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.

Six Cups Of Coffee (900mg/day): Three Too Much or Just About Right to Speed Up Lipolysis & Fatty Acid Oxidation?

The human equivalent of almost 900mg caffeine per day used in the study at hand did some good, but it also did some harm - read more and decide for yourselves which one you'd consider more important.

It amazes me time and again. Coffee and caffeine in particular are unquestionably the best-researched "supplements", nutraceuticals, drugs, or whatever you want to call. Yet, nevertheless, the number of interesting studies is increasing day by day. Let's see... 2.3+ studies related to caffeine in one way or another were published per day in 2012 and as of now it looks, as if we would easily top that this year. But enough of those stats. Let's get to one of the latest of the 515 hits for this year and take a look at what Eun-Young Choi and Yun-Ok Cho from the Department of Food and Nutrition at the  Duksung Women's University in Seoul has to bring to the table.

What? Another rodent study?

Yeah, I hear you. I would also prefer if the Korean scientists had taken human subjects fed them a standardized diet and gave them water with 0.12 g freeze-dried instant coffee/100 g body weight for 4 weeks, but I hardly doubt the Ethics Committee would have approved of the guys and girls being sacrificed and their organs being harvested at the end of the 4-week period to check, whether or not the combination of coffee supplementation, which was combined with a chronic exercise (treadmills for 30 minutes; 5 d per week, 15° incline, 0.5-0.8 km/h; the dosage was chosen to approximate maximal quantity reportedly consumed by physically active individuals, i.e. 895 mg of caffeine/60 kg/d) regimen in 50% of the animals exerted independent (c) or combined effects on the organ weight liver as well as the liver and muscle glycogen content or not (data see figure 1).

 Figure 1: Effect of acute exercise, training (=chronic exercise) and chronic caffeine intake on heart, spleen, liver and visceral fat weight  (left), serum glucose and liver and muscle glycogen (Choi. 2013)

Luckily, it is quite unlikely that the overall effect of training + supplementation, of which you can see in figure 1 that only the former or a combination of both did have significant effects on heart weight, visceral fat and liver glycogen content, would have been fundamentally different, if the study had been conducted on human beings.

"The heart weights were significantly higher in the two training groups (TC, TCF) than the two control groups (NTC, NTCF). The combined visceral fat masses were significantly lower in the two training groups (TC, TCF) than the two non-training groups (NTC, NTCF). No significant effects on spleen and liver weights were being observed." (Choi. 2013)

As far as the caffeine or rather "simulated coffee consumption" is concerned, however, only the change in liver glycogen was affected. Particularly,

• the chronically trained, caffeine guzzling rodents exhibited the higher liver glycogen levels (measured before acute exercise), while 
• the animals in the non-trained caffeine guzzling group who had been sacrificed immediately after a final short bout of exercise at the end of the fourth week had the lowest liver glycogen concentration 

Overall, "coffee intake decreased liver glycogen levels in the T group, but no significant differences were observed" (Choi. 2013) in the non-trained animals. The muscle glycogen levels, on the other hand, were not significantly effected by caffeine intake. The 4 weeks of training, on the other hand induced a statistically significant increase in muscle glycogen (after rest) in the trained vs. untrained group of rodents - an observation that has previously been made in human studies, where chronic exercise in the presence of adequate carbohydrate nutrition will progressively increase the size of the muscular glycogen stores (supercompensation principle).

Similar to the increase in muscle glycogen during the 4-week training regimen, the observation that all training and/or supplementation regimen increased the amount of free fatty acids (FFA). What may come as a non-necessarily positive surprise to everyone with elevated baseline FFA levels, though is that addition of caffeine to the equation effectively doubled the training induced increase in resting FFA levels in the caffeine + training group. The beneficial effect of training on liver and muscle triglyceride levels, on the other hand, was not significantly impaired. And what many of you will probably deem about as important: caffeine did not affect the muscle, liver and plasma protein levels.

So what did the study find then?

If we summarize the above, the main findings of the study at hand were not exactly revolutionary, but there were some. Worth mentioning are ...

1. 

