Mono-Sodium Glutamate (MSG) As Dieting Aid for the Avg. Glutton? MSG "Preload" Reduces Total Energy Intake per Meal by 3-5% - Adding Extra Protein Amplifies the Effect

Spicy Carrot Soup (recipe) - Would it be more satiating, if it was made with MSG? The study at hand shows: Yes, if it's eaten as an entree, it will actually reduce your food intake more than an MSG-free soup, you'd eat before a meal.

Mono-sodium glutamate, or MSG, as it is usually called, is a strange molecule. Previous research suggests it may have a paradoxically biphasic effect on appetite: Just as common wisdom tells you, it will increase your appetite while you are eating an MSG-flavored meal due to its (umami) flavour enhancing effect. On the other hand, there is also irrefutable evidence to show that that MSG will enhance subsequent satiety - an effect of which scientists believe that it is brought about by its proposed role as a predictor of protein content.

In their latest experiment, Una Masic and Martin R. Yeomans from the University of Sussex wanted to elucidate, whether one could make use of the satiety effect without increasing the risk of overeating.

Artificial sweeteners have a similarly bad reputation as MSG.

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Suez In the corresponding trial, which involved a total of thirty-six low-restraint (not dieting or thinking "Oh my god, I am gonna be fat, when I eat this!") males (mean age: 21 years; BMI: 22 kg/m²).

On all test days, the subjects received identical breakfasts [80 g cereal (Crunchy Nut Cornflakes; Kellogg’s), 200 g semi-skimmed milk (Sainsbury’s plc) and 200 g orange juice (Sainsbury’s plc) (total 2107 kJ (503·6 kcal))] before they consumed a MSG or no-MSG carrot and spice soup as an entree for lunch.

Figure 1: Graphical representation of the timings of the preload and ad libitum meals and the appetite ratings made on each test day.↓, Appetite rating made;■, fixed meal; □, ad libitum meal (Masic. 2014).

Subsequently, the scientists served pasta in tomato sauce followed by ice cream and recorded the amount of food the subjects ate.

Study shows insulin  sensitiziing effects of dreaded food additive | learn more

This is not the first study suggesting that MSG is not "all bad": Actually I have written about beneficial effects of MSG before. About it's insulin sensitizing effects in "Glutamate: Can It Be Use To Your Advantage? Study Shows Insulin Sensitizing Effects of Dreaded Food Additive" (read more) and about its beneficial effects on gut health in "Pigs Would Pick MSG - Glutamate Seals the Gut, Decreases Liver & Muscle Fat & Increases Plasma Amino Acids in Swine" (read more). So, maybe - just maybe, obviously, it's not all that bad, after all... well, one thing we should keep in mind though, is the fact that there is still the issue with attention deficit and other cognitive disorders, of which Thomas J. Sobotoka writes in a 2010 review that the evidence is insufficient.

Unlike the ADHD connection, the headaches and other symptoms some people suffer from, when they ingest large amounts of MSG are non-debatable, though. For me, personally, the existence of these effects is reason enough, not to use MSG deliberately as a supplement. It's yet not enough to run away, when I occasionally realize a food item I am about to eat contains some mono-sodium glutamate.

This simple procedure was repeated thrice. On occasions one and two with a soup with only 117kcal/100g, on occasion three and four and five and six with larger entrees containing ~280kcal/100g and either a balanced protein (45% pro / 38% cho) or high carbohydrate (2% pro / 81% carbohydrate) content.

Figure 1: Rel. changes in energy intake (% of non-MSG entree) in response to the consumption of MSG vs.
non-MSG carrot and spice soup as an entree (Masic. 2014)

The results were as expected (by the scientists, not by the layman ;-): There was a larger decrease in subsequent energy intake with the MSG soup as an entree.

Moreover, a larger preload produced a more significant reduction in energy intake on the subsequent main dish (Pasta) and dessert (Ice cream), than a small one. And last but not least, there was a significant advantage for the balanced, higher protein, lower carbohydrate version of the soup that had been spiked not just with MSG, but also with whey (in both the active and control trial; see Figure 1, right bars).

