Raspberry Ketones? Why, if Two Grande Caffe Americano Could Suffice To Keep Your Belly & Liver Fat Free and Your Heart Healthy, Even on a +40% Hypercaloric Crap Diet?

Image 1: If I had the choice to have a tasty cup of coffee with the beautiful young lady or a couple of overpriced  raspberry ketone caps with Dr. Oz, I would not even need scientific studies to make my choice ;-)

I am a huge fan of innovation, but when the name of the innovation begins with “raspberry” and ends on “ketones”, is pimped by TV doctors and sold on the 24h shopping channels, I can do well without it and better drink another cup of coffee and eat a couple of lycopene-laden tomatoes, whenever I feel the need to prevent hepatic steatosis on an obesogenic diet. I know this may not be as hip as investing 30-50 bucks in an underdosed “scientifically proven” (by exactly two dubious rodent trials, i.e. Miromoto. 2005, Wang. 2012) raspberry ketone supplement, but, on the other hand, it is also half as stupid and probably at least as efficient (Bahcecioglu. 2010; Vitaglione. 2010; Birerdinc. 2011; Molloy. 2011).

And what's more, picking cafeine over raspberry ketones would not only protect me and my virility from potential anti-androgenic effects of the latest nutraceutical rip-off (Ogawa. 2010), it could, according to a recently published study from the Department of Biological and Physical Sciences at the University of Southern Queensland in Toowoomba, Queensland, Australia, also help me to stay lean by simply blocking fatty acid synthase (FAS) in my adipose tissue (Panchal. 2012).

Caffeine? how boring is that!?

Contrary to the, as of late, often-cited study by Wang et al. on raspberry ketones (Wang. 2012), which is by the way one out of two peer-reviewed in vivo studies (the other one is Morimoto. 2005) to support the claim that raspberry ketones do anything, when they are not administered in unrealistic amounts to cells in a petri dish, Panchal et al. did not just measure a couple of serum markers, but investigated a host of metabolic parameters and structure and function of the heart and the liver of their 6-8 week old male Wistar rats that had been randomly assigned to what you might jokingly call the “pest or cholera” diets for 16 weeks: Corn starch diet (control), corn starch diet plus caffeine (CC), high-carbohydrate, high-fat diet (H), or high-carbohydrate high-fat diet plus caffeine (caffeine supplementation with 0.5g per kg chow took place only in the last 8 weeks of the 16-week study period).

Figure 1: Final body weight and body composition after 8 weeks without and another 8 weeks with caffeine supplementation (based on Panchal. 2012)

If we assume that the cornstarch only diet is pest and the high fat high carbohydrate diet is cholera, the data in figure 1 clearly indicates that 28.1mg/kg body weight caffeine ARE sufficient to reverse the effects of the pest and that 47.9mg/kg body weight caffeine are potent enough to survive any cholera epidemic; or put straight, the rodents on the

• standard cornstarch diet, which consumed 28.1mg caffeine per kg body weight (~360mg for a human being) per day, were leaner than their peers in the “control” group and that despite a 20% increase in energy intake
• high carbohydrate + high fat diet, which consumed 47.9mg caffeine per kg body weight (~612mg for a human) per day, were about as lean as the rodents on the standard diet and that despite a 40% higher energy intake (3% more than their peers in the high carbohydrate high fat diet without caffeine supplementation)

I guess none of you but maybe a few less educated minds could now reply: "Whatever... Dr. Oz said raspberry ketones are healthy; and everyone knows caffeine is not!" So, is this another case where Dr. Oz was at least partially right (cf. "Every Dog Has His Day: Dr. Oz Was Right, Exercise Does Not Just Make You Hungry, But Reduces Energy Intake!")? The increased glucose clearance and the reduction in visceral fat pad weight do speak a different language (cf. figure 2):

Figure 2: Parameters related to glucose and lipid metablism as well as visceral fat depot weight expressed relative to the non-supplemented rodents in the cornstarch control level (based on Panchal. 2012)