   Suggested read: "Coffee - The Good, The Bad & The Interesting: 2-4 Cups of Coffee for Adiponectin. Roasted Filtered Coffee & High LDL!? The Optimal Caffeine / Taurine Ratios & the Buzz ". Learn more about the good and bad sides of coffee / caffeine and find out whether taking taurine may buffer the side effects w/out compromising the benefits of exuberant amounts of caffeine, as they have been used in the study at hand? Or will it make things even worse? It certainly won't hurt the liver that's for sure (read more).

   an increase in free fatty acid release and usage during workouts (already well-established), which resulted in slightly more significant reductions in visceral fat, when training and caffeine were combined, 
2. a highly desirable and significant reduction in liver fat in the trained rodents "on coffee" (all day), and a greater reduction in liver trigs in the animals that were only exercised once
3. a more pronounced "in-and-out" of muscle triglycerides in the trained coffee guzzlers with significantly higher levels of muscle triglycerides before and significantly lower muscle triglyceride levels after a workout (probably a mechanism which contributes to the endurance boosting effects of caffeine; Sherman. 1995)
4. a (surprising?) null-result for changes in plasma glucose that should put the "caffeine will give everyone diabetes" fears at rest; you should however remember that the FFA increase can generally become problematic overtime, if there is a concommittant influx of fatty acids from the diet and no fasting / exercise to keep the overall levels in check
5. a significant reduction in glyocogen storage in the liver after a workout, of which I am yet not sure if this was not a result of a reduction in hepatic glycogen depletion due to the increase in fatty acid oxidation (the scientists do state that the training + caffeine group had the highest glycogen levels in the rested state)
6. no effects on muscle glycogen or protein, and no effect on protein levels in other tissues due to caffeine
7. a significant reduction in hematocrit in the coffee group the scientists ascribe to the hampered absorption of dietary iron

The overall image that emerges is thus rather a negative one - allegedly the increased visceral fat loss in nice, but it is not statistically significant compared to training alone (low iron = low oxygen carrying capacity = low performance; plus: low iron also hampers fatty acid oxidation so that even this benefit may be lost over time.

Another thing Alex Leaf, without even knowing it, reminded me about are the night-sweats and the 4AM wake up call, I know only too well from my own experience with copious amounts of stimulants. They could in fact be brought about by the inability to regenerate liver glycogen fast enough and the subsequent failure of providing your body with glucose from the liver while you sleep. This in turn will have you go hypoglycemic overnight. Your body reacts by spilling out stress hormones that will heat and wake you up...

---

Those three cups are probably as good as it gets, they protect your heart and can ward off cancer (learn more).

Bottom line: In view of the observed downsides, of which I would argue that (5) may actually be the worst for a healthy athlete, the study at hand appears to underline what I have told you before: the consumption of the equivalent of 800-900mg of caffeine per day is clearly counter-indicated even if you don't consume it all at once, and alongside its natural co-factors in coffee (learn more about coffee).

Stick to max. 400mg per day and you are more likely to get the benefits without the sides, about which you have read only a couple of days ago in a SuppVersity article discussing the acute ergogenic effects and accompanying side effects of different doses of caffeine (read more).

References:

• Sherman WM, Leenders N. Fat loading: the next magic bullet? Int J Sport Nutr. 1995 Jun;5 Suppl:S1-12. Review.

19x Increase in Growth Hormone 60min After Ingestion of 1g of Glycerophosphocholine (GPC) in Young Male Subjects

Image 1: Don't worry one thing is sure - GPC won't give you a gut like that ;-)

A couple of days ago, I have written about the exorbitant choline consumption of some of bodybuilding legends, Randy Roach writes about in his Muscle Smoke & Mirrors Vol. II  and to be honest, I was quite surprised that among the many responses I got, none broached the issue of the latest and greatest supplemental choline spin-off: Glycerophosphocholine, or short GPC - a supposedly superior, because fat-bound (hence "glycero" as in "glycerol) and highly bioavailable bean-derived form of choline. Whatever the reasons may be, I suppose you still won't mind to hear that a recent experiment that was conducted at the Faculty of Sport and Health Science of Ritsumeikan University in Shiga, Japan, yielded quite interesting results with respect to the endocrine and metabolic short-term effects of 1,000mg of GPC in 8 healthy male (25+/1y) subjects (Kawamura. 2012).

