Yohimbine & Berberine Protect From Death Due to LPS Intoxication; BCAAs Inhibit Serotonin Metabolism & Cause Anxiety, Tryptophan but not SSRIs Help; Sweet Tea Leaves Are PPAR-G Antagonists & Battle High Lipid + Leptin Levels

Skip the fireworks invest the money in some quality ingredients for a fondue or whatever you like and invest the (often non-negligible) rest of the money in a gym membership for the next year.

Actually my figure of the week is 115,000,000 EUR (~152,000,000 US Dollar), which is the sum my fellow country men and women are about to waste on pyrotechnics this year. And a scientifically unconfirmed addition based on my personal observation: 90% of the worst offenders as far as spending money for fireworks goes are at least overweight. Would be interesting to see, if the use of pyrotechnics on New Years Eve is directly associated with fat mass...

I mean, it could be that they spent so much money on their fireworks that they feel they can only afford the junkfood of which everybody and his/her mama still tend to believe that it would be cheaper than buying fresh products and preparing your own food from those.

Ah, I am ranting. That's usually Carl Lanore's task, so I will better go on with the items I have compiled for the today's last installment of On Short Notice in the year 2012:
 

• Berberine + yohimbine - a synergistic duo to prevent LPS toxicity (Li. 2012) -- With all the recent hoopla about the gut microbiome, I suppose that I don't have to tell you what the acronym LPS stands for, right? Hmm... just to make sure it stands for lipopolysaccharide endotoxins which are produced by gram negative bacteria in your gut and are so "toxic" (in fact they cause profound inflammation) that they can be lethal at higher doses.
  
  

  

  Figure 1: Survival rates (%) after ALB/c mice LPS injection (Li. 2012)

  A group of Chinese scientists have now found that aside from berberine the anti-inflammatory effects of which have been known for quite some time now, yohimbine administered in a daily dose of 2mg/kg (human equivalent 0.16mg/kg) does add to the survival rate of berberine treated rodents (human equivalent 4mg/kg) that were injected intragastrically (so not directly into the blood) with a potentially lethal dosage of 20mg/kg LPS. What's more, taken on its own yohimbine is even more potent than the alkaloid that's found in such plants as Berberis aquifolium, Oregon grape, Berberis vulgaris, Berberis aristata, Hydrastis canadensis (goldenseal), Phellodendron amurense, Coptis chinensis and Tinospora cordifolia.
  
  The mechanism is mediated by the prevention of liver injury, an upregulating of IL-10 production (an anti-inflammatory cytokine), and related anti-inflammatory effects resulting from the suppression of phosphorylation of IkBa, JNK, ERK and IRF3 in macrophages.

• Chronic 9-week high BCAA diet impairs brain tryptophan levels and causes anxiety (Coppola. 2012) -- Scientists from the Duke University took another look at the BCAA-tryptophan depression connection, you may have read about in the context of my "Sugar Addicted or Just Stressed Out?" post from January 3, 2012.
  
  According to the results Anna Coppola and her colleagues are about to publish in the American Journal of Physiology  - Endocrinololgy and Metabolism the provision of a BCAA-enriched diet for 9 weeks leads to both reductions in brain tryptophan levels and an increased turnover of serotonin (5-HT) in rodent brains:
  

  

  Figure 2: Composition of low fat  (LF) and high fat (HF) diets with or without added BCAAs (left); effects on the ratio of tryptophan  to the molar sum of large neutral amino acids with and without supplemental  tryptophan in the drinking water and 5HT turnover in the brain (no supplemental trp, right; Coppola. 2012)

  Both groups (BCAA and non-BCAA) consumed about identical amounts of food as the rodents in the complementary (LF or HF) groups, which confirms that the BCAA content did not modify the taste of the chow or rendered it unpalatable (cannot have been cheap bulk powder then ;-). The reduction in both the availability of tryptophan as well as the increase in serotonin (5-HT) turnover in the brain must in fact have been a consequence of the added BCAAs and are most likely the root of the disrupted transport of tryptophan across the BBB in rats, leading to reduced exploratory behavior of rats in EPM testing, a sign of increased anxiety.

  "Recent studies demonstrating a strong  association between BCAA levels, obesity, and obesity-related metabolic disorders, when linked to the findings reported here, may help to explain the strong association between obesity and behavioral abnormalities, including depression and anxiety." (Coppola. 2012)

  

  As the slight differences between the high an low carb diets show, other nutrients can influence serotonin as well (read more)

  In this regard it is important to point out that these negative side effects were mostly reversible by the provision of 15 mg/100 ml tryptophan in the drinking water of the rodents, but were not alleviated by  the administration of the common serotonine reuptake inhibitor fluoxetine (at 10 mg/kg/day for four weeks).
  
  Bottom line: Isolation is not what you want if what your body has been build for is complex food. And while the single serving of BCAAs you may gulp down during or right before a workout, on the other hand, probably isn't going to harm you. The "I need BCAAs every 30min" approach to gaining muscle mass, may well turn you into a psychotic wrack if you follow it day in and day out for months or years - at least without chronically adding some l-tryptophan to the equation.

• Sweet tea leaves protect against obesity: Once more via PPAR-gamma blockade (Zhou. 2012) -- Actually this is probably not news to anyone out there with a degree in Traditional Chinese medicine. After all, Lithocarpus polystachyus Rehd.(Sweet Tea) is Chinese folkloric medicine that has always been used to treat obesity, diabetes, and hypertension in South China:
  

  "Previous experiments revealed that it contains plentiful bioactive flavonoids and polyphenolic compounds, e.g. phlorizin, trilobatin, 3-hydroxy-phlorizin, etc. These components have extensive pharmacological activities, such as anti-diabetes, memory improvement, anti-aging, inhibition of lipid peroxidation and the growth of human colon cancer cells, and so on." (Zhang. 2012)

  From a "scientific" perspective, however, the efficacy of this herbal medicine as an obesity treatment had still to be elucidated.

  

  Figure 4: Effects of oral gavage of 75 mg, 150 mg and 300 mg/kg of body weight/day of sweet tea extract or placebo (DIO) in conjunction with the 8 weeks on a obesogenic diet (Zhang. 2012)

  In this context it is yet worth mentioning that this study demonstrated for the first time that the aqueous dry leaves extract of Lithocarpus polystachyus Rehd. can potently reduce the worst metabolic side effects of obesity, such as the hypolipidemia, hypoleptinaemia and the degree of insulin resistance (FINS, HOMA-IR, cf. figure 3) what it does not answer, however, is whether the decline in PPAR-gamma is tissue specific, what exactly is behind the profound decline in leptin levels and whether or not lean rodents, let alone humans, who don't consume an obesogenic diet will see anywhere similar benefits.
  
  In other words, this is research in progress, but I suppose something you are going to hear more about at the Supppversity in 2013.

* * * * * *

Apropos hearing or rather reading more, I guess you will realize that you have reached the end of today's installment of On Short Notice which means that you will have to progress to the SuppVersity Facebook Wall if you want a second serving of news on...

• The history of vitamin A as a light sensor and beyond - actually a free full-text I guess those of you who like to "think paleo" may enjoy (read more)
• A paper on "good" and "bad" inflammation, where the author points out that soothing inflammation too much can lead to a reduction in energy expenditure and may therefore not be the king's road to getting rid of the last blubber (read more)
• The food-hitlist of young Americans - Featuring sugar, sugary drinks, sugary bakery, sugary ... as their main energy and carbohydrate sources... (read more)
• Problems with synthroid and generics that have surfaced in a recent study on their efficacy in the treatment of congenital hypothyrodism (read more)

as well as a handful of other news, which are already there or are going to be posted within the next hours. Have a great weekend, everyone! 

References

• Coppola A, Wenner BR, Ilkayeva O, Stevens RD, Maggioni M, Slotkin TA, Levin ED, Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab. 2012 Dec 18.
• Li H, Wang Y, Zhang H, Jia B, Wang D, et al. Yohimbine Enhances Protection of Berberine against LPS-Induced Mouse Lethality through Multiple Mechanisms. PLoS ONE. 2012; 7(12): e52863. 
• Zhou CJ, Huang S, Liu JQ, Qiu SQ, Xie FY, Song HP, Li YS, Hou SZ, Lai XP. Sweet tea leaves extract improves leptin resistance in diet-induced obese rats. J Ethnopharmacol. 2013 Jan 9;145(1):386-92.