Wtf, how does this work? The authors suggest two possible explanations. Firstly, the sensory quality generated by the addition of MSG may have made the experience of protein more salient, and did thus enhance the satiating effects of protein in the meal. Alternatively, the improved compensation of protein in the MSG+ condition could be related to a post-ingestive sti- mulation of gut glutamate sen- sors which have been related to enhanced satiety in animal studies (Niijima. 2000; San Gabriel. 2007; Kondoh. 2008).

Bottom line: Overall, the study at hand clearly refutes the commonly held believe that MSG would make you overeat. Rather than that, an MSG preload has similar effects as the previously discussed whey preload before a meal (learn more).

And while the effect does not depend on the presence of additional protein in the MSG-containing entree, it is amplified (albeit non-significantly), if the soup, or whatever else you may be eating before your main dish, contains both MSG and a high amount of protein (see Figure 1, right). As the authors say their evidence does therefore clearly "suggest that moderate increases in the energy content of a food through the addition of protein and MSG, for example as a savoury snack, may reduce the likelihood of subsequent overconsumption" (Masic. 2014) - a result that goes against almost everything you'll read about MSG on the Internet | Comment on Facebook!

References:

• Kondoh, Takashi, and Kunio Torii. "MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague–Dawley rats." Physiology & behavior 95.1 (2008): 135-144. 
• Monosodium glutamate delivered in a protein-rich soup improves
  subsequent energy compensation
• Niijima, Akira. "Reflex effects of oral, gastrointestinal and hepatoportal glutamate sensors on vagal nerve activity." The Journal of nutrition 130.4 (2000): 971S-973S. 
• San Gabriel, Ana M., et al. "mGluR1 in the fundic glands of rat stomach." FEBS letters 581.6 (2007): 1119-1123.
• Sobotka, Thomas J. "Overview and Evaluation of Proposed Association Between Artificial Food Colors and Attention Deficit Hyperactivity Disorders (ADHD) and Problem Behaviors in Children." US FDA Food Advisory Committee Meeting Materials-Interim Toxicology Review Memorandum (Certified Color Additives). 2010.

Glutamate: Can It Be Use To Your Advantage? Study Shows Insulin Sensitizing Effects of Dreaded Food Additive

"Now you've got me confused!"

In the context of MSG scare, glutamate has gotten such a bad rep that it seems highly counterintuitive to assume that there was anything good about the major excitatory amino acid in the human body and still, a recent study from the Department of Kinesiology at the University of Waterloo clearly suggests that "MSG and carbohydrate supplementation can be used to manipulate plasma glutamate" (Sebastiano. 2013)... and no, we are not talking about an in-vitro or rodent study here.

With 9 perfectly healthy, recreationally active men aged 23.9+/-1.9y and a BMI of 25kg/m² the results can however be taken as being representative for at least large parts of the ever-decreasing number of "normal-weight" individuals.

There is a potential string attached

Usually, the "on the other hands", are something I am talking about at the end of the article, but in this case, of which I expect that it's going to become pretty controversial it appears prudent to address them right away: there was a hitherto unexplained dichotomy in the insulin response of the 9 subjects after the ingestion of the 150 mg/kg body weight MSG or placebo capsules, the subjects ingested after an overnight fast and 30 minutes before they consumed a 75 g carbohydrate or a non-energy placebo drink.

Figure 1: AUC for glucose and insulin across the trials (left); serum insulin and glucose concentrations in the post-prandial period during the glutamate and no-glutamate trials (Sebastiano. 2013)

What looks like a Taubs'ian nightmare is actually nothing but a perfectly normal insulin response to the ingestion of 75g of carbohydrates. In a healthy individual, the insulin response is proportional to the influx of glucose from the digestive tract and ensures that the latter is getting stored in muscle, liver and fat (with the former being topped of first, cf. figure 3 in previous article).

On average, we do the the same if not less insulin with a greater reduction in glucose

That being said, there is no debating that contrary to the scientists' working hypothesis, the average insulin secretion was not on augmented in the GLU+CHO, while the onslaught of glucose was significantly reduced (see figure 1, bottom right) compared with the CHO only trial.

Epidemiology paints a different picture of MSG (learn more)

"[I]t appears that glutamate, when combined with carbohydrate, elicits one of two insulin responses, depending on the individual.