19x more growth hormone 60 min after the ingestion of 1,000 mg GPC, ...

And no, the subheading above does not contain a typo, at least not in the number, which is "nineteen" as in +1800%, which was, as the data in figure 1 shows, the average increase in serum growth hormone concentration exactly 60 minutes the lean subjects (11% body fat) experienced after ingestion of the GPC caps compared to placebo (the study was double-blinded and randomized, there was a period of two weeks in-between the testing days).

Figure 1: Fatty acid metabolism (left), choline levels (middle) and growth hormone levels (right)  6min0 and 120 min after the ingestion of placebo pills or 1,000mg glycerophosphocholine (Kawamura. 2012)

It is unquestionable the data in figure 1  looks pretty impressive. Yet not all changes are in fact statistical significant (I marked them by adding the relative differences between active and placebo arm) and as exciting a growth hormone spike of +1800% may sound, the subsequent drop to levels below the placebo arm should remind you, a seasoned SuppVersity veteran of the futility of supplemental "growth hormone secretagogues", such as arginine, leucine, a combination of both etc.; they all share a fundamental weakness - after each spike there is a huge trough.

...but just  6.88x more GH production over 2h

And therefore it should not really surprise you that we have the 2-h AUC, i.e. the area under growth hormone curve, a measure for the total amount of growth hormone that is released in the course of the timespan for which the AUC was measured, was "only" 6.88x larger after the ingestion of the glycerophasphatecholine supplement, than after placebo(cf. figure 2).

Figure 2: 2h AUC for free choline, free fatty acid, 3-hydroxbutyrate (ketones) and growth hormone after the ingestion of 1,000mg GPC; data expressed relative to placebo control (Kawamura. 2012)

Still, even this obviously transient increase in growth hormone in the fasted that occured in response to the +38-51% increase in circulating plasma choline went hand in hand with profound increases in free fatty acids (due to the lipolytic effects of GH; cf. Marcus. 1994) and ketone bodies, which is a sign of increased fatty acid metabolism must be a good thing,... right? It would appear so, but without answering the following two fundamental questions "How does it work?" and "What does that mean", we will be having a hard time to justify this conclusion. After all, the ingestion of 4mg/kg caffeine have been shown to illicit a >500% increase in free fatty acids (FFA) after only 40min in trained subjects (LeBlanc. 1985) and still none of the caffeine laden "fat burners" with other ingredients, which further augment the lipolytic effects of caffeine will actively burn body fat.

So what's the mechanism of action? And what does it tell us about the real world implications?

The working principle Kawamura et al. suggest is actually quite straight forward: With increasing serum choline levels, the influx of choline into the brain will increase as well. This will augment the synthesis of acetylcholine, which, in turn, has been found to decrease the concentration of somatotropin release-inhibiting factors right at the hypothalamic level and thus disinhibit the production of growth hormone (Blusztajn. 1983). Put simply: Somewhere down the line the increase in serum choline will pull the breaks that keep your body from producing growth hormone.

A note to all the stim-junkies out there: I guess, you will be intrigued (or shocked?) to hear that blocking the catecholamine induced stimulation of the a2-adrenergic receptor with yohimbine has been shown to negate the aforementioned growth hormone promoting cascade. And that irrespective of whether you try to augment it by supplements or just want to keep your natural rhythm intact (Minamitani. 1989). The first real-world implication would thus be "don't take your GPC alongside alpha-2 antagonists such as yohimbine" (better not take those at all ;-)!

