Tangeritin, Natural Metformin from the Rind of Mandarin Oranges Hits the OFF-Switch on Diet Induced Obesity

Image 1: Tell me the truth! How much "natural metformin" did you throw away with those mandarine rinds in your life? Update (08/11/2012) Scroll down to the red box on dosing, I added, to check out why you better start saving your mandarine rinds now to be able to do a "tangeritine cycle" in a couple of years ;-)
I guess it is about time for another longer post on the "Supp" part of SuppVersity and what would be better suited than providing my readers from inside the business to spice up their #1 selling product which has as of late lost yet two other "all natural" ingredients in the never-ending arsenal of funky herbs, spices, -amines and -ephrines. Luckily the supplies nature has in stock are endless and with 5, 6, 7, 8, 40-pentamethoxyflavone (I am not kidding, now that 1,3 DMAA is gone, you will have to remember a couple more numbers ;-) the "next big" thing that's ready to get out of the starting blocks could actually prove to be more than just a stim and an actual weight loss adjuvant! After all, the AMPK boosting effects of tangeretin, which is abundant in the rinds of citrus fruits, such as mandarin orange, rutaceae and yuhu in Korea, appear to be everything but "ordinary" and they are not even the most interesting effect this compound may have on your metabolism.

Tangeritin, is not be be confused with citrus aurantium, is no stim and could thus actually work!

In a paper that has recently been published in the Journal of Molecular and Cellular Endocrinology Kim et al. report that the administration of of 200mg/kg (human equivalent 1.3g) of tangeritin per day to mice on a high fat diet did not only slow down weight gain and the development of glucose intolerance and hypercholesterolemia, but also had beneficial modulatory effects on the secretion of the adipokines adiponectin, leptin and resistin, as well as the release of IL-6 and MCP-1.
Figure 1: Adipocytokine expression and body weight gain of mice after 27 and 55 days on control, high fat (HFD) or high fat diet with 200mg/kg tangeritin (HFD + 200Tan; left) and in vitro glucose uptake of isolated myocytes upon incubation with tangeritin at doses of 25, 50 and 100mMol (right; data adapted from Kim. 2012)
For Kim et al. the profound effects wich lower leptin, aidponectin, resistin and IL-6 expression in the HFD + Tangeritin group than in the control (I wish we had the body fat levels, I am curious if those were not lower with HFD + tangeritin than in the control group, as well) did yet not come as a surprise.
Additional figure: How much rind (in g) do you need to produce 1g of tangeritin by water extraction at different temperatures and extraction times (data calculated based on Xu. 2012)
Update (08/11/2012): In response to questions both on Facebook as well as in the comment section I have compiled the graph on the right, which shows you how much rind (in grams) you need if you wanted to water-extract your 1g daily dose of tangeritin from Satsuma mandarin, which is probably the type of mandarin that is most widely sold here in the West and the more exotic, but tangeritin-rich Ponkan. If you take a closer look at the data from Xu et al. you will yet have to acknowledge that it is probably not feasible to produce your own extract at home - even if you you managed to extract ALL the tangeritin from the Ponkan, which obviously won't work by simply cooking it up, you would still need 232g of rind per day!
In previous in vitro experiments on isolated muscle cells (C2C12 myotubes), the researchers had already established that tangeritin, when it is appropriately dosed (!), exerts extraordinary powerful effects on the expression of the energy sensor and metabolic switch AMPK, which has as of late gotten quite some attention in  the laypress as the target for "the exercise pill", the "ultimate antiobesity + antidiabetes pill", the "anticancer and longevity pill",... well basically everything that could make a respective drug a pharmacological "bockboster" (read more about AMPK in the SuppVersity Intermittent Thougths Series: "The AMPK/mTOR Seesaw".

Figure 2: Hand in hand with the beneficial effects on adipocytokine production, the addition of tangerine to the high fat diet also ameliorated the growth and necrosis of adipocytes (Kim. 2012)
They also knew from previous studies that aside from its role as an inducer of AMPK and GLUT-4 expression in the muscle tissue, tangeretin posses anti-cancer, anti-oxidant and anti-inflammatory properties, as well (Yoon. 2011; Xu. 2008). Kim et al. also point out that
In addition to its anti-oxidant effects, tangeretin has been reported to inhibit the growth of hepatocytes both in vitro and in vivo via inhibition of mTOR/p70S6 kinase (Cheng. 2011). Regarding tangeretin-mediated effects on neuronal disease, a number of studies have shown that tangeretin reduces dopaminergic neurotoxin-induced neuronal injury and prevents tunicamycin-induced cell death in mice through an increase in glucose-regulated protein (GRP)78 and heme oxygenase (HO)-1 expression in renal tubular epithelium (Takano. 2007).
Moreover, another recent study by Choi et al. reports that tangeritin also has protective effects against the lipopolysaccharide (LPS) induced nitric oxide (NO) expression in the digestive tract and could thus offer acute and chronic protection from LPS induced cell damage (Choi. 2007).