SuppVersity Cellulite Special: The Etiology of Cellulite, Genetical and Behavioural Risk Factors? Physical and Supplemental Treatment Strategies & Their Efficacy

This photo of a 37-year old woman some of you may already have seen Facebook testifies to the success of 12 weeks on 333U/cc retinol cream + high intensity laser pulses (Fink. 2006)

I guess, or should I say, I'd hope (?) that some of you have already been waiting eagerly for the write-up of yesterday's Special Installment of the SuppVersity Science Round-Up on the Super Human Network and all the details and obviously the supps, Carl and I could not squeeze into this 1h+ show.

Before you go over this huge (and this is also why it took me so long to post this) serving of the "Seconds", I do yet highly recommend that you download and listen to the podcast, first. You can grap the MP3, right here.  It's free and if you don't like the ads, just skip forward, but please come to terms with the fact that a daily 2h radio has to be financed one way or another!

Let's dig right into this lumpy-bumby skin condition, now!

Despite the fact that they did not identify the underlying reasons for the development of cellulite correctly, Alquier and Paviot (1920), who described cellulite as a non-inflammatory complex cellular dystrophy of the mesenchymal tissue caused by a disorder of water metabolism, which produced saturation of adjacent tissues by interstitial liquids that was brought about by a reaction to traumatic, topical, infectious or glandular stimuli, already had a pretty decent understanding of the structural characteristics of cellulite (cf. Rossi. 2000).

Figure 1: Overview of the four main stages in the development of cellulite. If you take closer look they actually reflect much of what Alquier & Paviot (1920) already suspected: a disorder in water metabolism and a complex tissue dystrophy, which can yet become inflammatory in the late stages

The fact that cellulite is nothing but the highly visible manifestation of the messed up structural grid that holds the skin (epidermis) and the underlying fat layer in place is also important in view of the fact that up to today, way too many people look at cellulite as if it was something like a transient allergic reactions you could get rid of, once you stop eating things high GI carbs or whatever the contemporary dietary villain may be.

Unfortunately, this is not the case so that Nürnber et al. are not totally off, when they write a a 1978 paper about the ..

“[…] the essential normality and inevitability of [cellulite] in women, the supervention of it in hormonally feminized men, and the near futility of treating the non-disease” (Review by Nürnberger. 1978)

It is, and this is something that was completely missing from the previously cited first description of the “disease”, in fact partly Mother Nature who is to blame for the

• abnormal hyperpolymerization of the connective tissue,
• primary alterations in the fatty tissue,
• microcirculatory alterations

with genetic and hormonal factors determining the basic risk profile and inactivity, a messed up diet, obesity, medication etc. being nothing but corroborating factors.

If you will, the X-chromosome and is myriad downstream effects that make a man a men could even be perceived as a genetic factor – a highly protective one that is.

Figure 2: Relative contribution of perpendicular, tilted and parallel septae to the "structural part" of the dermis (left; Querleux. 2002); comparison female vs. male skin (Rosenbaum. 1998), note: the comparison misses the important parallel structures esp. in the male skin, but I guess it still conveys the basic idea

As you can see in figure 2 (right), the mere fact that the upper most parts of the skin, the Epidermis and the Corium is much thicker in men than in women would already conceal major parts of the pumpy structure in a man. In women, on the other hand, the sclerotic macronodules that form during step four in the etiology of cellulite are highly visible through the “thin skin” of a woman.

Female skin with and without cellulite – what are the differences?

Figure 3: Photos of patients with grade II-IV cellulite. Mind the extreme difference between the contracted and uncontrated state in grade II (top vs. bottom; Rossi. 2002)

In addition to the general sex differences, Querleux et al. (2002) observed that women who suffer from cellulite have a 4x higher fat volume in the dermis, than normal women (note: the total amount of fat in men and women is not significantly different).

It goes without saying that this increase in volume would actually require an increase in strength or the number of stabilizing elements in the flexible structure that holds the fat, liquids and other components of the skin in place.In conjunction with the increased interstitial pressure that is a result of the microcirculatory alterations and the defect in collagen synthesis this increase in fat volume is however more than the comparatively unorganized fibrous structure of the female skin can hold.

If you think of the skin as three-dimensional grid that is filled with balls and lacks the structural components that separate the balls in the 1st row from those in the 2nd, 3rd, … etc. row, it should be obvious that any endogenously (interstitial pressure) or exogenously applied pressure (from within = muscle; or from outside = pinching) will push the balls or rather fat cells against the top-layer that's covering the grid (the uppermost parts of the skin) and cause pumps to appear at the surface.

A very similar mechanism is responsible for the appearance of the bumps and the valleys you see through the thin layer that’s covering the underlying fluid and fat-filled part of the dermis in women with cellulite.

Cold, not valsodilated & "lumpy-bumpy"

The presence of the sclerotic perpendicular macronodules in-between the pumps and dentures, only contribute to the nasty appearance and do little to maintain the structural integrity of the tissue that’s actually supposed to be pervaded by numerous small & flexible, randomly but highly crosslinked septae that keep the fat cells in place.

Figure 4: I assume you would not have needed this thermograph to tell me that cellulite ain't exactly hot ;-)

If you look at the thermograph to the right of this paragraph you will also notice that the metabolic activity of the tissue is similarly irregular and (don’t get fooled by the colors) overall much lower in women with cellulite compared to their “healthy” counterparts.

This is both a contributing factor, as well as a results of the decreased micro-circulation in the dermis (see cold green areas) and contributes to the increased water retention in the skin. The latter will increase the pressure and worsen the condition… it is a self-perpetuating viscous cycle, yet one that opens therapeutic doors not to reverse, but at least to halt the progress of the ongoing dystrophic processes.

Estrogen drives cellulite development

And while we are going to deal with the "therapeutic" options in just a minute, let's briefly recapitulate, what I said about the causes / confounding factors during yesterday's show (listen to the podcast for details):

• genes and sex - simply being a women predisposes you to develop cellulite; I know it's not fair, but that's how it is; the same goes for the genes: if your mother and grandmother had it, chances are you will develop it, as well 

• 

  Figure 5: The influence of estrogen on the pathophysiology of cellulite (Rossi. 2002); easy to see, estrogen is the motor of cellulite development

  high estrogen, low progesterone (e.g. puberty, pregnancy, birth control, PMS; partial revision in menopause possible) - estrogen (E2) increases the accumulation of fat, spec. in the areas that are typically affected by cellulite, it renders the fibroblasts more hydrophobic and predisposes to water retention and edema, it increases the permeability and thus the leakage from the cells and promotes the formation of sclerotic tissue (figure 5)
• insulin resistance / diabetes - does not only accelerate fat gain (at least as long as there is still some insulin around), but will also increase the production of glycosaminoglycans which will draw even more water into the tissue (Lotti. 1990)
• obesity (and obesogenic diets) - the faster the fat accumulates and the larger the cells become the greater the demand on the structural components of the dermis and the more likely it will give in and the bumps and start to appear (remember: cellulite is not about having too much body fat, if it is acquired slowly and you are not genetically pre-dispositioned to cellulite you can accumulate quite an amount of fat without developing cellulite)
• hypothyroidism - thyroid hormone increases hyaluronic acid and chondroitin sulphate production, low levels will thus hamper the formation and renewal of the structural parts of the dermis
• stress / corticosteroids - if you are not taking exogenous corticosteroids like prednisone, stress and high corticosteroid levels are actually identical and have similar effects as low thyroid hormone (by the way, stress, even "eu-stress" such as exercise, will also have thyroid hormone levels plummet; learn more)
• lack of exercise - decreased vasodilation, increased weight gain, increased water retention, increased risk of diabetes... I don't have to enumerate all of them, right?
• low potassium, zinc, copper and selenium intake - while the former will help your body regulate the water balance, zinc and copper are important for the formation of the net that keeps the fat in place and have, just as selenium anti-oxidant properties as part of Copper/Zinc Superoxide Dismutase
• smoking and boozing - both will promote the decline in micro-circulation

Now that you know what you cannot change and / or should not do, let's take a look at what you can do as far as physical treatments and supplements / drugs are concerned.