Now this raises the question does that matter? With arginine and lysine, we already know that it doesn't, but maybe we just have a larger effect size here? To answer the last question first - the spike is in fact spectacular and way above the average response to the long-touted GH boosters arginine, lysine or glutamine, which ranges from "no effect at all" (Carlson. 1989) over 4.5x (Welbourne. 1995) to the whopping 13x increase in response to an intravenous injection of  0.5 g arginine/kg (Tanaka. 1991). If do yet take another look figure 2 you will notice that I inserted a quote from Kawamura et al.'s discussion of the results into the graph - a quote that is of paramount importance to quantify the real world significance of these ostensibly HUGE increase in GH (which you will certainly see referenced by respective supplement manufacturers in their glossy marketing material, very soon):

"The GPC-induced increases in GH levels observed in this study were of a comparable degree to the increase induced by moderate-intensity exercise"

I guess, you don't need me to tell you how "effective" popping a couple of those pills is thus going to be compared to training and diet alone in furthering your muscle gains and fat loss. And in terms of overall and cardiovascular health, you should already know from my previous blogpost, "Old School Supplements: Choline  Faster, Stronger, Leaner & more Muscular" that regular dietary choline as in eggs, meats, fish, leafy greens, etc. will do just as fine.

How much choline do you need? According to Coates et al. plasma choline concentrations can double after a 2-egg meal (~225mg choline) by up to two-fold (Coates. 2005). That would effectively be more than what we see as peak increase in the study at hand. And certainly puts the "need" for supplemental choline into perspective. The LD50, i.e. the purportedly fatal dosis, after the ingestion of which 50% of the subjects would die, is "of the order of 200-400g" (Gilman. 1980) - an amount of choline your tummy probably would not hold o to long enough to be absorbed, anyway ;-)

And in the unfortunate case that you do believe that you are running short of choline, because you don't eat all the good choline containing foods out of ethical or whatever other reasons, and thus insist on supplementing, I suggest you yourself a 500g container of choline bitartrate powder (don't let that become wet, though! It will stink like rotten fish ;-). Those 500g of choline bitartrate (40% choline, 60% tartate) will cost you about as much as 60x300mg caps of the overpriced GPC and has been "scientifically proven" (not in supplement company terms, but in SuppVersity terms) to safely increase circulating and brain choline levels and its metabolites after oral ingestion, as well (Stoll. 1996; Babb. 2004). And let's be honest, even if the effects on growth hormone were GPC specific - even on the boards, people have meanwhile realized none of those arginine + lysine GH boosters does make a difference and not because they would not produce transient increases in GH, but simply because those are physiologically meaningless and mostly compensated for in the course of 24h.

References:

1. Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM. Oral choline increases choline metabolites in human brain. Psychiatry Res. 2004 Jan 15;130(1):1-9.
2. Blusztajn JK, Wurtman RJ. Choline and cholinergic neurons. Science 1983;221:614–20.
3. Coates, P.M., Blackman, M.R., Cragg, G.M., Levine, M., Moss, J., White, J.D. (Ed), Encyclopedia of Dietary Supplements. Marcel Dekker, New York, NY. 2005. p. 108. . 
4. Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co. Inc. 1980. p. 1575. 
5. Carlson HE, Miglietta JT, Roginsky MS, Stegnik LD. Stimulation of pituitary hormone secretion by neurotransmitter amino acids in humans. Metabolism 1989;38:1179
6. Kawamura T, Okubo T, Sato K, Fujita S, Goto K, Hamaoka T, Iemitsu M. Glycerophosphocholine enhances growth hormone secretion and fat oxidation in young adults. Nutrition. 2012 Jun 5. 
7. LeBlanc J, Jobin M, Côté J, Samson P, Labrie A. Enhanced metabolic response to caffeine in exercise-trained human subjects. J Appl Physiol. 1985 Sep;59(3):832-7.  
8. Liu H, Bravata DM, Olkin I, Friedlander A, Liu V, Roberts B, Bendavid E, Saynina O, Salpeter SR, Garber AM, Hoffman AR. Systematic review: the effects of growth hormone on athletic performance. Ann Intern Med. 2008 May 20;148(10):747-58. Epub 2008 Mar 17.
9. Marcus C, Bolme P, Micha-Johansson G, Margery V, Brönnegård M. Growth hormone increases the lipolytic sensitivity for catecholamines in adipocytes from healthy adults. Life Sci.1994;54(18):1335-41.
10. Minamitani N, Chihara K, Kaji H, Kodama H, Kita T, Fujita T. Alpha 2-adrenergic control of growth hormone (GH) secretion in conscious male rabbits: involvement of endogenous GH-releasing factor and somatostatin. Endocrinology 1989;125:2839–45.
11. Stoll AL, Renshaw PF, De Micheli E, Wurtman R, Pillay SS, Cohen BM. Choline ingestion increases the resonance of choline-containing compounds in human brain: an in vivo proton magnetic resonance study. Biol Psychiatry. 1995 Feb 1;37(3):170-4. 
12. Welbourne TC. Increased plasma bicarbonate and growth hormone after an oral glutamine load. Am J Clin Nutr 1995;61:1058