Although the present study was not designed to explore this question, we did remark that the differences between these two groups of participants were not explained by factors associated with glucose handling, such as habitual activity levels (assessed using the Baecke questionnaire), fasting glucose, available glutamate or insulin sensitivity." (Sebastiano. 2013)

Now this is quite astonishing as it would suggest that the co-ingestion of glutamate does actually improve the insulin sensitivity only in some. In those the effect must yet have been so pronounced, though, that the "non-responders" didn't carry any weight...

---

Apropos weight, in order to confirm whether or not you can use glutamate to your advantage, we would need at least two follow up studies:

Will the additional butter on top of the potatoes reduce the insulin response? Learn the answer to this other questions in one of the famous installments of the "True or False?" Series on the SuppVersity (learn more)

• One study to elucidate the long-term consequence of the addition of glutamate to every (high) carbohydrate meal in healthy human subjects (the hypothesis would be that we should lower HOMA-IR and HbA1C levels as a sign of improved glucose metabolism).

• And another study to make sure that the obvious insulin-sensitizing effects glutamate appears to exert in at least some subjects are not adipose-tissue specific - or, in other words, that it is not an increase in fatty acid synthethase and subsequent storage of glucose as fat that's behind the significantly reduced glycemia the scientists observed.

What? You think all that is bullocks, because "we all know" that glutamate is going to make you fat? Well, in a non-calorically controlled scenario this may still be the case.

YamYol: Yeast extract = MSG

Did you know that almost all producers of convenience "food" are tricking their consumers by claiming their products were free of added flavor enhancer, MSG-free or at least free of artificial flavor enhancers only to add yeast extract as an ingredient. Now being an ingredient it's no longer an additive and in view of the fact that most consumers are not aware that it is basically MSG, nobody will complain... besides you, obviously ;-)

To understand that you will however have to get rid of your false prejudices against insulin, the release of which also acts as a satiety signal (in the insulin sensitive individual) and will have you stop eating (Verdich. 2001). With your glutamate laden super size fast food menu, your body may not even recognize that you have just been downing a Big Mac, XXL French fries and an XXL Coke, estimating that the stuff you ate was probably a Happy Meal with only 50% of the calories. In other words, in the real world, McGlutamate and ChinaMSG are probably still not the best places to dine regularly ;-)

References:

• Di Sebastiano KM, Bell KE, Barnes T, Weeraratne A, Premji T, Mourtzakis M. Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. Br J Nutr. 2013 Jun 11:1-8. [Epub ahead of print] 
• Verdich C, Toubro S, Buemann B, Lysgård Madsen J, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety--effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001 Aug;25(8):1206-14.

Pigs Would Pick MSG - Glutamate Seals the Gut, Decreases Liver & Muscle Fat & Increases Plasma Amino Acids in Swine

Piglets would buy MSG food ;-)

Mono-sodium glutamate (MSG) and the "Chinese restaurant syndrome", obesity and overeating are often thrown together into a single psedo-scientific crock pot with the result being a brew that's 50% hear-say, 40% fear and 10% science. The study we are going to look at today is unquestionably part of the latter ingredient and its results do stand in line with my previously stated concern "that MSG is one of those substances that is usually found in foods with a whole host of other nutrient-poor ingredients, anti-nutrients and proven obesogenic, pro-inflammatory and otherwise unhealthy substances and food additives" ("MSG, NFALD, Leaky Gut & Brain ...") and could thus rather be corollary to, than causative of the toll the fast, convenient and nutrient deficient foods in the Western diet are taking on our health.

Published ahead of print in the online version of the journal Amino Acids you will find a study by a group of researchers from the Texas A&M University. The study was, according to the authors intended to "fill [the] important gap of knowledge about glutamate nutrition and metabolism in animals" (Rezaei. 2012). Luckily their study subjects were pigs, allegedly young pigs, but still omnivores like us and one of the best models of the human digestive tract we have:

"Both humans and pigs are highly dependent on dietary quality since symbiotic microorganisms within the gut play a relatively minor role in modifying the nutrients that are ingested. Intestinal  transit times and digestive efficiencies are comparable. Postabsorptive metabolism is also similar in many respects, although the wide differences in length of gestation and the numbers of young born introduce a potentially significant divergence in nutrient needs for reproduction. [...] Nevertheless, when minimum nutrient requirements of swine and established recommended daily allow­ ances of humans are expressed per kilogram of dietary dry matter (assuming an intake of 500 to 800 g of dry matter per day by teenagers and adults), these values are highly related. It is only reasonable that one not draw unsupport­able inferences from one species to another, but with the possible exception of nonhuman primates, it is apparent that the omnivorous pig is one of the best models for study of nutrition issues in the omnivorous human." (Miller. 1987)

Against that background it is quite intriguing that Rezaei. et al. did not find any of the suspected negative side effects of MSG up to a dosage of 4% in the diet of their piglets.

Figure 1: Weight development and feed intake and effciacy in pigs on diet containing different amounts of supplemental MSG (data based on Rezaei. 2012)

In fact, instead of eating more, the pigs that received the MSG-supplemented diets consumed slightly, but significantly less food than their peers. Despite these appetite suppressing effects of the diet, the piglets in the high MSG arm of the study still gained the most body weight and thusly had the 'optimal' (for lovers of Chines restaurant probably rather 'most detrimental') gain:feed ratio.

The amino acid modifying effects of MSG

When we are seaching for the underlying reasons of these changes, it may be worth taking a look at the amino acid composition of the plasma of the piglets after 21 days on diets supplemented with different amounts of MSG at 1 and 4 h after feeding. During this prostprandial phase, the scientists observed

• 

  More about MSG in human health

  significant increases  in aspartate, glutamate, glutamine, histidine, citrulline, arginine, taurine, alanine, methionine, valine, phenylalanine, isoleucine, leucine, proline, cysteine, ornithine, and lysine in plasma at both time points, i.e. one and four hours after feedin,
• highly significant increases in asparagine, serine, threonine, tryptophan, and tyrosine 1h after feeding and
• significant increases in alanine, citrulline, glutamate, methionine, ornithine, phenylalanine, proline, and tryptophan in the first hour of the postprandial window

If we also take into account previous rodent studies which have shown that MSG reduces the deposition of fatty acids in white adipose tissue (Kondoh. 2008), it cannot be ruled out though that these increases in weight gain were related to increases in lean- not fat tissue (remember: muscle is heavier than fat); after all we are dealing with growing young pigs, in which you would expect an increase in essential and non essential amino acid availability to help with skeletal muscle metabolism (Mahan. 1998).

Figure 2: Total lipid content in percent of control in response to MSG feeding at different doses (left) and the modulatory effects of sodium intake (NaCl) on the effects of MSG (right; data based on Rezaei. 2012)

As the data in figure 2 goes to show this hypothesis appears to stand in line with the decreased fatty acid deposition in liver and skeletal muscle, which will at the same time prevent negative side effects of intra-hepatic and -skeletal lipid accumulation on liver and muscle glucose uptake.

Does salt modify the effects of MSG? And what's the role of the gut in all this?

Against that background it is actually a pitty that we don't have data on the fatty acid content of liver and muscle tissue in response to the different levels of dietary salt in the diets (figure 2, right). I mean, at first sight it appears that more salt could 'ameliorate' the detrimental effects of MSG feeding on the body weight of the rodents, but if the latter was not detrimental, but beneficial, this would certainly entail the question if it's not MSG per se, but rather it's co-appearance with too much, or due to it's ability to boost all taste perception to little sodium in the previously mentioned fast, convenient and nutrient deficient foods, way too many people have gotten addicted to.

You see, just as so many times before things are way more complex than they may seem at first sight and if the interactions of body weight, lean mass, intrahepatic and intramuscular lipids and dietary salt with MSG was not already enough, the data in figure 3 brings another (side?) effect into play the importance of which must not be underestimated - the effect of MSG on the intestinal morphology of the pigs:

Figure 3: Jejunal morphology and jejunal concentrations of DNA, RNA, protein, ATP, and glutathione in 28-day-old pigs weaned at 21 days of age (Rezaei. 2012)

I don't know if you remember the side effect of the chronic ingestion of zinc on the intestinal structure of rodents that caused quite a stir in the zinc-loving bodybuilding community back in June!? In essence, the effects of mono-sodium glutamate on the microvilli, which are responsible for the absorption of nutrients look very similar to the ones that were observed by Taneja et al.in response to Zinc supplementation (SuppVersity: June 13, 2012). As previously mentioned this is per se not a bad thing and could in fact come very hand to people with chronic inflammatory conditions suffering from a "leaky gut" or people who want to protect their gut from the side effects of the chronic use of NSAIDs, where MSG has only recently been implicated as a viable tool to prevent and heal mucosal damage (Amagas. 2012).