The same goes for the cardiovascular and liver parameters who give a damn about the increases in total cholesterol, free fatty acid and triglyceride levels, if those are the result of increased lipolysis (release of fattty acids from aidpose tissue), decreased fatty acid deposition in adipose tissue and an overall increase in metabolic rate, which is a long-established consequence of methylxanthine (=caffeine) intake in rodents and human beings (Bracco. 1995):

"[...] there was removal of fat from the abdominal area, and this fat was not transported to the
other fat-storing areas, including subcutaneous fat [...] The increase in plasma lipid components, especially NEFA, reflects the removal of fat from the abdomen [...with] the excess plasma
lipids are being metabolized rather than stored in the organs [...]" (Panchal. 2012)

The fact that the fat is simply "burned off" also explains that the increased non-esterified fatty acid concentrations, scientists usually associate with cardiovascular dysfunction and hepatic steatosis (fatty liver) did not lead to any of these complications in the study at hand. On the contrary, ...

[...] despite much higher plasma concentrations of NEFA in the caffeine-supplemented rats [..t]hese rats showed decreased infiltration of inflammatory cells, decreased collagen deposition, and decreased diastolic stiffness in the left ventricle, attenuation of non-alcoholic steatohepatitis [...]

Now, the question still remains: Why, are not all Starbucks customers lean then? The answer is pretty simple and "visualized" in image 2, it carries names such as "Peppermint White Chocolate Mocha" contains the sugar equivalent of 8½ scoops Edy’s Slow Churned Rich and Creamy Coffee Ice Cream and is "America's Worst Espresso Drink" - at least according to foodfacts.com. And while you can easily make it worse by adding some caramel syrup or junk, the average normal weight woman (if those still exist today) would almost get the +40% caloric intake the rodents in the high fat high carbohydrate diet consumed from that one "coffee" alone!

2-3 cups of black coffee would suffice!

Image 2: Starbucks Peppermint White Chocolate Mocha with Whipped Cream, 660kcal, sugar equivalent: 8½ scoops Edy’s Slow Churned Rich and Creamy Coffee Ice Cream (foodfacts.com)

If you pass those diabolic sugar bombs and pick up one Grande Caffe Americano (225mg caffeine per serving) in the AM and another one in the afternoon or before your workout (cf. "Pre-Workout Caffeine: Fat Liberator, Substrate Modulator, Trans-Fatty Acid Eliminator & Performance Upregulator!"), make sure to get your 20g+ of protein with every meal and refrain from drinking 100 bottle of Pinot Noir every day, to make sure to  get your share of fat-burning, strength building and endurance enhancing resveratrol (cf. "Resveratrol from 100l of 1994 Pinot Noir Could Increase Fat Oxidation by 71%, Strength by 18-58% and Endurance by 20%"), your liver, heart and metabolic health will thank you for that. Your belly and the raspberry ketone producers and snake oil vendors, on the other hand, will probably be offended - but I guess, you can live with that, right?

References:

1. Bahcecioglu IH, Kuzu N, Metin K, Ozercan IH, Ustündag B, Sahin K, Kucuk O. Lycopene prevents development of steatohepatitis in experimental nonalcoholic steatohepatitis model induced by high-fat diet. Vet Med Int. 2010
2. Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012 Jan;35(1):76-82. doi: 10.1111/j.1365-2036.2011.04916.x. Epub 2011 Nov 7.
3. Bracco D, Ferrarra JM, Arnaud MJ, Jéquier E, Schutz Y. Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women. Am J Physiol. 1995 Oct;269(4 Pt 1):E671-8.
4. Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012 Feb;55(2):429-36. doi: 10.1002/hep.24731. Epub 2011 Dec 22.
5. Morimoto C, Satoh Y, Hara M, Inoue S, Tsujita T, Okuda H. Anti-obese action of raspberry ketone. Life Sci. 2005 May 27;77(2):194-204. Epub 2005 Feb 25.
6. Ogawa Y, Akamatsu M, Hotta Y, Hosoda A, Tamura H. Effect of essential oils, such as raspberry ketone and its derivatives, on antiandrogenic activity based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2111-4. Epub 2010 Feb 21.
7. Panchal SK, Wong WY, Kauter K, Ward LC, Brown L. Caffeine attenuates metabolic syndrome in diet-induced obese rats. Nutrition. 2012 Jun 19. [Epub ahead of print]
8. Vitaglione P, Morisco F, Mazzone G, Amoruso DC, Ribecco MT, Romano A, Fogliano V, Caporaso N, D'Argenio G. Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology. 2010 Nov;52(5):1652-61.
9. Wang L, Meng X, Zhang F. Raspberry ketone protects rats fed high-fat diets against nonalcoholic steatohepatitis. J Med Food. 2012 May;15(5):495-503.