Science Round-Up Seconds: All About Cortisol, Fat Loss, Body Composition and the Efficacy & Safety of 7-Keto & Co

Believe it or not. High dose hydrocortisone can decrease body fat levels (Babikian. 1962; see further down) and the acute administration of prednisolone has repeatedly been shown to have pronounced endurance performance (e.g. +61%; Arlettaz. 2007).

It's not like the Science Round Up was a request show, but I still want to start the Seconds to yesterday's installment of the show (download the podcast) with an honest an sincere apology to one of our listeners. Yeah, there is no debating, Carl and I had promised to talk about the "cortisol blockers can cause necrosis of the liver" study (Zou. 2013) and then simply forgot about it. I guess this was due to the unplanned "copper + HFCS = arrhythmia" excursion at the beginning of the show, but I don't want to give the impression I was looking for excuses here. Instead, I decided to make up for our negligence by taking the opportunity to go beyond simply answering the question whether the recently published data on the pro-necrotic effects of 11beta HSD reductase inhibition is a reason of concern for those of you have been taking respective products in the past and - as a bonus - discuss the effects of cortisol and cortisol inhibitors on body composition, in general.

All clear-signal - You are not going to die!

Let me answer the health related question first: I don't think there is reason to be concerned even if you've been using the 7-oxo's, -keto's and all the other caps and creams that are supposed to annihilate the "bad, bad" cortisol in the past. Due to the fact that Zou and colleagues did not use any of the common OTC supplements, but genetic ablation or UE2316, another 11beta-HSD that's commonly used in pertinent studies, it is not even certain that the DHEA-metabolites you can buy at every supplement store will produce identical / identically pronounced negative side effects.

From a previous installment of the Seconds (go back): Effect of estradiol (E2), DHEA and its metabolites 7-OXO & co on breast cancer cell proliferation (based on Miller 2012)

Since both the genetic ablation and the research drug the scientists used are working by inhibiting the same enzyme as the DHEA-metabolites that are sold as "cortisol blockers", it is yet almost sure that they would have the potential to do so.

That being said, the mere potential of hepatic necrosis, or even liver failure which would yet require the liver to be thoroughly beat up already,  should not be a problem for smart SuppVersity readers like yourself, anyway. After all, you do know about the janus-faced nature of cortisol, as well as its physiological importance and would therefore never try and annihilate this powerful fat solvent, right?

"Cortisol a fat solvent? What are you talking about?"

I know, for those of you for whom this is the first visit to the SuppVersity after years of being bamboozled by  conventional wisdom, it will probably sound crazy to call cortisol, "the fattening hormone" that's to blame for your belly and your skinny arms at the same time as a "fat solvent". So let's briefly take a look at what cortisol actually does.

Suggested read for the SuppVersity Freshmen (and -women ;-): Scientists cover 6 months contest prep of natural body builder who loses almost exlusively fat despite (or should I say due to?) +100% elevated cortisol and tanking testosterone levels (read more).

Firstly, cortisol is a profound anti-inflammatory. It does not cause inflammation, but rises in response to inflammation (the downside obviously are it's immuno-supressive effects). Secondly, cortisol is a glucocorticoid and makes sure that there is alway enough glucose floating around in your system by (a) digging into the fat and protein stores of your body to fuel your acute energy demands and (b) decreasing insulin release and sensitivity to spare glucose (Andrews. 1999).