Figure 4: Postprandial glucose levels (left) and intestinal morphology (right) of mice on diets with different concentrations of mono-sodium glutamate (Rezaei. 2012)

As figure 4 goes to show this could actually work with MSG without the zinc-induced increases in insulin and blood glucose (see figure 2 in previous article). Whether these effects are directly related to the ingestion of MSG or its glutamin-sparing effects n the gut cannot be said for sure, though:

"Grant alert" Despite the fact that I am pretty sure that the actuall data in this study is accurately reported, I still want to point out that the scientists received "a grant from the International Glutamate Technical Committee". It's explicitly listed in the "acknowledgments" and probably not much of an issue outside of the discussion in which you will obviously miss references to potential negative side effects (which have not been observed in the study, though).

"Thus, dietary supplementation with glutamate may enhance the availability of dietary glutamine in plasma. As a versatile amino acid, glutamate participates in both synthetic and oxidative pathways in the small intestine, resulting in the production of proteins, ornithine, citrulline, proline, arginine, alanine, aspartate, glutathione, CO2, and ATP. Therefore, dietary supplementation with glutamate increased the plasma concentrations of these amino acids  and jejunal concentrations of glutathione in weaned pigs. Compelling evidence shows that dietary glutamate is a major energy substrate for the small intestine, which is an organ with a particularly high met- abolic rate. In support of this notion, we found that dietary MSG supplementation increased jejunal concentrations of ATP in weaned pigs. Additionally, glutamate is an excitatory neurotransmitter, thereby regulating the motility of the gastrointestinal tract. Thus, when a weaning diet is deficient in glutamate, gut atrophy occurs and the efficiency of utilization of dietary protein for growth and other physiological functions is greatly decreased." (Rezaei. 2012)

As evidence from previous studies by Kondoh et al. suggests, the effects of glutamate do not end at the intestinal brush border. Its centrally mediated downstream effects after interacting with l-Glutamate receptors in the intestines are however still not fully understood and could either be beneficial (as the work by Kondoh et al. would suggest; Kondoh. 2008 & 2009), be without physiological consequences or - as the mainstream myth suggests - "be the devil"; with the latter being much more likely in people with genetic or already established metabolic problems which result in a deficiency of glutamate dehydrogenase (Stanley. 2009).

Bottom line: The last mentioned problems certain individuals who have inherited or acquired problems with the enzymatic conversion of glutamate are yet not the only reason why I strongly caution against taking the results of the study at hand as a free ticket for limitless MSG consumption. If it's not the MSG that's going to make you fat, I can assure you that those 'foods' in which it is used will be getting the job done pretty quickly and will thus compensate for any possibly existent improvements in intestinal and whole body amino acid metabolism.

Parmigiano Reggiano aside from seaweed the #1 "real food" offender in terms of MSG and still good for your bones (Pampaloni. 2011) - one of many examples of the fallacy of black-and-white thinking. To heal your gut, glutamine would yet still be your better choice, I suppose ;-)

That said, there are still unresolved issues related to the negative effects of MSG on the immune system and the thymus. The dosages that are required to observe toxic effects may be hilarious if you take into account how much of it you find in an individual food item, and even if you started supplementing with MSG, or lived on fast- and convenient food, only, you will probably be hard pressed to get up to the 50g+ human equivalent of mono-sodium glutamate which was sufficient to significantly decrease thymus cell viability in rats (Pavlovic. 2009). In case you feel you are endangered and belong to the people who rather wear a helmet than stop hammering their head against a wall, you could try to counter that with an additional 6-7g of vitamin C (for the rodents that worked)... but let's be honest, wouldn't your life be much easier, if you simply stuck to whole foods and don't worry about the occasional piece of aged Parmesan cheese with 1680 mg glutamate per 100g. It could not just be good for your gut, but has been shown to be good for your bones (Pampaloni. 2011), probably not because, but at least despite the high MSG content.