Currently available physical "treatment" options

I highly encourage you to also listen to the podcast, as I am going to keep this short in view of the fact that Carl went through all the items, anyway:

• Iontophoresis: Applies a galvanic current on the surface of the skin to depolarize it and alllow drugs pass through the dermis; it is also used to increase the vasomotor action (vasoconstriction, followed by vasodilation) of which practitioners of this method believe that it may have a positive effect on the compromised metabolism in cellulite skin
• Acoustic wave therapy / ultrasound: Uses high frequency vibrations, which have a thermic and vasodilator effect; is also used as an adjunct to "hammer" drugs into the skin; there is some evidence that it can provoke lipolysis and is thus used during liposculpture procedures. Russe-Wifingseder et al. reported only recently that the use of ultrasaund that acts only on the subcutaneous tissue produced "improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference" (Russe-Wifingseder. 2013) in placebo-controlled trial.
• Thermotherapy: The heat is suppose to increase vasodilation. Experts say that its effectiveness is questionable, as some reports suggest that it did actually aggravated cellulite, maybe in consequent protein denaturation due to the high temperature. 
• Pressotherapy / Massage therapy: Either done by hand or with a pneumatic massager, the intention is to help the skin to release the liquid that's accumulating in the tissue and activate the venous return; it is also used to to treat lymphatic, venous or mixed oedema of the limbs, so that you can expect cosmetic effects of unknown (probably short ;-) duration
• Lymphatic drainage: While it has been used since 1936, the pumping movements using gentle and rhythmic pressures will stimulate the lymphatic flux, but have no proven and above all persistent effect on cellulite
• Laser therapy Low‐level, dual‐beam laser energy, as well as high intensity pulsed laser that are commonly used for "body-contouring" have been reported in several studies to "help" with cellulite. Most of those do yet only report reductions in subcutaneous fat and results like "increased well-being" among the particpants.
• Elecrolipophyresis: Unlike with the #1 on the list the electric current is not applied to the surface of the skin, but rather to several pairs of thin (0.3 mm) long (5–15 cm) needles which are connected to a low frequency current generator. This generates an electromagnetic field which is supposed to modify the interstitial tissue and aid in the circulatory drainage, as well as lipolytic processes. High quality evidence for its usefulness is absent.
• Mesotherapy – This is the well known injections of "solvents" into the adipose tissues. While there are various protocols available most involve phosphatidylcholine. What they all have in common is a highly questionable safety profile and the fact that they yield very ambiguous (mainly negative in peer-reviewed studies) results. Aside from that, dissolving the fat cells within an already corrupted structure is not exactly what I would deem helpful...

Before we go on to the supplements, let me briefly mention that a meta-analysis of cosmetic products marketed for cellulite reduction did show an overall effect, with respect to the thigh circumference (-0.46cm, analysis of 21 original papers; cf. Turati. 2013), while there was no consistent improvement in the nasty look of the skin.

Supplements & drugs for cellulite prevention (and reduction!?)

As mentioned on the show, most of the supplements in the following list are going to help mitigate some of the symptoms, reduce the fat load (literally) on the weak structure of improve the micro-circulation. Aside from retinol and maybe silicon, of which esp. the former appears to have a direct effect on what's going on beneath the surface of the skin, most don't hold much promise for getting rid of the underlying problems.

• 

  Suggested read: "Brown Algae Extract Reduces Body Fat Without Dieting or Exercise. Ecklonia Cava Polyphenols Help Shed Weight Even in The Presence of a Slight Caloric Surplus." | read more...

  Supplements to burn the fat - Methylxanthines (theobromine, theophylline, aminophylline, caffeine), which act through phosphodiesterase inhibition, isoproterenol and adrenaline which are beta-adrenergic agonists, and yohimbine, piperoxan, phentolamine and dihydroergotamine which are alpha-antagonists and will "encourage" the fat cells in this "stubborn fat area" to release more of the fat that's stored in them -- just pick the next best fat-burner from your local supplement story invent something that will have it pass through the stratum corneum and you got your "topical fat burner", of which I can only repeat that it will not get rid of the bumps - if anything it will reduce the severity.
  
  In view of the importance of Co-enzyme A in this process, adequate vitamin B5 and cysteine, which are used for its synthesis and maybe even carnitine, which helps to transport and burn the fat that's actually released from the fat traps on your thighs can enhance the effects of the previously mentioned agents. This is important because free fatty acids may saturate the system, leading to negative feedback of lipolysis (Di Salvo. 1995).

• 

  Suggested read: "How Working Out Changes the Morphology of Your Body Fat" | read more...

  Supplements to increase micro-circulation: Ivy and Indian chestnut extracts, ginkgo biloba and rutin, maybe pycegnol and the pharmacological agent Pentoxifylline, which is a drug commonly sold by Aventis under the brand name Trental it improves microcirculatory perfusion through its effect on haemorrheological factors, including erythrocyte shape, platelet aggregation and plasma fibrinogen concentration. While Pentoxifylline has been used to treat chronic venous insufficiency, stasis ulcers in controlled studies, its efficacy wrt to cellulite has not been proven.

• Antioxidant and immune modulatory supplements: Vitis Vinifera, borage oil, fucus. The latter is a common type of brown algae, that will also enhance the metabolism and reduce the oedema and intestinal inflammation.  

• Asiatic centella extract aka guta cola: The main reason this is a standalone is the frequency with which it is mentioned in the literature. Centella has a vegetable origin and consists of asiaticosideo (40%), madecassic acid (30%) and Asiatic acid (30%), triterpenic derivatives which act in vitro on fibroblasts, stimulating collagen and mucopolysaccharide synthesis.
  
  

  

  Chronic overtraining is no solution and the stress could in fact cause your to your cellulite problems. In addition, it is also the cause of chronic injuries, which persist even, when you finally realized that your own ambition is about to ruin your health (learn more).

  It has been used in the past both topically and systemically, and reported benefits of the oral administration route must probably be ascribed to its beneficial effects on the micro-circulation. According to Hausen (1993) it does neither lead to cutaneous hypersensitivity, nor does it have a toxic effect, when it is ingested.
  
  In a histopathological, double-blind study by Hachem & Borgoin from the late seventies it the administration of 60 mg of dry Asiatic centella extract orally once a day for 90 days brought about a significant reduction in the diameter of adipocytes in both the deltaoid and gluteofemoral regions in the patients who received centella compared to those who received placebo. Interestingly, this reduction was more apparent on the gluteofemoral region and went in hand with a decrease in interadipocyte fibrosis. 
  
  If it were not for the missing placebo control in most of the hitherto published studies, this could actually be a supplement worth trying.

• 

  Suggested read: "Evidence From the Metabolic Ward: 1.6-2.4g/kg Protein Turn Short Term Weight Loss Intervention into a Fat Loss Diet" 2x-3x higher than RDA protein intakes work equally well for men and women, to get and stay lean and lose fat and build / maintain muscle - it does not always take supplements, you see (learn more)?

  Sillicium: While you probably never thought about it, sillicium (organic) is present in celery, peppers, carrots, potatoes, unrefined grains and cereals and beets, all sorts of veggies and fruits, basically everything that growth on earth that has silica in it. The maximum daily recommended dose is 10.5 mg Si/day; and being a structural element of the connective tissue, it is actually not surprising that studies (mostly in vitro or rodent, unfortunately) have demonstrated that silanols (groups of hydrogen and sillicium compounds, similar to the hydrocarbides) provoke the formation of bridges between the hydroxylated amino acids of the elastic fibres and collagen fibres protecting them from non-enzymatic glycolysation and decreasing their degradation rate.
  
  Sillicum also acts as a coenzyme during interstitial matrix macromolecule synthesis. As such it helps reorganize structural glycoproteins and proteoglycans by stimulating polar amino acid grouping and normalizing hydrophilic capacity. Both effects which would obviously be highly desirable for someone suffering from a compromised dermal glycoprotein matrix. 
  