While those of you who have already been "on" a cortisol inhibitor may have felt the negative sides of function #1 in their joints, few people acknowledge that the inhibition of cortisol and it's ability to increase the lypolytic rate (=release of fat) in adipocytes by 50% and more (Djurhuus. 2002; Cambell. 2011) could actually hamper, not accelerate weight loss while you are dieting.

There is no debating: Cortisol can be a mean bitch, but...

Now, the last four words of the previous paragraph are in fact what's making all the difference here. As long as you give your body the chance to actually burn off the fat that's getting pushed out of the fat cells by cortisol, the "beneficial" effects cortisol has on adipogenesis are nothing to be afraid of (Campbell. 2011). In the unfortunate case you are constantly stressed, overeating and chronically inflamed, however, the chronically elevated cortisol + insulin levels will however create a "perfect" obesogenic storm.

There is no conclusive evidence for the beneficial effects of OTC 11beta HSD inhibitors as fat loss adjuvants: Even in obese subjects and sponsored studies published in "author pays" journals such as Current Therapeutic Research, neither the body fat loss (p=0.41), nor the change in basal metabolic rate (p=0.86; not change in T3), or the fat free mass changes (p=0.39) were different between those subjects who dieted and exercised with a placebo and those who consumed a commercially available 7-keto supplement (Zenk. 2002). Against that background I was surprised when I was lectured earlier today by someone whose opinion I really respect that for him the use of the current #1 seller made a huge difference. How come? Well, if we also imply the results of the follow-up study by Zenk (Zenk. 2005), this time sponsored by iSatori where the multi-ingredient product Lean System 7 did prevent the drop in metabolic rate in obese (BMI ~33kg/m²) subjects, it would appear that the reason for the benefits are brought about by one or all of the additional ingredients, of which coleus forskohlii and piper nigrum are also part of the proprietary blend of the previously mentioned product. That the maintenance of a higher metabolic rate did yet not translate into increased fat loss and the subjects in the active arm actually los lean mass, while those in the placebo arm did not puts yet another question mark behind the "7-keto promotes body recomposition" hypothesis.

This storm is self-perpetuating as the chronically inflamed and ever growing visceral adipose organ, which contributes "approximately two-thirds [...] to splanchnic cortisol production in healthy men" (Andrew. 2005; the rest is produced in the liver), will spill out more and more cortisol. The cortisol, in turn will increase lipolysis and have the free fatty acid and triglyceride levels skyrocket. This, on the other hand, worsens the pre-existing insulin resistance, ... It's a vicious cycle and to my mind the only scenario where the interventional use of an 11beta-HSD reductase inhibitor like 7-keto & co could be a promising strategy.

If we do however take into account that the underlying cause of the pathological upregulation of the 11beta HSD reductase activity and cortisol production in the adipose organ is nothing but the well-known inflammation of the visceral fat stores that's not a consequence, but a in fact the cause of chronically elevated cortisol levels (Lee. 2013), it does not really seem to be prudent to manage the disease by targeting the well-meant (since anti-inflammatory) increase in cortisol. Any promising treatment (vs. management) strategy should thus aim at eliminating the underlying reasons of the inflammation, which are in 90% of the cases an obesogenic diet and a lack of exercise. And instead of supressing the downstream reaction to increased levels of TNF-alpha and its pro-inflammatory cousins with 11beta-HSD inhibitors, anti-inflammatory agents like curcumin, green tea and the like could be used to keep the inflammation while the underlying reasons are taken care of.

... cortisol also drives fat loss on a diet

I guess I don't have to remind you of the recently published SuppVersity article with the title "Scientific BB Contest Prep Coverage" (read more) and the skyrocketing cortisol levels of the subject in the pertinent study. What I guess may be worth mentioning again, though, is the fact that the impressive reduction of body fat to the sub-5% range did not take place despite, but at least in part due to this increase in our bodies' most powerful long-acting fat liberator (the catecholamines are the short-acting ones). A hormone, by the way, which supplied the body of the "starving" athlete with all the fats it needed to keep going in a situation the subject's body must have interpreted as a bad harvest that was accompanied by the disappearance of major parts of the local fauna. A situation which would have left our ancestors "looking for food" (=spending energy working out) all day, while still being rewarded with ~25% less than they would actually need to maintain their unaesthetic, but live-saving energy depots (=body fat).