Diet + Exercise + Kitchen Sink Fat Burner Promote Weight Loss in Two-Months Study on Overweight Adults. Additional 2kg Fat Loss - Are Ozzy's Raspberries to "Blame"?

No this is not Liza Oz after taking Mehmet's beloved RK supplements ;-)

The Journal of the International Society of Sports Nutrition is one of the few "major" scientific journals, where scientists can actually publish those studies, "healthy freaks" (no, not "health freaks", but people who are still healthy and thus freaks ;-) like us are interested in. Studies such as the one Hector L Lopez and his colleagues conducted; studies that investigate the effects and effectiveness of dietary supplements such as Prograde Metabolism (TM), a proprietary blend "fat burner" containing your usual blend of B-vitamins, chromium, caffeine, citrus aurantium, ginger, garlic, capsaicin, l-theanine and piper nigrum... ah, and of course as the #1 ingredient on the label Raspberry-K(TM).

Too much blubber? "Grab the rasp and berry it off!" Ah, well...

Hold on, another of those "proprietary blend studies"? Can we even trust the data? Allegedly, the authors Lopez and Ziegenfuss have worked for raw material suppliers, nutraceutical and dietary supplement companies in the past and openly declare that in the paper at hand, but guess how many of the authors of studies on medications have worked for the pharma industry and were / are still involved in the development of the respective drugs? If we really started to question the results of each and every study on the basis of the mere assumption that it was a product pimp job, we would probably have to discard 95% of the currently available research. Just remember: In 99.9% of the cases it's the conclusions and interpretations that can be problematic, and not the data, itself.

If we take a closer look at the ingredient profile of "METABO", we notice that Dr. Oz's beloved raspberry ketones are right on the top of the ingredient list of the 1,000mg proprietary blend single 2-cap serving of the product contains. With caffeine and a 10% synephrine extract from citrus aurantium, which are usually dosed at around 200mg and 100-150mg (to deliver 10-15mg of synephrine as part of the Advantra-Z formula; cf. Seifert. 2006), respectivley, being the #2 and #3 on that list, we can safely assume that the maximal amount of Razberi K in a single serving of the supplement is 600mg.... that's actually quite nice, because that's so little that we do not even have to use a calculator to know that this is hilariously underdosed compared to what the rodents in the heavily cited anti-obesity (I repeat: anti-obesity, not weight loss) trials by Morimoto et al. reaceived as part of their regular chow (1-2% of the whole chow was nothing but pure raspberry ketones; cf. Morimoto. 2005)

Figure 1: Body weight, fat mass, lean mass and waist circumference after 4 and 8 weeks of dieting + exercise + supplement / placebo (Lopez. 2013)

In the end, that's yet good news. Firstly, we can safely assume that this is way too little to induce any of the anti-androgenic effects Ogawa et al. observed in their 2010 in-vitro study (Ogawa. 2010).

And secondly, the low dose of raspberry ketones left some room for the other ingredients, of which you can see in the data I plotted in figure 1 that they were very well capable of promoting the weight loss success of the 70 "obese but otherwise healthy subjects" in the Lopez study.