References:

• Amagase K, Ochi A, Kojo A, Mizunoe A, Taue M, Kinoshita N, Nakamura E, Takeuchi K. New therapeutic strategy for amino acid medicine: prophylactic and healing promoting effect of monosodium glutamate against NSAID-induced enteropathy. J Pharmacol Sci. 2012;118(2):131-7.
• Kondoh T, Torii K (2008) MSG intake suppresses weight gain, fat deposition, and plasma leptin levels in male Sprague-Dawley rats. Physiol Behav 95:135–144.
• Kondoh T, Mallick HN, Torii K. Activation of the gut-brain axis by dietary glutamate and physiologic significance in energy homeostasis. Am J Clin Nutr. 2009 Sep;90(3):832S-837S.
• Mahan DC, Shields RG Jr. Essential and nonessential amino acid composition of pigs from birth to 145 kilograms of body weight, and comparison to other studies. J Anim Sci. 1998 Feb;76(2):513-21.
• Miller ER, Ullrey DE. The pig as a model for human nutrition. Annu Rev Nutr. 1987;7:361-82. 
• Pampaloni B, Bartolini E, Brandi ML. Parmigiano Reggiano cheese and bone health. Clin Cases Miner Bone Metab. 2011 Sep;8(3):33-6.
• Pavlovic V, Pavlovic D, Kocic G, Sokolovic D, Sarac M, Jovic Z. Ascorbic acid modulates monosodium glutamate induced cytotoxicity in rat thymus. Bratisl Lek Listy. 2009;110(4):205-9.
• Stanley CA. Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr. 2009 Sep;90(3):862S-866S.
• Rezaei R, Knabe DA, Tekwe CD, Dahanayaka S, Ficken MD, Fielder SE, Eide SJ, Lovering SL, Wu G. Dietary supplementation with monosodium glutamate is safe and improves growth performance in postweaning pigs. Amino Acids. 2012 Nov 2.

Mono-Sodium Glutamate (MSG), NAFLD, Leptin Resistance, Trans-Fats, HFCS, Gluttony, Leaky Gut & Brain, the Vagus Nerve and the Chinese Restaurant Syndrome - Bon Appetit!

Image 1 (msg-exposed.com): Is obesity the inevitable, unnatural metabolic long-term equivalent of the dreaded "Chinese Restaurant Syndrome"?

Earlier today, I posted a blurb from a recently published epidemiological study on the effects of mono-sodium glutamate, aka MSG, an umami = all taste receptor activator that is commonly found in all sorts of ready made foods that would otherwise taste as lame as their individual fake ingredients, on the SuppVersity facebook wall (Insawang . 2012). The scientists had evaluated the data from 324 families (349 adult subjects, age 35–55 years) from a rural area of Thailand and found that the prevalence of metabolic syndrome was not just significantly higher in the tertile with the highest MSG intake, but that the "odds ratio", i.e. the chance that a certain parameter, in this case "obese, yes/no" would be found to be true, increased with every 1 g increase in total MSG intake irrespective of  the total energy intake and the level of physical activity.It took roughly 2 minutes for the first sharp-witted "SuppVersity student", in this case that was Wyatt Brown, to spot that post and ask what I believed could explain this observation.

Honestly, I had not really thought about that before, but simply assumed that the effects were probably mediated via not yet fully elucidated effects of dietary glutamate on the balance of excitatory and inhibitory neurotransmitters... after thinking about that for a moment I realized that in the absence of hyperphagia (i.e. extreme hunger and subsequently higher caloric intake), which was obviously not the case for the obese Thais with high MSG intakes, this explanation was not really satisfactory.

Does it all come back to food quality once again?