So, if caloric deficit + diet + training + adequate protein + high natural cortisol = fat loss, you could suspect that using the synthetic glucocorticoids like hydrocortisone, prednisone & co should be a neat way to lose  body fat, right? Now, as surprising as this may sound this is in fact exactly what Levon G. Babikian did observe back in the 1960s, when he was able to show that medium and high dosages of 0.12mg and 0.18mg hydrocortisone per day lead to significant increases (medium dose), respetively decreases (high dose) in total and visceral body fat of mature male albino mice (a low dose of 0.09mg of hydrocortisone did not have any effect). And with a -30% total and -40% reduction in visceral body fat mass (not percentage!) those changes were not just statistically, but also physiologically highly significant. After all, the rodents in the high dose arm did thus have 2.4% less body fat than those in the control group (7.4% body fat vs. 10%).

"So does that mean that an increase in cortisol will get you ripped?"

Even if it were not for all the other nasty side effects (high blood pressure, immune suppression, loss of potassium, etc.), a high dose of hydrocortisone certainly ain't the "weight loss adjuvant of choice" for physical culturists who do not have a weight class as a ceiling to his / her overall body mass. After all, the impressive figures from the Babikian cannot hide the fact that it's not all fat mass you'd lose - despite statistically significant improvement in body fat percentage.

What about testosterone? Contrary to a Sep. 2003 1-week trial by Armani et al., where 7g of licorice lead to significant reductions in total (but not free!) testosterone, a larger scale 4-week trial with 100g/day of licorice containing 0.15% glycyrrhizic acid could not find any significant changes in sex steroid hormones (Sigurjonsdottir. 2005)

Against that background, it is somewhat surprising that the consumption of the 3g/day of licorice, a purported testosterone antagonist (see figure) and proven inhibitor of the oxidase of cortisol to cortisone and potentiator of glucocorticoid function (Whorwood. 1993; Asl. 2008), for 4 weeks lead to a ~2% reduction in body fat in 15 normal-weight subjects (7 males, age 22-26 yr, and 8 females, age 21-26 yr)  - and that in the absence of of prescribed or voluntary dietary restriction, exercise or overall weight loss (Armani. July 2003). Major side effect were not observed. The increase in extracellular water (5% in men and 1% in women) could yet obscure at least some of the beneficial effects, while you are actually "on" the glycyrrhizinic acid containing herb (whether the effects can be avoided if you keep an eye on adequate potassium intake has, afaik not been studied).

Promising fat loss results (2mm reduction in superficial tigh fat) have also been observed upon topical application of glycyrrhetinic acid, the main active ingredient in licorice, to the tighs of 18 healthy women (20-33 years) in a 2005 by the same Italian researchers. Still, despite the fact that this study used a glycyrrhetinic acid concentrate, we cannot exclude that part of the previously observed weight loss effects are brought about by non-cortisol amplifying components in licorice or the synergism of the latter with the inhibitory effects glycyrrhetinic acid exerts on the inactivation of cortisol.

---

Bottom line: As I already hinted at towards the end of the last paragraph on licorice, it's beneficial effects on fat loss, as statistical significant as they may be are about as dubious as the meager weight loss (not fat loss) effects in the sponsored 7-keto studies in obese individuals. Aside from the initial message that you probably won't whack your liver, if you use DHEA metabolites as cortisol blockers, the "bottom line" of the above treatise would be: In normalweight, healthy individuals, the use of agents DHEA metabolits to inhibit and skew the natural glucocorticoid metabolism for fat loss or body recomposition purposes is not supported by the currently available literature.

I did decide not to bore you with the issue of transient exercise induced cortisol and testosterone spikes in this article. If you want to learn more about that take a look at this, this (middle) and this (bottom) article. Without giving away too much in advance - this is another instance where the bad guy ain't necessarily as bad as you may have been told.