  In view of the fact that it has also been reported to increase microcirculation by modifying venous capillary and lymphatic permeability and has even been shown to stimulates cAMP synthesis as well as triglyceride hydrolysis and thus promote the release of fatty acids from the stored fat cells, it appears to be the perfect nutrient for any woman suffering from cellulite... in view of this fact it is surprising that I could not find a single reputable study proving its effects (note: I did not find one showing the opposite either) 

Actually, the next and last item on the list would be retinol,  but instead of just adding it to the bottom I want to briefly recapitulate that it was a 12-week treatment with weekly applications of intense pulsed light (the equipment used was a Quadra Q4 IPL) with a wavelength of 585-nm and nightly applications of a compounded retinyl-based cream (330 U/cc) that was applied after the ladies had used some aceton to remove the protecive layer of the skin 5x / week (Fink. 2006).

Some more details on the retinol / retinyl palmitat studies

In that it is interesting to note that the scientists picked retinyl palmitate not just for its better safety profile (compared to all-trans-retinoic acid) but also due to its short half-life, its well-known ability to stimulate type I collagen, and its ability to resist air oxidation.

Figure 6: Increase in blood flow in 20 women with moderate cellulite of the thighs treated twice daily on one side for 6 months with a 0.3% stabilized retinol cream while the opposite side was treated with the vehicle (Kligman. 1999)

In a previous study by Kligman et al. (1999) a similar cream containing 0.3% stabilized retinol did lead to marked increases in the blood flow as well as the synthesis of glycosaminoglycans and collagen in a group of 20 women with moderate cellulite on the thighs. Moreover, ...

"[t]here was also a marked reduction in the density of hypoechogenic areas on the retinol sides, from 53% to 18% of black pixels on image analysis. Blood flow measurements were unchanged on the vehicle sides but increased significantly on the retinol sides. Thickness measurements by ultrasound scan were unchanged on the vehicle sides but increased significantly on the retinol sides, from 1.44 to 1.60 mm." (Kligman. 1999)

In their study, Fink et al. observed responses in both the patients who received the combination treatment with the pulsed laser and retinol, as well as in those who received only the laser therapy; and with 60% (9) of their patients having a ≥ 50% improvement in cellulite at 3 months that lasted for 7 of the women up to the 8-months follow up, the overall results are pretty impressive.

Visible not just measurable improvements most likely due to vitamin A

Before and after pictures of the second, 50 year old patient in the vitamin A + pulsed laser study (Fink. 2006)

As I already mentioned on the show, though, the actual reason I picked this study to anchor the show were the two before and after pictures. The first set of which (see top of the page) is the one I already published on the SuppVersity Facebook Wall as a sneak preview, the other one that was taken from a 50 year-old patient (see image to the right) shows similar improvements. Due to the fact that she started out with a higher grade of cellulite, the end-result is yet not as astonishing as the one of the 37 year-old women you "know" already. Both women were in the combined treatment group and in all honesty, I personally consider the retinol the more promising therapeutic agent of the two.

As I told Carl on the show it cannot be excluded that the combination of tissue breakdown from the laser and the "collagen-anabolic" effects of retinol are perfect synergists. Similarly, it is difficult to say, whether the use of aceton only rendered the 2x/day application that was used in the Kligman study unnecessary or whether it was the removal of the stratum corneum that made the treatment so effective.

---

Bottom line: I would hope to see ongoing research in particular with regards to topical based retinol treatments for cellulite. And if respective results are published outside of the bazillion of small scale "studies" that come with the endless (and endlessly hilarious) amount of patents for all sorts of snake oil, I can guarantee that they will be part of the regular SuppVersity news (NO, I am not going to write another special, I am exhausted any you can keep all typos and worse mistakes for yourself ;-)


References:

• Di Salvo RM. Controlling the appearance of cellulite: surveying the cellulite reduction effectiveness of xanthines, silanes, CoA, 1-carnitine and herbal extracts. Cosm Toil 1995; 110: 50–59.
• Fink JS, Mermelstein H, Thomas A, Trow R. Use of intense pulsed light and a retinyl-based cream as a potential treatment for cellulite: a pilot study. J Cosmet Dermatol. 2006 Sep;5(3):254-62.
• Hachem A, Borgoin JY. Étude anatomo – clinique des effets de l’extrait titré de centella asiatica dans la lipodystrophie localisée. La Méd Prat 1979; 12(4): 17–21.
• Hausen BM. Centella asiatica (indian pennywort), an effective therapeutic but a weak Sensitizer. Contact Dermatitis. 1993; 29(4): 175–179. 
• Kligman AM, Pagnoni A, Stoudemayer T. Topical retinol improves cellulite. Journal of Dermatological Treatment. 1999; 10: 119–25
• Lotti T, Ghersetich I, Grappone C, Dini G. Proteoglycans in so-called cellulite. Int J Dermatol. 1990 May;29(4):272-4.
• Querleux B, Cornillon C, Jolivet O, Bittoun J. Anatomy and physiology of subcutaneous adipose tissue by in vivo magnetic resonance imaging and spectroscopy: relationships with sex and presence of cellulite. Skin Res Technol. 2002 May;8(2):118-24.
• Rosenbaum M, Prieto V, Hellmer J, Boschmann M, Krueger J, Leibel RL, Ship AG. An exploratory investigation of the morphology and biochemistry of cellulite. Plast Reconstr Surg. 1998 Jun;101(7):1934-9.
• Rossi AB, Vergnanini AL. Cellulite: a review. J Eur Acad Dermatol Venereol. 2000 Jul;14(4):251-62.
• Russe-Wilflingseder K, Russe E, Vester JC, Haller G, Novak P, Krotz A. Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT(®)) for cellulite treatment. J Cosmet Laser Ther. 2013 Jun;15(3):155-62.
• Turati F, Pelucchi C, Marzatico F, Ferraroni M, Decarli A, Gallus S, La Vecchia C, Galeone C. Efficacy of cosmetic products in cellulite reduction: systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2013 Jun 14.

Higenamine: PES Introduces New "Fat Burner" to the Market. Potent Thermogenic or Dangerous Stimulant?

Image 1: The reformulated PES Alpha T2
contains higenamine, alpha yohimbine
and 3.3-diiodo-l-thyronine

I just received an advertisement email containing some information about the reformulation of PES popular fatburner Alpha T2 (make sure to read "T2 a Fat Burner for Bulking?" for some details on the thyroid stimulating properties of 3.5-diiodo-l-tyronine the metabolically more active "brother" of the 3.3.-diiodo-l-tyronine in PES Alpha T2) mentioning a compound that is advertised as "an all new beta-agonist", that would have been found to be "more effective" than synephrine. While this claim did not impress me at all, I took the time and dug up some information about "higenamine"...

The adrenergic effects of higenamine (Hig. demethylcoclaurine) have been well established since the 1980s (Park. 1984). In fact, the cardioactive benzylisoquinoline alkaloid isolated from Aconiti tuber has long been used as a cardiotonic in traditional Chinese medicine (Zhou. 2003). Its inotropic effects, i.e. its effect on the contractivity of the heart muscle have been studied in various models and range, dependend on dose, from mild stimulation and a minor but significant increase in the effective refractory period (which would be beneficial for patients with bradyarrhythmias, i.e. slow heart beat, to tachycardia, the medical definition of which is an elevated heart rate that remains >100 beats per minute, even in the rested state (Yu. 1985).

In ancient Rome, high doses of Aconit powder were commonly used to poison unwanted enemies, who then died of a 'sudden and unexpected heart attack'. In that, it should be mentioned that the Romans used the whole plant, which, higenamine aside, contains other Aconites which potentially modified it's effects; interestingly, though Kimura et al. (Kimura. 1995) report that aconitine, another compound derived from aconite extract, does the exact opposite, i.e. it induces bradycardia (slow heart) beat and - if administered together (which is how nature meant it to be ;-) - higenamine and aconitine more or less neutralize each other.Enough of TCM and homeopathy... let's get back on the subject at hand.

Will this stuff burn away your love handles or will it literally break your heart? 
 
In order to answer these questions, we would, first of all,need to know how much higenamine actually is in the product - according to the original PES-writeup the reformulated ALPHA T2 contains 40mg higenamine per serving (2 caps).

Q: Is 40mg of higenamine a dangerous dose?  

A: 40mg taken orally appear to be perfectly save.

Details: According to a 1997 rodent-study on the acute toxicity of higenamine by Lo and Chen (Lo. 1997), orally administered even 2.0g/kg higenamine did no harm in the mouse model. For an adult human being this would translate to 160mg/kg or roughly 13g for someone who weighs 80kg. I would nevertheless refrain from consuming all 90 caps one bottle contains, at once - after all, you are no 160pound mouse, are you?

