Tuesday, October 16, 2012

Rhein, PPAR-Gamma Antagonist from Rhubarb, Blunts Diet Induced Weight Gain, Increases Thermogenesis, Blocks Fat Storage, Improves Glucose Metabolism & More!

With 2lbs of rhubarb in the self-made syrup base, this Rhubarb Mojito (img +recipe metropochris.com) could be a real "fat loss drink"... well, if you sweetened the syrup with stevia and used it all at once with just a tiny amount of alcohol  ;-)
Allegedly, autumn it is not exactly rhubarb season, but it is the season where we usually begin to assemble our share of winter fat and that is, as you will probably understand after having read today's SuppVersity post, actually reason enough to turn it into "rhubarb" season. Chinese rhubarb, to be precise. The same rhubarb that has been used 2700BC already and is still one of the mainstays of TCM that's being hailed for its purging effects, as well as its ability to suppress feverish conditions, to cure stomach ailments and as a “cathartic” (an agent used to relieve severe constipation). According to a review by Steven foster, da-huang, as it is called by TCM practicioners, also has antibacterial effects and has been used to treat shingles, fevers, hypertension, burns, acute appendicitis, acute infectious hepatitis, conjunctivitis, swelling and pain of gums, and sores of the mouth or tongue (Foster. 2006).

Yet though many of these effects could come handy for anyone who is looking to make it through the coming winter season in good health, none of them tailors so directly to the aforementioned nasty winter fat as one of the less known "side-effects" of da-huang: its ability to suppress diet induced weight gain!

Rhein from Chinese rhubarb could keep (seasonal) weight gain at bay

According to Zhang et al. the ability of Rhein, one out of six potentially bioactive constituents of Rheum palmatum (see figure in the bluish infobox at the end of this article for a detailed analysis), which has not only recently been shown to directly inhibit the differentiation of 3T3-L1 adipocyte in vitro (Liu. 2011), has...
Figure 1: Molecular structure of Rhein (Zhang. 2012)
"[...] also been reported to have pharmacological and biochemical effects on the inhibition of liver fibrosis and insulin sensitizing and prevent hepatic steatosis through LXR inhibition in a high-fat diet-induced obese mouse model." (Zhang. 2012)
What still has to be elucidated, though, is whether these effects of Rhein, many of which have been observed in the petri dish, only, can provide protection against diet induced obesity in the "real world" (in this case first of all in the real world of rodents).

To be assess the in-vivo efficacy of Rhein as an anti-obesity supplement, the scientists from the Shanghai University of Traditional Chinese Medicine conducted an 8-week experimental trial, in the course of which two groups of obesity prone DB/DB and normal mice were fed a high fat diet (20% protein, 20% carbs, 60% fats; relative to total energy) with or without 0.1% Rhein in it and compared that to the effects of a species-appropriate low fat diet containing 20%, 70% and 10% of the total energy from proteins, carbohydrates and fats, respectively.
Figure 2: Effect of control, high fat(HF) and high fat + Rhein (HF + RH) on body weight, adipocyte size, and body temperature after cold exposure (4°C) of C57BL/6 (=normal) mice. Mice were fed a high-fat diet for 8 weeks and Rhein was powdered and mixed in the diet at 0.1% (Zhang. 2012).
I guess, even if it was not for the data in figure 2, you probably won't be surprised, when I am telling you now that the results of the 8-week dietary intervention were more than just promising for both the obesity prone, but also the normal mice (I guess, otherwise the study would not have made it into the SuppVersity news, anyways, right?). In fact the addition of no more than 3mg of Rhein /day (see blueish infobox at the end of the article for a calculation of the human equivalent dose) effectively ...
  • reduced fat weight in db/db mice from 45.2 ± 1.4 g to 40.8 ± 1.4 g, while the lean and fluid weights remained unaffected between all groups (data not shown, since less relevant)
  • blocked the weight gain and increase the energy expenditure in normal mice on a high fat diet, who had similar food intake as the control mice, but still remained as lean as the mice on the regular diet (see figure 2)
Yet despite the fact that it's always nice to have a supplement help the "geneticall disadvantaged" among our hairy friends - in other words the leptin mutants, scientists refer to as "obesity proe DB/BD mice - for you (probably no DB/DB human, right?) the weight stability of the normal mice, which was brought about at least in part by an increase in thermogenesis and uncoupling protein expression in the brown adipose (BAT) tissue of the rodents are is probably of greater relevance.

The significance of BAT and UCP-activity measures in mice remains questionable

Figure 3: There is more to the weight loss effect of Rhein than its effects on UCP expression in BAT - mRNA levels of selected hepatic genes involved in the metabolism of fatty acids (top, right), and glucose response to intravenous glucose load (bottom, left; Zhang. 2012).
That said, it is unfortunately, whether and to which extend these effects will observed in human beings. After all, the amount of brown adipose we have on our frame appears to be highly very low, and way less active that that of the critters in the study at hand.