My next thought was that this could yet again be an issue of food quality vs. food quantity. After all, junk food and all sorts of foodstuff that's made with tons of food-additives to disguise their inferior, nutrient-poor and thus "tasteless" ingredients are the most likely candidates with respect to the MSG exposure in the Western and Eastern "developed" *rofl* world are concerned. In view of the fact that "diet quality" was (as so often) not among the variables Insawang et al. had assessed, their study did not allow for any conclusions in this respect, so that I had to dig deeper and came up with a couple of interesting findings,  I did not want to hold back from me (sorry, Stephen, for postponing the "HIIT Manual"-post, once again, but think about it like that, what's the use of working out if your MSG intake would quash your results anyway ;-)

• * See figure 2 for exact data on the average daily human intake of MSG - with 91mg MSG /kg body weight, an amount that would translate to a daily intake of ~500+mg MSG in humans, the mice in the Collison were representative of the average American, yet not the Thai, Japanese and Korean MSG intake; against that background it is  important to note that MSG ingestion alone did not result in microscopic fat deposits in the liver. These effects were exclusively observed upon co-ingestion of the MSG with a diet with ~9% TFA content!
  "MSG intake at doses similar to human average daily intake[*] caused hepatic microsteatosis and the expression of beta-oxidative genes." - in a 2009 study, Collison confirmed the negative effects of even moderate MSG intake on liver health in a rodent model; only the common combination of trans-fatty acids (TFA) + MSG that is one of the main characteristics of modern "convenience" foods, did yet induce statistically significant increases in liver weight and hepatic triglyceride content; the increases in total, but also HDL cholesterol due to MSG + TFA were accompanied by profound increases in circulating leptin levels, probably in response to developing leptin resistance and increased storage of lipids in the white adipose tissue stores of the nine-week old C57BL/6J mice (Collison. 2009); in a follow up study Collison et al. confirmed that the double-whammy of trans-fatty acids + MSG becomes even more toxic if a third villain is added to the mixture, high fructose corn syrup (Collison. 2011) - and I don't have to tell you where in the human food chain you will find this unholy trinity, do I?
• "MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels" - in a 2008 trial Kondoh and Torii observed a very different and in fact surprisingly pronounced beneficial effect of the ingestion of a 1% solution (in biology this means 1g per 100ml) MSG resulted in decreases in weight gain, body fat mass and plasma leptin levels in male Sprague-Dawley rats irrespective of the energy content of their diets (!) and without effecting total energy intake or food intake, but in the presence of a profound decrease in 24h-water intake (2g vs. 9g); these effects were observed in both adult and young animals, in the latter without any negative side effects on the normal development of body length

  

  Figure 1: Leptin levels (ng/ml) on diets with different energy density and macronturient composition with or without MSG added to the water (data based on Kondoh. 2008)

  this leaves more than enough room to speculate about centrally mediated increases in energy expenditure in response to the ~20mg total MSG (equivalent to 33mg/kg for a rodent and a human equivalent dose of ~5.5mg/kg) intake of which Kondoh and Torii speculate that they may be "mediated via gut [glutamate] receptors functionally linked to the afferent branches of the vagus." (Kondoh. 2008); subsequent studies into the effects of MSG on the "gut brain axis" appear to support this hypothesis (cf. Kondoh. 2009a,b; Otsubo. 2011)
• " MSG, in spite of mild hypophagia [reduced food intake], caused severe increase in fat body weight ratio, via leptin resistance" - in 2011 Afifi and Abbas, two researchers from the Department of Biochemistry at the Zagazig University in Egypt, report that feeding high amounts of MSG to pregnant rat dams had similar negative effects on body composition and leptin sensitivity as a hypercaloric diet and that despite an overall reduction in total food intake; moreover, despite similar gains in body fat, the negative effects on the offspring of those pregnant rats was more pronounced than in the rats on the "normal" hypercaloric diet (Afifi. 2011)
• If you suffer from "Chinese Restaurant Syndrome", you should check whether increased gastrointestinal permeability could be the root cause of your problems and avoid all foods with any of the following "ingredients": E620 Glutamic acid, E621 Mono-sodium glutamate, E622 Mono-potassium glutamate, E623 Calcium diglutamate, E624 Mono-ammonium glutamate, E625 Magnesium diglutamate!
  "Findings from the literature indicate that there is no consistent evidence to suggest that individuals may be uniquely sensitive to MSG" - in one of the few reviews evaluating exclusively human studies, Freeman did not find any placebo controlled research that would confirm the universal existence of side-effects (e.g. headaches, chest pain, flushing, numbness or burning in or around the mouth, sense of facial pressure or swelling and sweating) as a direct consequence of the consumption of food-borne mono-sodium glutamate; e.g.
  