Image 2: Seeds of Aconitum nepellus.
The whole plant contains Aconites,
their concentration is yet particularly
high in the roots of the plant.

If we take into account the results of a 1996 study of the same authors (Lo. 1996), which found that oral bioavailability of higenamine in rabbits, is somewhere between 2.84% and 5.5%, and assume similar bioavailability in humans (rabbits are certainly not the most adequate model for human metabolism), one serving of alpha T2 would effectively deliver no more than 1.14mg-2.2mg of higenamine to your blood stream. This does not sound particularly potent, especially, if you consider the short terminal half-life of 22min (the short half-life does not contradict PES' claim that subjects in their tests felt effects of higenamine for 60 minutes; remember half-life != clearance). It took a dose of 50mg/kg, i.e. 4mg/kg to kill 50% of the mice in the aforementioned study by Lo (Lo. 1997). For our standard human being, weighing 80kg this would equal 320mg or 145x the maximally absorbed amount of higenamine in one serving of Alpha T2 - all that under the hypothetical assumption that we can translate absorption-kinetics observed in a rabbit model to human beings by using a standardized formula that is solely based on the ratio of body weight to surface area of man or rabbit respectively. Before we are trying to speculate about "effective dosages", however, we should initially establish that higenamine is in fact more than a inotopic agent in the arsenal of traditional Chinese medicine; or, in other words, that it does "burn" fat.

A note of caution! If you are taking blood thinning or antiplatelet medications, you should be aware that higenamine itself is a weak anticoagulant (Pyo. 2007; 2008). That being said anybody without respective health conditions should not be too worried and might even benefit from higenamine's anticoagulant effect, of which Yun-Choi et al. (Yun-Choi. 2002) found that it particularly antagonizes epinephrine induced aggregation. With epinephrine being elevated by the beta-adrenergic effects of higenamine, the latter effectively counters its own negative side effects (again, in healthy individuals).

Q: Will taking higenamine help me lose fat?

A: Higenamine is a beta-1 and beta-2 adrenergic agonist, meaning that it will raise your heart rate (beta-1) and help with lipolysis, i.e. the release of triglycerides from your fat cells, but you will still have to "burn" that fat on your own.

Figure 1: Chemical structure
of higenamine (Bai. 2008)

Details: The number of studies that are relevant to our fatloss question is relatively limited and studies from the late 1990s and early 2000s seem to suggest that, despite its stimulating effects on cardiomyocytes (heart muscle cells), higenamine would rather make you tired than spike you up: Shin et al. (Shin. 1999), for example, observed a decrease in tyrosine hydroxylase activity and consequently dopamine content of PC12 cell lines. This downregulation of the dopamine content in cells that, among various other functions, also synthesize, store and secrete catecholamines, would initially suggest the opposite, i.e. a calming and fat-sparing effect - after all, catecholamine induced beta-oxidation is what most of the fat burners out there are all about. More recently, however, Bai et al. (Bai. 2008) identified higenamine as the active, i.e. beta2-adrenergic ingredient, in Radix Aconiti Lateralis Preparata; results, which have since then been confirmed by Tsukiyama et al. (Tsukiyama. 2009) for higenamine isolated from Nandina domestica Thunberg. If you add to that the beta-1 agonistic effects observed in a study by Kimura et al. (Kimura. 1994) you have - just as PES promises - a synephrine analogue.

That being said, the aforementioned study on higenamine's effects on bronchoconstriction by Bai et al. (Bai. 2008) also provides useful information about the potential applicability of Aconti as a "fat burner". The scientists had used an in-vitro cell model, to elucidate the beta2-adrenergic activity of an extract from Aconiti Lateralis Preparata (RALP); and though the latter had not been specifically standardized for its hygenamine content, chromatographic and mass spectrometric analyses revealed that the active ingredient in the extract was in fact the same bioactive plant-alkaloid PES is now introducing to the supplement market. Other than Bai et al., who were interested in the ameliorative effects higenamine, as a beta2-agonists could exhibit on bronchoconstriction, our interest, however, is directed at its use as "fat burner". I assume, most of you will be familiar with the notion that commercially available pharmacological beta2-agonists, above all clenbuterol and its short acting relative albuterol, are widely (ab-)used by bodybuilders and fitness competitors as fat burners and/or ergogenics. Consequently, it stands out of question that higenamine will further liposlysis and may thus facilitate fat loss, the question is yet, to what extend?


Q: How effective is higenamine compared to prescription and over-the-counter beta-2 agonists?

A: It will work, and it is probably more potent than regular (and I guess even methyl-)synephrine. Data on its actual fat loss effects, is yet still not available.

Details: From the Bai study we know that the stimulating effects of higenamine on beta2-adrenoreceptors is dose dependent. We also know that the 40mg of higenamine each serving of the reformulated PES Alpha T2 will activate the beta2-receptors to some extent, what we do not know, yet is whether those 2.2mg that could potentially make it to your fat tissue would be enough to "increase your fat burning" (PES official write-up) significantly.

Figure 2: Dose [in mg/ml] response curves of the activity of albuterol, synephrine and higenamine in CHO-β2-AR-CRE-GFP cells.  Data are expressed as the mean percentage of the maximal response of the individual ligand (data adapted from Bai. 2008 and Bay. 2009).

If we now combine the data Gang Bai and his colleagues from the Nankai University  in Tianjin, China, collected for synephrine (Bay. 2009) and higenamine (Bai. 2008) a (I did that for you in figure 2), it seems that  higenamine is milligram by miligram less potent than regular synephrine, let alone its methylated version, which was used in the original formula and is specifically mentioned in the newsletter. But this does not necessarily mean that its absolute potency as a beta2-agonist falls behind, as well, since the values in figure 2 are expressed as percentage of the maximal activation of the individual ligand.

Since we have no data on lypolisis, we have to turn to the anti-astmatic effects of the compounds in order to judge the magnitude of the effect. At a dosis of 1ng/ml, albuterol was about 4x as potent in the ginea pig asthma model used in Bay. 2009, while higenamine at the same dosage exerted about 3/4 or 75% of the effect of salbutamol in the same model in Bai. 2008. Taken together this data suggest that

• the dose response curve of higenamine inclines more steeply, than the one of synephrine or the presciption drug albuterol, thus finding the right dose could be a little more difficult
• judged by its effects on bronchoconstriction in a ginea pig model, higenamine would be 75% as potent as albuterol and about 3x as potent as regular synephrine (I suppose methyl-synephrine would be somewhat more potent, but suspect that it would still fall short of higenamine)

Note that the above calculations are of hypothetical nature, as they are based on data from two different studies, despite using identical models and have been calculated on the relative magnitude of the bronchorelaxant effects measured in isolted guinea pig tracheal muscle. Definite conclusions with respect to the lipolytic effects of all three beta2-agonists discussed in this write-up are illegitimate. The above statements must thus be regarded as working hypothesis which still warrant validation by future research!

Concluding remarks

Whether and to what extend the 40mg of higenamine from PES reformulated Alpha T2 actually facilitate "fat burning" does yet remain to be seen, because the dosages from in-vitro data derived in an animal model cannot be translated into dosing regimens for human beings, as it would be the case in an in-vivo placebo controlled study, where rodents were actually supplemented with different amounts of higenamine or the full spectrum of ingredients present in PES' reformulated Alpha T2. Until such data is available all I can say is. The new Alpha T2 probably works just as well, if not better than the old one. I'll leave it up to you to decide whether that was "good" or "bad" ;-)

On a side note: You may have noticed that Performance Enhancing Supplement (PES) products in general and Alpha T2 in particular have been on "blow-out sale" for some time. While this may have been in preperation for the new product line to replace the old one, it is also probable that the PES guys are preparing for future legislative regulations. Synephrine has been way up on the list of substances scheduled to be added to the ban list ever since 2005 (cf. Position Statement of the Council for Responsible Nutrition. 2005). Thus, replacing the methyl-synephrine in the original formula may turn out to be a smart move regardless of whether or not the fat loss effects of higenamine are more or less pronounced than those of methyl-synephrine - at least they could still sell their products, when the FDA strikes again.