Effects? Yes! Effects due to raspberries? Questionable.

There is no debating that the combination of multiple "thermogenic", appetite suppressing and anti-oxidant / insulin sensitizing weight loss adjuvants in METABO did promote the loss of fat mass over what the diet + exercise progra alone could achieve. The former, i.e. the diet, had by the way been designed by a "state-licensed, registered dietitian" to provide three meals and two snacks per day (the latter are obviously useless; cf. Whybrow. 2007) and a total energy intake that would deliver approximately 500 kilocalories per day less from a 40% carbohydrate, 30% protein and 30% fat diet than the subjects actually "required" (dietary requirements that were calculated with the Mifflin-St. Jeor equation and an activity factor of 1.2; learn more).

This dietary regimen was accompanied by an 8-week workout regimen of which I would usually write that it was "surprisingly sound". In view of the fact that the study, appeared in the Journal of the International Society of Sports Nutrition and not Obesity or JAMA it is yet only "sound" and not surprising that the subjects had to work out three times per week for 60 minutes of which not a single minute was wasted on steady state cardio in the non-existing fat-burning zone. Instead, they performed a...

It sure sounds ufair, but women have a harder time shedding fat. Against that background it's all the more important for the average "I don't eat meat" lady to get her share of fat burning protein - after all a reasonable amount of protein speed fat loss in both sexes (learn more).

• 10 minute warm-up (i.e. walking, light jogging, or biking),

• 30 minutes of circuit training (upper and lower body each session, which consisted of a combination of 
• mountain climbers, squat thrusts, 
• jumping jacks, squat kickouts, walking lunges, 
• push-ups, dips, 
• resistance band elbow flexion, extension and 
• shoulder presses, 

• additional 10 minutes abdominals/core work, and 

• a subsequent 10 minutes cool down/stretching

Against that background it is however "surprising" that the fat loss in the placebo group was pretty pathetic (~115g per week), after all the participants had more than enough (32.6kg) of fat to lose.

Dieting alone "fails", the supplement "works" - what's more surprising

Now, the first thing that comes to mind, whenever a diet fails, is a bogey called "non-adherence". With the supervised and controlled exercise protocol and the official data on the energy and nutrient intake not showing significant inter-group differences, it is however difficult to pin the success / failure of the groups exclusively on non-compliance. The consistently higher food cravings in the placebo group do yet put another questionmark behing behind the accuracy of the already notoriously unreliable self-reported food intakes.

Figure 2: Cravings for energy, sweets, fatty fast food, fat in general, carbs and healthy foods in the subjects in the placebo and MTEABO group (Lopez. 2013)

According to the latter, the subjects in the placebo group consumed almost the same amount of energy, which does not appear totally unlikely in view of the fact that the cravings in the placebo group were so real that they even started to crave "healthy foods" (figure 2, orange) - a tell-tale sign that diters are seriously hungry and don't just want to satisfy their food-cravings.

Significant fat loss without significant health benefits? Surprisingly, the measured markers of glucose and lipid metabolism, namely total cholesterol, HDL, LDL, cholesterol/HDL ratio and TAG did not show significant improvements in any of the groups. There was however "a strong trend (p < 0.07) for TAG concentrations to decrease more in the  METABO group (-15.9%) compared to the placebo group (-2.6%)" (Lopez. 2013) and a significant decrease in leptin that was likewise observed exclusively in the supplement group.

Since hunger is associated with increased ghrelin levels and those have only recently been confirmed as a significant correlate and potential cause for weight loss interventions to fail (Liu. 2013), it may in the end not even matter, whether the subjects gave in to their cravings and "cheated" or whether they starved and their bodies simply stopped shedding body fat - the net result would have been identical in both conditions and if a single agent or the synergy of all of the ingredients in METABO was responsible for the satiety effect the weight loss advantage would in fact have been brought by the dietary supplement.