However, even if the direct fat burning effects won't translate 1:1 or even 10:1 from mice to men, we may still be left with improved triglycerides and LDL-C levels (data not shown) and, maybe even more importantly, an improved glucose disposal (see figure 3, top); two factors that certainly won't hurt your health and/or ability to lose body fat, specifically since they come hand in hand with increases in LPL (= fat breakdown), and decreases in FAS (= lipid synthesis) in the livers of the animals that consumed the Rhein enriched chow.

And if that's not yet reason enough to look with different eyes on the allegedly somewhat sour rhubarb stalks you have certainly seen at the super, farmers, or whatever market you are shopping, its
  • antagonistic effect on the PPAR-gamma receptor (data from test with rosiglitazone in white adipose tissue not shown), by which it blocks fat storage and induces weight loss (cf. Huang. 2006; Gong. 2009), as well as the ...
  • distinct drop in hepatic fatty acid translocase CD36 activity (see figure 3, top right) that could offer at least some protection against NAFLD and subsequent insulin resistance even in the presence of a the sugar and fat overload of the standard American diet (Miquilena-Colina. 2011), 
may eventually convince you that this stuff is not so bad - in the end, some stevia will turn even the sourest rhubarb shake or stew into a nightmarishly sweet treat ;-).
"I guess eating rhubarb won't suffice, right?" Wrong!


How much do I have to take? The human equivalent of 0.1% Rhein at a daily food intake of 3g/mouse and a mean body weight of 45g (at the beginning of the study) would be ~5.4mg/kg body weight. And what's best, with a Rhein content of 0.96 mg/g and 1.12mg/g in regular raw rhubarb and Mongolian rhubarb, respectively (see figure above with data from Shang. 2003). You could theoretically get your daily dose of 300-550mg of Rhein from 300-550g of rhubarb per day. Whether your digestive tract will like that, remains to be seen, though ;-)
Apropos, rhubarb, I guess you will probably be expecting that this is another instance, where the "fat burner" may be "naturally occuring", but only in so minuscule amounts that you will have to wait for some supplement producer to read this post and come up with a "standardized extract" in a product carrying an imaginative name like RhubaLean(TM).

Now the good news is: If we assume that (a) none of the six other ingredients interferes with the effects of Rhein (in the study at hand, Zhang et al. tested whether Emodin would have similar weight loss effects - it did not; however, that does not mean that it would negate the effects of Rhein) and (b) you'd simple need the dose equivalent of the ~3mg the mice in the study consumed, an extract is not really necessary. According to my calculations (see blueish info-box to the right), approximately 300-500g of rhubarb per day would be enough!

Well, I know, that's plenty, but if we assume that the Rhein in the rhubarb stalks is not extremely susceptible to heat, mechanical processing etc., there are countless ways for you to incorporate it into your diet. And once you are fed up of rhubarb shakes, cakes, salad dressing, ice cream, etc. you could theoretically still create your own extract.

An important note of caution: Making your own or buying an extract would also have the advantage of being able to avoid the potentially toxic oxalic acid overload, you could get if (a) your rhubarb is of the high oxalic acid variety (500-750mg/100g; the lower end would be 150-250mg/100g) and you consumed so much of it that you got in the "danger zone" of >5g/day of oxalic acid. That said, most of the oxalic acid is contained in the leaves which have once been recommended as a replacement for spinach, while the edible part, i.e. the petioles of rhubarb leaves are just that, i.e. edible, because of the low oxalate content (Barceloux. 2009)

References:
  • Barceloux DG. Rhubarb and oxalosis (Rheum species). Dis Mon. 2009 Jun;55(6):403-11.
  • Foster, Steven. Desk Reference to Nature's Medicine. Washington, D.C.: National Geographic Society. 2006. 104–105.
  • Gong Z, Huang C, Sheng X, Zhang Y, Li Q, Wang MW, Peng L, Zang YQ. The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. Endocrinology. 2009 Jan;150(1):104-13.
  • Huang C, Zhang Y, Gong Z, Sheng X, Li Z, Zhang W, Qin Y. Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway. Biochem Biophys Res Commun. 2006 Sep 22;348(2):571-8.
  • Liu Q, Zhang XL, Tao RY, Niu YJ, Chen XG, Tian JY, Ye F. Rhein, an inhibitor of adipocyte differentiation and adipogenesis. J Asian Nat Prod Res. 2011 Aug;13(8):714-23.
  • Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, Lozano-Rodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B, Aspichueta P, González-Gallego J, García-Monzón C. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut. 2011 Oct;60(10):1394-402.
  • Shang X, Yuan Z. Determination of hydroxyanthraquinoids in Rhubarb by cyclodextrin-modified micellar electrokinetic chromatography using a mixed micellar system of sodium dodecyl sulfate and sodium cholate. J Pharm Biomed Anal. 2003 Feb 5;31(1):75-81.
  • Zhang Y, Fan S, Hu N, Gu M, Chu C, Li Y, Lu X, Huang C. Rhein Reduces Fat Weight in db/db Mouse and Prevents Diet-Induced Obesity in C57Bl/6 Mouse through the Inhibition of PPARγ Signaling. PPAR Res. 2012;2012:374936. doi: 10.1155/2012/374936. Epub 2012 Sep 25.