Yerba Mate, Yohimbine & Yucca - Potent Fat or Unhealthy Money Burners? Tea Catechins Were Yesterday, Saponins Are the Future! GMO Rice "Safe for Human Consumption"?

Are you living in one of the hotspots of diabesity and laziness? Check out the map in the bottom right of my little collage and find out what the CDC data from 2008 can tell you about the regional differences in the US. Which are the top (=healthy & active; violet) and which the flop (=diabetic and sedentary; blue) counties in the US?

58%, that's not just the SuppVersity Figure of the Week it is also statistical testimony to the superiority of lifestyle interventions over drugs. Why? Well it is the rate by which even the CDC admits the diabetes risk of the average US citizen would drop, if he or she lost 5-7% of body weight (I know, I would likewise prefer a body fat number) and increased their "exercise" level to 150min of brisk walking (or more intense exercise) per week.

I know this is nothing new to you, but we all know one of these people who are subservient to "authorities" and like to get their (often oversimplyfied) advice right from the feds. So I suggest you just email the introduction to this article along with the picture on the right to this person... in 99% of the cases it won't help, but who knows, maybe he or she asks you if you can help!?

I am pretty sure that a diligent student of the SuppVersity as you are will have no problem whatsoever with getting him / her set up for a healthier and consequently longer life - right?

The SuppVersity short news for calender week 24 | read all previous installments

A-Z Supplement Review - "Y" as in Yerba Mate, Yohimbine & Yucca (Godfrey. 2013) -- If you have been following the SuppVersity Facebook News for more than just the past 3 weeks, you will have heard about the "A-Z Supplement Review" series, the British Journal of Sports Medicine has been running for years, now. Meanwhile they have arrived at "Y" (for thematic reasons they did not stick to the A-Z sequence with every article in the past, though); and in this issue S.J. Stear, RJ Godfrey and MW Laupheimer have compiled mini-reviews on the usefulness of yerba mate, yohimbine and yucca, respectively.

"In sport, yohimbine is perceived to reduce body fat and mobilise lipid, as well as to enhance endurance. Accordingly, it is often used in bodybuilding and other aesthetic sports, and in sports where there is a significant aerobic component. However, despite these claims, research findings actually refute any ergogenic benefit for sport (Ostojic. 2006; Herda. 2008) In addition, [...] adverse effects have been established."

I know, I know the highly questionable fat loss in the Ostjic study would speak a different language, but it has never been replicated in another trial. In fact, a previous study in 43 men using dosages of 41(!) mg/day did not observe any effects on body composition (Sax. 1991). And a more recent review by Climolai et al. states "There is no conclusive evidence for this drug to be of benefit in bodybuilding, exercise tolerance, physical performance, or desirable alterations of body mass." (Climolai. 2011)

Did you know that mate has about the same amount of caffeine than coffee? 150ml = 75mg; according to Stear for coffee that's what you get from ~250ml with most roasts... I have my doubts about that, and would rather believe that the content is about identical (usually the caffeine content of coffee is said to be 55-85mg/100ml). Still, being rich in chlorogenic acid and caffeic acid mate could probably serve as a replacement for regular coffee, for those who don't like the taste of coffee.

Don't despair, we do still have two other supplements in the review, so let's see... what about yerba maté? Being made of dried leaves of the Ilex paraguariensis tree this tea has been widely consumed in South America for centuries. Maté tee contains numerous active phytochemicals of which chlorogenic acid and the xantines caffeine and obromine are the most abundant ones. It does yet also contain alkaloids (caffeic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid), flavonoids (quercetin, kaempferol and rutin), amino acids, minerals (phosphorus, iron and calcium) and vitamins (C, B₁ and B₂).

That certainly sounds promising, unfortunately the evidence on its ergogenic effects is not conclusive and while it has been shown to be hypocholesterolaemic, hepatoprotective, a central nervous system stimulant, diuretic, antioxidant, of benefit to the cardiovascular system, and associated with both the prevention and increased risk of some types of cancers (Heck. 2007), Stear is right that the high amount of active ingredients will also increase the risk of unwanted side effects - or as my friend Carl likes to say: "The good thins is that yerba maté works, the bad thing, on the other hand, is that it works [and thus has effects and side effects]" ;-)

A major problem about yucca, the last item on the list is probably that there is no such thing as a specific yucca plant. The term "yucca" refers to a whole series of 40–50 medicinally potent plant species that generally thrive in arid parts of southwestern USA and Mexico. As Laupheimer points out:

While yucca is actually one of the few supplements I have not yet covered on the SuppVersity, you may want to read up on the leptin sensitizing effects of yerba maté in a previous article (read more)

"The yucca extract is widely used as an animal feed additive to increase growth rate, improve feed conversion efficiency and to ease joint pains in horses and dogs. Yucca has also been shown to have antioxidant, anticancer, antidiabetic, antimicrobial and hypocholesterolaemic properties. [...] Yucca saponins are precursors to cortisone. Yuccaols and resveratrol, which are mainly found in the yucca bark, are known to have a variety of actions, including inhibitors of the nuclear transcription factor κB (NFκB) and thus anti-inflammatory, antioxidant and free radical scavengers In addition, resveratrol has been shown to have an influence on muscle fibres, strength and possible ergogenic effects."

As usual there is yet insufficient evidence to formulate scientifically warranted dose recommendations and  evidence of ergogenic benefit in sports performance is missing.

---

Bottom line: From the three "Y"s in the latest installment of the Supplement Review, maté is probably the one with the best scientific support for it's ergogenic effects. If nothing else, the high caffeine content alone would classify the South American tea as a performance booster. The most promising agent may in fact be the yucca extracts, but it is certainly premature to recommend taking respective supplements.

And what about yohimbine? It's if anything useful during a fast on a very hard diet + exercise regimen to further the release of fatty acids from the "stubborn fat areas", where alpha- instead of beta receptors are the main mediators of FFA release. If you want still want to try it, make sure you use the clean HCL version - with the extracts you have no idea what it is you are actually getting.

~ ~ ~ ~ ~ ~

Catechins are so yesterday, tea saponins are the future (Yu. 2013) - You will be aware that we have long ascribed the beneficial health effects of green, black, white and other teas to the catechins (e.g. EGCG, ECG, etc.) they contain. A recent study from the University of Wollongong in China does now suggest that we may have been missing an important part of the natural (not proprietary ;-) anti-obesity blend in the Camellia sinensis (that's the scientific name of the "tea plant") brews we have been making for centuries.

Figure 1: The restored leptin sensitivity is probably the reason why the rodents did not overeat and thus returned to and maintained a relatively normal body weight (Yu. 2013)

Tea saponins! This is a term by which the researchers refer to a whole class of triterpenes that are present in different concentrations in various types of tea. These molecules are natural antagonist of the NF-kB signaling and have anti-inflammatory potential.

No wonder Yu et al. suspected that they could be used to treat diet induced obesity. To validate this hypothesis they fed a group of mice a high fat diet for 40days. At the end of that period all rats were obese, inflamed, insulin and leptin resistant. Another 21 days and thus 21x 10mg servings of 96% pure tea saponins from Aladdin Chemistry Co. Ltd, China, later 50% of the mice were not exactly lean, but had achieved a new, lower maintenance weight (see figure 1).

Based on the data they have, the scientists concluded that these benefits were brought about by the rostoatin of brain leptin sensitivity that went hand in hand in with increases in insulin sensitivity... hold on insulin sensitivity? Yeah that's right and you are not mistaken, both, leptin and insulin were in the news today, before. In the face book news, to be precise: "There is no such thing as 'leptin resistance'" (read more)

---

Wrong! Fat does not ameliorate, but potentiate the insulin response to carbs (learn more)

Bottom line: If we take the decreased inflammation, the ameliorated weight gain, the increased expression of POMC neurons low levels of which which have previously implicated in human weight gain (learn more), and the other beneficial effects Yan et al. observed in the study hand  and combine that with the previously mentioned hypothesis by Nazarians-Armavil, Menchella and Belsha.

The message is thus quite clear: Tea saponins are a potent insulin resensitizer. Once they have done their job, and your body is able to "hear" the most important signal in the metabolic concert again, the rest will fall into place.