From a mechanistic perspective, it would even seem counter-indicated, especially in the context of low calorie and low carbohydrate diets, where the skyrocketing cortisol levels, the increase in lipolysis and the decrease in insulin release and sensitivity are actually necessary to maintain stable blood glucose levels by sparing the available glucose and providing enough fat as a substrate to fuel your daily energy demands. If this energy source ain't available any longer, the result is profound fatique (aka adrenal fatique) that will - regardless of all other metabolic effects certainly not help you shed body fat.

I don't want to exclude that certain individuals with whatever pre-existing cortisol issues can benefit from the use of these products, but as it was the case with Isatori's 7-keto product it is not unlikely that additional ingredients (for Lean System 7 these were yerba mate, guarana, citrus aurantium, coleus forskohlii, dandelion leaf, and piper nigrum) and/or the use of other supplements, as well as the concomitant diet and exercise programs people are following are responsible for the rave N=1 reviews some of these products get on the pertinent bulletin boards.

I mean, how will the authors of those reviews know they would not have seen the same effects without 7-keto and co. Everyone who is serious about improving his physique, will tell you that no two diets are the same and comparisons to previous diets are not necessarily objective. And finally, we don't want to forget the influence of sponsored logs, the "rep system" and the "brocebo effect" have on a trainees motivation (if you spend money, you want to make sure you made it right, after all it worked magically for X, Y & Z) and the perceived contribution the ingestion of a couple of pills had to his success, do we?

References:

• Andrew R, Westerbacka J, Wahren J, Yki-Järvinen H, Walker BR. The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005 May;54(5):1364-70.
• Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond). 1999; 96:513–523
• Arlettaz A, Portier H, Lecoq AM, Rieth N, De Ceaurriz J, Collomp K. Effects of short-term prednisolone intake during submaximal exercise. Med Sci Sports Exerc. 2007 Sep;39(9):1672-8. 
• Armanini D, De Palo CB, Mattarello MJ, Spinella P, Zaccaria M, Ermolao A, Palermo M, Fiore C, Sartorato P, Francini-Pesenti F, Karbowiak I. Effect of licorice on the reduction of body fat mass in healthy subjects. J Endocrinol Invest. 2003 Jul;26(7):646-50.
• Armanini D, Bonanni G, Mattarello MJ, Fiore C, Sartorato P, Palermo M. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes. 2003 Sep;111(6):341-3.
• Armanini D, Nacamulli D, Francini-Pesenti F, Battagin G, Ragazzi E, Fiore C. Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical application. Steroids. 2005 Jul;70(8):538-42. Epub 2005 Apr 12.
• Asl MN, Hosseinzadeh H. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008 Jun;22(6):709-24. doi: 10.1002/ptr.2362. Review.
• Babikian LG. Effect of Hydrocortisone, Corticosterone, and Cortisone on Visceral and Total Body Fat in Albino Mice Physiological Zoology. 1962; 35(4):314-322.
• Lee JH, Gao Z, Ye J. Regulation of 11β-HSD1 Expression during Adipose Tissue Expansion by Hypoxia through Different Activities of NF-kB and HIF-1α. Am J Physiol Endocrinol Metab. 2013 Mar 19.
• Kerstens MN, Riemens SC, Sluiter WJ, Pratt JJ, Wolthers BG, Dullaart RP. Lack of relationship between 11beta-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients. Clin Endocrinol (Oxf). 2000 Apr;52(4):403-11.
• Sigurjonsdottir HA, Axelson M, Johannsson G, Manhem K, Nystrom E, Wallerstedt S. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Horm Res. 2006;65(2):106-10.
• Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology. 1993 Jun;132(6):2287-92.
• Zenk, JL, Tami RH, Laurie JK, and Michael AK. The effect of 7-Keto Naturalean™ on weight loss: A randomized, double-blind, placebo-controlled trial. Current therapeutic research. 2002; 63(2): 263-272.
• Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. Effect of lean system 7 on metabolic rate and body composition. Nutrition. 2005 Feb;21(2):179-85.
• Zou X, Pellicoro A, Aucott R, Ramachandran P, Clarkson M, Webster1 SP, Iredale JP, Walker BR, Michailidou Z. 11βHSD1 deficiency increases susceptibility to liver fibrosis by activating hepatic stellate cells. Endocrine Abstracts. 2013; 31(P315)