Awesome? Well, in a way it may be, but in the end most of what we see is a result of pushing the right switches and in this regards tangeritin appears to be outstandingly good - for a supplement to say the least; that you don't need exercise in a pill if you hit the gym three to five times a week and lead an active life is something I don't have to tell you anyway, right?
Figure 3: Unlike thiazolidinedione like Rosiglitazone and "harmless" health supplements as fish oil (Neschen. 2006) tangeritin does not work its antihyperlipidemic (=triglyceride lowering) and anti-hyperglycemic (=blood sugar lowering) effects effects by inducing PPAR-gamma and thus allowing your body to stash away even more energy as body fat. On the contrary, reduces ppar-gamma expression and consequently stops the expansion of adipose tissue even in the presence of a hypercaloric high fat diet (cf. figure 1, tissue samples) - the beneficial effects of PPAR-gamma blockade have only recently been investigated by Lohdi et al. who call it an "off switch" for diet induced obesity (Lohdi. 2012).
Implications: Now, we are certainly not dealing with the "supplemental reinvention of the wheel here", and still: The effect size in the Tan200 group was so pronounced that I felt that the news on tangeritin, which had originally been part of last weeks "On Short Notice" deserved it's own post - not the least, because  it will not have you pay dearly for the improved glucose tolerance and lower blood lipid levels as thiazolidinediones like Rosiglitazone and even fish oil, both of which have been shown to reduce serum glucose and triglyceride levels via PAR-gamma dependent mechanisms (figure 3; specifically for fish oil Neschen. 2006) and thusly promote not block fat loss. Tangeritin, on the other hand decreases the PPAR-gamma activity and therefore acts as an "off-switch" for dietary induced obesity (Lohdi. 2012) .

Moreover, the reduced obesity was not a mere side effect of a loss of appetite and subsequent anorexia. The animals in the HFD and the HFD + Tan200 group consumed the exact same amount of chow - with the one small but absolutely critical difference that the rodents in the Tan200 group did not store the superfluous energy as body fat. It is this "anti-fat" effect which is not borne by negative health effect as it is the case for conjugated linoleic acid (CLA), for example (cf. "CLA Destroys Body Fat") which makes tangeretin a very interesting candidate for a weight loss supplement for both obese and lean dieters and, when I come to think about it, probably even for people who want to bulk.

There are however a few potential downsides and questions that remain to be answered before we celebrate the advent of yet another "next big thing" that will then line up with the rest of the supplemental non-starters:
  • First of all, the mechanism of action does remind me of alpha lipoic acid (ALA), which is still a very good supplement for obese or at least insulin resistant dieters, but turned out to be useless, even potentially counterproductive in exactly those lean selectively (muscle) insulin sensitive athletes it is currently heavily marketed to as "repartitioning agent" (see "Lean and Muscular With Alpha Lipoic Acid?"). So the question is: "Is tangeritin only another ALA?" Is it better or worse and will it work fr lean people as well as it did for the mice on the obesogenic diet in the study at hand?
  • Secondly, despite the fact that tangeritin acts in an almost metformin-esque fashion via AMPK and PGC-1alpha, which is much more likely to work in humans as well than your usual beta-3 agonist (e.g. synephrine) or other thermogenic with promising rodent data and absolute no effects in human beings, we still need controlled human trials to see whether or not this nquestionably promising flavenoid does work in humans at all.
  • And thirdly, in view of the fact that only the high dose tangeritin (100mMol) elicited a pronounced increase in glucose uptake in the in-vitro study (cf. figure 1), it will be of utmost importance that future supplements or pharmacological agents are appropriately dosed - and we all know that this is in 90% of the cases where the raw material is more expensive than caffeine anhydrous simply not the case. 
That said, I would venture the guess that (assuming one of the smaller supplement companies finds a bulk supplier in China) we are going to see "Tange(R)iburn" or a tangerine based substrate repartitioning agent (after all those sell pretty well, too) in the near future - before anyone has a clue what dosages will be necessary to see beneficial effects and probably with way less than the 1g+ of tangeritin in it than Kim et al.'s results would suggest as a minimal daily dose for an adult to see similarly outstanding results as our hairy friends in the study at hand.

  • Cheng Z, Surichan S, Ruparelia K, Arroo R, Boarder MR. Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. Br J Pharmacol. 2011 Apr;162(8):1781-91.
  • Choi SY, Ko HC, Ko SY, Hwang JH. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. Choi, S.Y., Ko, H.C., Ko, S.Y., Hwang, J.H., 2007. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. 30, 772–778.; 30, 772–778. 
  • Lodhi IJ, Yin L, Jensen-Urstad AP, Funai K, Coleman T, Baird JH, El Ramahi MK, Razani B, Song H, Fu-Hsu F, Turk J, Semenkovich CF. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARĪ³ Activation to Decrease Diet-Induced Obesity. Cell Metab. 2012 Aug 1.
  • Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006 Apr;55(4):924-8. 
  • Kim MS, Hur HJ, Kwon DY, Hwang JT. Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Mol Cell Endocrinol. 2012 Jul 6;358(1):127-34. 
  • Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Cell Physiol. 2007 Jan;292(1):C353-61.
  • Xu HG, Chen CJ, Liu DH, Minerals, phenolic compounds, and antioxidant capacity of citrus peel extract by hot water. J. Food Sci. 2008; 73, C11–C18. 
  • Yoon JH, Lim TG, Lee KM. Tangeretin reduces ultraviolet B (UVB)-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking mitogen-activated protein kinase (MAPK) activation and reactive oxygen species (ROS) generation. J. Agric. Food Chem. 2011; 59, 222–228
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