~ ~ ~ ~ ~ ~

GMO rice safe for rat consumption Chinese scientists say (Yuan. 2013) - While I am not sure whether there are any hidden ties of the Genetically Modified Organisms Breeding Major Projects of P.R. China grant to the usually suspects from the West, it appears unlikely that Monsanto & Co were involved in the latest study from the Laboratory of Food Safety at the College of Food Science and Nutritional Engineering of the China Agricultural University in Beijing.

Figure 2: The short-term safety is accompanied by an unexpected weight gain in the male rodents that starts at weight 6, and does (lucky for the sponsors) not reach significance before the study was terminated (Yuan. 2013)

Now, it still goes without saying that the Chinese government will have a vested interest in developing a GMO variant of their bread-and-butter food item that produces the gram-positive spore-Bt toxin they would otherwise have to apply to the crop to protect it on it's own. It is therefore good news (for the Chinese) that none of the dozen parameters the scientists monitored (microflora composition, intestinal permeability, epithelial structure, fecal enzymes, bacterial activity, intestinal immunity + all the standard measures you can think of) did not show any effect of the chronic ingestion of the BT/GMO rice.

What is yet hidden in the supplemental material that came with the study is the weight development of the rodents. In the course of the hilariously short study (I suspect the researchers wanted to make sure they would not observe anything similar to the tumors that brought their French colleagues right into the headlines of the mainstream media outlets; cf. gofl-ball sized tumors due to GMO corn), there was an unexpected and though not yet statistically significant difference in the weight development of the male rodents in the GMO rice group, who began gaining weight at an increased rate 12 weeks into the study.

---

Bottom line: If you conduct a rodents study and don't chose a study duration that would allow for long-term effects to surface (it should be obvious that this does not apply to a 90-day study period), you can hardly argue that the product you are testing is "safe" for human consumption - well unless we are talking about short-term consumption.

Aside from being able to assess the effects the GMO rice has on cancer rates (remember cancer takes time to grow) and all-cause mortality, even the sudden disconnect in body weight development in the male animals after 6 weeks would - at least in my humble opinion - warrant further studies, before you can unleash the genetically modified beast on your people, but I guess the Chinese official think "wtf. we have enough workers for our economy to flourish and if they die early, we don't have to pay their pensions"...

That's it for this week,...

... and the one thing that's still left to do is to wish all of you an active and happy weekend. Ah..., right. For those of you who still have some time to kill before whatever activity will start, here are a couple of SuppVersity Facebook News, you may want to read before finally starting into the "active part" of the weekend:

• 

  Many of the underlying causes of "self-inflicted hypthyrodism" will also hamper your performance in the gym and elsewhere. Now, what's particularly nasty, is the fact that for many gymrats performance or "looking" good naked, respectively the strive for any or both of the two are the (over-)motivational roots of the misery (read more)

  A new whey (all puns intended) to treat cystic fibrosis (CF) - Researchers from the Macdonald Campus of McGill University in Canada have found that pressurized whey protein hydrolysate could be a cheap and effective way to ameliorate cystic fibrosis | read more
• Are only phospholipid pound "omega 3s" good omega 3s? Paper puts another emphasis on the superiority of phospholipid bound DHA & EPA (as in food) over triglyceride bound DHA & EPA (as in fish oil caps), when it comes to the touted health benefits of high(er) omega 3 intakes | read more
• "No extra-shoes necessary" that's the message a recent study that investigated whether people who overpronate would need special (expensive) running equipment | read more
• Oldie but goldie: If reverse T3 is protein sparing at all, it has no direct effect and works only by blocking the receptor | read more

Alright, now you are good to go. So log out and come back in ~12h for more Facebook news and ~24h for the Sunday's SuppVersity article, of which I believe it will revolve around fasting - alternate day fasting and macronutrient composition... hah, now I got you hooked, right?

References:

• Cimolai N, Cimolai T. Yohimbine use for physical enhancement and its potential toxicity. J Diet Suppl. 2011 Dec;8(4):346-54.
• Godfrey RJ, Laupheimer MW, Stear SJ, Burke LM, Castell LM. A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance: Part 45. Br J Sports Med. 2013 Jul;47(10):659-60.
• Heck CI, de Mejia EG. Yerba Mate Tea (Ilex paraguariensis): a comprehensive review on chemistry, health implications, and technological considerations. J Food Sci. 2007 Nov;72(9):R138-51. Review. 
• Herda TJ, Ryan ED, Stout JR, Cramer JT. Effects of a supplement designed to increase ATP levels on muscle strength, power output, and endurance. J Int Soc Sports Nutr. 2008 Jan 29;5:3.
• Ostojic SM. Yohimbine: the effects on body composition and exercise performance in soccer players. Res Sports Med 2006;14:289–99.
• Nazarians-Armavil A, Menchella JA, Belsham DD. Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. Mol Endocrinol. 2013 Jun;27(6):990-1003. 
• Sax L. Yohimbine does not affect fat distribution in men. Int J Obes. 1991 Sep;15(9):561-5.
• Yu Y, Wu Y, Szabo A, Wu Z, Wang H, Li D, Huang XF. Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice. Endocrinology. 2013 Jun 10. [Epub ahead of print]
• Yuan Y, Xu W, He X, Liu H, Cao S, Qi X, Huang K, Luo Y. Effects of genetically modified T2A-1 rice on the GI health of rats after 90-day supplement. Sci Rep. 2013 Jun 11;3:1962.
   

True or False: Yohimbine Sheds "Stubborn" Ab & Thigh Fat in Women (+Men)? Plus: Does is the Way You Administer the Alpha-2 Antagonist the Main Determinant of Fat Loss?

If all the training and dieting in the world won't let the thigh-fat (women) and abdominal blubber (men) melt, it's about time to buy some yohimbine...true?

It's part of the bro-scientific basics: If you use yohimbine, it's effects on the alpha-receptors will help you to preferentially burn "stubborn" body fat. This is supposed to be true for women, in particular. Unlike men, who are carrying most of their body fat in the abdominal region, the ladies are usually battling their "healthy", but ugly fat stores in the thigh region.

Now this wouldn't be so much of a problem, if those nasty fat pads didn't persist until other, certainly more aesthetic "fat pads" in the upper body shriveled away. So, if yohimbine, which is usually combined with a whopping dose of caffeine, would work the way the bros say it does, this would certainly be an awesome thing for both ladies and gents ;-)

You can find more True or False articles at the SuppVersity

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

You Can Drum Yourself Lean

You Can Wash Pesticides Away

Milk = Poisonous Hormone Cocktail

Studies that investigate the effects of yohimbine on fat loss are scarce and the number of studies comparing upper-body vs. lower-body fat loss is almost non-existent.

The phrase "almost non-existent", does yet imply that there are a handful of studies, which investigated both the amount of fat the subjects lost and the body part(s) where this fat came from. Unfortunately, the over-cited soccer-player study by Sergej M. Ostojic (2006).

Figure 1: Body fat (%) before and after the 21-day 20mg/day yohimbine intervention in (20 top-level male soccer players; note: there were no statistically significant changes muscle mass between trials (Ostejic. 2006)

In said study the administration of 20mg/day of yohimbine HCL was associated with a reduction in body-fat percentage (see Figure 1). Notwithstanding the potentiating effects of α-adrenergic blockade by yohimbine on lipolysis and exercise energy expenditure (Zahorska-Markiewicz. 1986), these effects are so pronounced that I have my doubts about the validity of the skinfold measures, of which a recent study shows that they are only accurate, when they are performed by "an experienced skinfold assessor" (Shim. 2014).

The pharmacology of yohimbine (Tam. 2001): If you want to use it appropriately, you will obviously have to know something about its bioavailability (20-30%, orally), its half-life (15-50 min) and the time it takes for the serum levels to achive maximal concentrations (20-40 min). Furthermore you should keep in mind that the ingestion of food will blunt all the neat "fat burning effects" of yohimbine. To make the most of your yohimbine, you should thus use it fasted and refrain from eating for at least 2h after the ingestion.

And even if the data from the Ostejic study was accurate, the absence of body-part specific data makes it impossible to judge if the guys lost abdominal, tigh or back fat.

Figure 2: Effect of alpha-2 agonist stimu- lation on glycerol levels in dialysate from human subcu- taneous adipose tissue (Galitzky. 1993) - Note: As an apha-2 antagonist, yohimbine, unlike clonidine, an alpha-2 agonist, will increase not decrease the release of glycerol from abdominal adipose tissue!