---

If you clicked on the links that redirect you to the overviews of SuppVersity articles on capsaicin, piperine, citrus aurantium etc. you will have realized that many of them were also on my list of PPAR-gamma antagonists (learn more).

Bottom line: The most likely explanation for the beneficial effects Lopez et al. observed as a result of 2,000mg of the proprietary blend are thus the...

1. fat loss benefits (I initially wanted to write "effects", but that's probably an exaggeration) of ingredients such as caffeine (Greenway. 2001), capsaicin (Snitkner. 2009), citrus aurantium (Bent. 2004; Stohs. 2012), ginger (Mahmoud. 2013), piperine, and / or 
2. satiety effects of caffeine (Westerterp-Plantenga. 2005a), capsaicin (Westerterp-Plantenga. 2005b), ginger (Mansour. 2012), ...

... I guess you see the picture that's emerging here. It is, as the scientists point out, "the combination of ingredients with potentially complementary and interactive mechanisms of action" (Lopez. 2013) which does the trick.

Against that background it is pretty useless to single out any of the ingredients, but if we wanted to do just that, it would certainly be the raspberry ketones which are the least-proven weight-loss adjuvant in Prograde Metabolism - an ingredient celebrated as the goto fat burner by the uneducated mainstream and an ingredient without any scientific backup from human studies. So, if I had to answer the gonzo rhetoric question in the title of this article in a binary = yes/no fashion, the most likely answer would be "no!" ;-)

References:

• Bent S, Padula A, Neuhaus J. Safety and efficacy of citrus aurantium for weight loss. Am J Cardiol. 2004 Nov 15;94(10):1359-61.
• Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev. 2001 Aug;2(3):199-211.
• Ogawa Y, Akamatsu M, Hotta Y, Hosoda A, Tamura H. Effect of essential oils, such as raspberry ketone and its derivatives, on antiandrogenic activity based on in vitro reporter gene assay. Bioorg Med Chem Lett. 2010 Apr 1;20(7):2111-4.
• Lopez HL, Ziegenfuss TN, Hofheins JE, Habowski SM, Arent SM, Weir JP, Ferrando AA. Eight weeks of supplementation with a multi-ingredient weight loss product enhances body composition, reduces hip and waist girth, and increases energy levels in overweight men and women. Journal of the International Society of Sports Nutrition. 2013; 10(22).
• Mahmoud RH, Elnour WA. Comparative evaluation of the efficacy of ginger and orlistat on obesity management, pancreatic lipase and liver peroxisomal catalase enzyme in male albino rats. Eur Rev Med Pharmacol Sci. 2013 Jan;17(1):75-83. 
• Mansour MS, Ni YM, Roberts AL, Kelleman M, Roychoudhury A, St-Onge MP. Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: a pilot study. Metabolism. 2012 Oct;61(10):1347-52.
• Morimoto C, Satoh Y, Hara M, Inoue S, Tsujita T, Okuda H. Anti-obese action of raspberry ketone. Life Sci. 2005 May 27;77(2):194-204.
• Snitker S, Fujishima Y, Shen H, Ott S, Pi-Sunyer X, Furuhata Y, Sato H, Takahashi M. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am J Clin Nutr. 2009 Jan;89(1):45-50. 
• Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Int J Med Sci. 2012;9(7):527-38. Epub 2012 Aug 29.
• Westerterp-Plantenga MS, Lejeune MP, Kovacs EM. Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation. Obes Res. 2005a Jul;13(7):1195-204.
• Westerterp-Plantenga MS, Smeets A, Lejeune MP. Sensory and gastrointestinal satiety effects of capsaicin on food intake. Int J Obes (Lond). 2005b Jun;29(6):682-8.
• Whybrow S, Mayer C, Kirk TR, Mazlan N, Stubbs RJ. Effects of two weeks' mandatory snack consumption on energy intake and energy balance. Obesity (Silver Spring). 2007 Mar;15(3):673-85.