is not going to result in selenium toxicity has, by the way, been shown only very recently in one of those studies that analyze traditional diets, which have become so in-vogue, as of late. Lemire et al., who analyzed blood (B-Se) and plasma (P-Se) samples from members of the communities which live along the Tapajós River in Brazil, did not only find that these people had selenium levels well beyond what is "considered toxic" in the US, they also state that their results "support the need to re-assess Se toxicity considering factors such as the chemical form of Se exposure, route of exposure (inhaled versus ingested), co-exposures to toxic elements such as mercury" and hint at "a possible association between high Se status and cardiometabolic health in this study population." (Lemire. 2011) So, men or woman, fertile or infertile, fat or lean... you better make sure you get your share of brazil nuts, today ;-)