Theoretically speaking the notion to use alpha-2 adrenoreceptor modulators like yohimbine to selectively burn tigh or but fat is sound. As the data from a 1993 study by Galitzky et al. clearly shows, the increased expression of alpha-2 receptors in the abdominal fat has direct consequences on the amount of lipid that is released, when corresponding fat cells are exposed to alpha-2 agonists (see Figure 2). Administering an antagonist, on the other hand, will inhibit the blockade and thus result in an increased release of fat from "stubborn" fat depots in the abdominal area.

Theory and practice are yet oftentimes two very different animals, which is probably why it is very difficult to find data from controlled trials to confirm that orally administered yohimbine will lead to a local increase in fat loss.

Yohimbine is considerably safe, but still not harmless: When it's used in reasonable amounts (0.1mg/lbs body weight in the non-obese), the cardiovascular and nervous system side effects of yohimbine are well-tolerable. Upon dose-escalation and in individuals with a high susceptibility to alpha-adrenergic stimulation it can yet have pretty nasty side effects. The latter is particularly true, when it's used as an adjunct to the classic ephedrine + caffeine stack, where it leads to significant increases in cardiac work during dynamic exercise (Waluga. 1998). This is a pitty, because the lipid-mobilizing action of yohimbine is reinforced during physical exercise (Galitzky. 1998)

Obviously, I am not the first person to realize that there is a lack of data on the long(er) term effect of yohimbine supplements on overall, let alone regional fat loss in men and women. In an extensive review of the literature that appeared in the peer-reviewed scientific journal Medical Hypotheses in 2002 McCarthy voices similar complaints, when he points out that yohimbine will elevate the serum levels of FFAs as well as those of glycerol and norepinephrine (but not epniphrine), when it is administered as a single oral dose of 0.2 mg/kg during a fast. He goes on to point out that ...

"this dose of yohimbine likewise markedly potentiates exercise-induced FFA and norepinephrine release, during and following exercise. The impact of yohimbine on post-exercise FFAs is  particularly marked, 30 minutes after a 30-minute aerobic exercise, FFA levels were virtually doubled in subjects who had ingested yohimbine prior to the exercise (Galitzky. 1988)."

The pro-lipolytic effects McCarthy describes are presumably triggered by (a) the central activation of sympathetic tone (the `flip-side' of the anti-sympathetic activity of the alpha-2 agonist clonidine; see Figure 2) (b) a direct interference with the feedback mechanism whereby pre-synaptic alpha-2 adrenoreceptors suppress further release of norepinephrine from sympathetic neurons and (c) the blockade of the adipocyte alpha-2 adrenoreceptors that suppress lipolysis (most notably in the gynoid depots of women; cf .Lafontan. 1992).

Transdermal application as a viable alternative? About five to ten years ago "fat loss" gels and cremes were all the rage in the fitness community. These days, however, many topicals carve out a miserable existence in the "clearance" section of the average supplement store. Wrongfully, if you put some faith into the results Frank L. Greenway and George A. Bray from the UCLA School of Medicine, and the University of Southern California present in a paper from the late 1980s (Greenway. 1987). The results of the corresponding experiments do yet only confirm that it is likely that yohimbine makes an excellent adjunct to a cream that's based on the combination of a beta stimulator with a phosphodiesterase inhibitor (forskolin and aminophylline + yohimbine) - a combination of which Greenway & Bray found that it reduces the thigh circumference by an additonal 2.03 ± 1.36 cm compared to diet alone. The effects of yohimine, alone (dosed at 10mmol/L), which were tested in a seperate experiment, were albeit hardly significant.

Sounds pretty logical, right? Yohimbine unblocks the blocked release of fatty acids in the "stubborn fat" areas and allows you to shed the abdominal (men) and thigh (women) fat you've been battling for years... well, there is just one problem: There is not a single credible peer-reviewed study that would support the notion that orally administered yohimbine will do just that.

On the contrary, if you do a database search, you will even find studies which found no effects of yohimbine on total and / or regional body fat, at all. A study in Lancaster General Hospital, for example reports no difference in body fat and fat distribution as measured both by waist-to-hip ratio and by CT scan (Sax. 1991)  - and that in spite of the fact that the subjects in the Sax study consumed an incremental amount of yohimbine (16–43 mg), exercised thrice a week and consumed an energy restricted diet (1,800kcal / day) for 6 months!

In view of the results of the Sax study and a hand full of other studies with similar results (e.g. Berlin. 1985), in which yohimbine produced only side (impaired sleep, nervousness, headache, arthralgia; Sax. 1991) but not the desired fat loss effects, the notion that yohimbine would do anything in terms of fat loss and / or redistribution must be considered to be debunked - at least for the male part of the population.

Particulalry useful over- weight female slow weight losers? An examination of the metabolic properties of the adipocytes obtained from slow and fast weight losers by Hellstrom et al. (1997) revealed that the fat cells of the slow weight losers were ten-fold more sensitive to the anti-lipolytic effects of alpha-2 agonists than those of rapid weight losers. This finding is clearly consistent with the possibility that increased expression and/or activity of adipocyte alpha-2 adrenoreceptors is a key reason for the relative resistance to fat loss noted in many obese women, for whom the use of yohimbine may thus be a particularly promising weight loss strategy.

Bottom line: Based on the contemporary evidence, it's difficult to say whether yohimbine will help you burn fat "locally". Theoretically it's effects on the alpha-receptor laden fat stores in the female lower body should facilitate local fat loss. Practically speaking, most people will probably compromise their own results by not following McCarthy's advice to "administer a moderate dose of yohimbine (perhaps 5±10 mg) once per day, in the morning just prior to exercise" (McCarthy. 2002) and fast for at least 4 hours afterwards.

In view of the fact that it's unlikely to hamper weight loss, it may thus be worth a try to use 200mg of caffeine and 10mg of yohimbine HCL for a month before each of your morning cardio sessions. Without the exercise and the subsequent fast, however, you will probably be wasting time and money - even if you are an overweight female slow weight loser or older individual in whom the classic beta-agonists lose their efficacy while the anti-lipolytic response to alpha-2 agonists and thus the potential beneficial effects of yohimbine are fully preserved (Lönnqvist. 1990)

References:

• Berlin, I., et al. "[Lack of efficacy of yohimbine in the treatment of obesity]." Journal de pharmacologie 17.3 (1985): 343-347.
• Galitzky, J., et al. "α2‐Antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect of oral yohimbine in healthy male volunteers." European journal of clinical investigation 18.6 (1988): 587-594. 
• Galitzky, J., et al. "Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue." Journal of Clinical Investigation 91.5 (1993): 1997. 
• Lafontan, Max, et al. "Alpha-2 adrenoceptors in lipolysis: alpha 2 antagonists and lipid-mobilizing strategies." The American journal of clinical nutrition 55.1 (1992): 219S-227S. 
• Lönnqvist, F., et al. "Catecholamine-induced lipolysis in adipose tissue of the elderly." Journal of Clinical Investigation 85.5 (1990): 1614.
• Ostojic, Sergej M. "Yohimbine: the effects on body composition and exercise performance in soccer players." Research in Sports Medicine 14.4 (2006): 289-299.
• Sax, L. "Yohimbine does not affect fat distribution in men." International journal of obesity 15.9 (1991): 561-565. 
• Shim, Andrew, et al. "Assessing Various Body Composition Measurements as An Appropriate Tool for Estimating Body Fat in National Collegiate Athletic Association Division I Female Collegiate Athletes." American Journal of Sports Science and Medicine 2.1 (2014): 1-5. 
• Tam, S. William, Manuel Worcel, and Michael Wyllie. "Yohimbine: a clinical review." Pharmacology & therapeutics 91.3 (2001): 215-243.
• Waluga, Marek, et al. "Cardiovascular effects of ephedrine, caffeine and yohimbine measured by thoracic electrical bioimpedance in obese women." Clinical Physiology 18.1 (1998): 69-76. 
• Zahorska-Markiewicz, B., C. Kucio, and D. Piskorska. "Adrenergic control of lipolysis and metabolic responses in obesity." Hormone and metabolic research 18.10 (1986): 693-697.