  "The present study led to the conclusion that 'Chinese Restaurant Syndrome' is an anecdote applied to a variety of postprandial illnesses; rigorous and realistic scientific evidence linking the syndrome to MSG could not be found." (Tarasov. 1993)

  instead, the author suggests that "unique sensitivities" could explain the documented case reports (Freeman. 2008 // see also Walker. 2000; Geha. 2000); given the emerging evidence of the existence of something you could call a "leaky brain" (in analogy to "leaky gut"), it appears likely that an unnaturally increased permeability of the blood-brain-barrier and subsequent penetration of large amounts of glutamate into the brain even at lower serum concentrations could well explain those differences (although not directly related to MSG, I would still like to point you to the results of a recently released study, which found a profound decrease in the permeability of the BBB in response to an oral 1mg/kg (HED ~0.16mg/kg) Lycium barbarum extract in an experimental stroke model; Yang. 2012)
• "dietary antioxidants have protective potential against oxidative stress induced by MSG" - in 2006 Faromby and Onyema observed that previously described oxidative damage to the liver and subsequent steatosis (lipid accumulation) in response to the intra-peritoneal administration of ridiculously high amounts of MSG (4g/kg body weight) could be ameliorated by vitamin C + vitamin E + quercitin; these results suggest that exorbitantly high doses of MSG (human equivalent ~51g/day) are probably a result of an increase in reactive oxygen species
• "after intragastric administration of MSG, the MSG is preferentially metabolized through gluconeogenesis in B6 mice, whereas thermogenesis is the predominant process for 129 mice" - in previous studies scientists had observed profound differences in terms of the effects of MSG on food intake and preference; in 2009 Bachmanov et al. traced those differences back to genetic polymorphisms and respective differences in the metabolic response to / utilization of MSG - if we assume that similar differences exist in human beings, those would provide another explanation for the different incarnations of the "Chinese Restaurant Syndrome" with the classic headaches, high blood pressure and sweating in people who would be long to the human equivalent of the 129 mice and the highly rewarding and appetite stimulating gluconeogenic (hepatic production of glucose from the glutamate) effects in those humans with a similar genetic programming as the B6 mice

I could certainly go on for hours, citing study after study with "evidence" and "counter-evidence", or rather what the respective authors consider as such, but I believe that you have read enough to see a couple of basic patterns emerge, here.

So what about those differences? Genes, dosages, or what?

One of these patterns is also brought up by Kondoha and Torii in the discussion of the results of their study (remember: decrease in body fat and increase in energy expenditure; purported mechanism = activation of glutamate receptors that are linked to the vagus nerve), in which the researchers state that they believe that the diametrically opposed results of their, compared to other studies (most of which report an increase not a decrease in body fat that is accompanied by increases in circulating leptin and decreases in leptin sensitivity and not vice versa as in the Kondoh study), may well be explained by

[previous] studies [being] designed specifically to produce toxic effects in the brain (where GLU is an excitatory neurotransmitter), through the administration of extremely high doses (2000 mg/kg or more, administered repeatedly) to infant animals, either by single, direct injection or intubation (Kondoh. 2008).

Those high dosages could in fact have lead to blood glutamate concentrations that would allow the flux of the excitatory amino acid even across intact blood-brain-barriers. The more realistic, orally administered dosages  Kondoh and Torii used in their experiment, on the other hand, did not induce any (not even statistically non-significant) elevations of serum glutamate levels.

Hence, the effects seen in the present study, as discussed above, are probably linked via a physiologic mechanism, to a local action of GLU in the gut, rather than via a pharmacologic/toxicologic mechanism to a distant action of exogenous GLU forced on the brain (Kondoh. 2008).

If you review the brief rundown of the literature I've provided in the previous paragraphs you will have to acknowledge the validity of this remark (remember: the steatosis in the Collison study required co-administration of trans-fatty acids /TFA/ and even then the increase solely due to MSG was marginal compared to that of the TFAs, alone).

Without a leaky gut, you would probably have to eat pure MSG all day to do harm

If you also take into account, that in healthy individuals only <5% of the dietary glutamate are actually absorbed into systemic circulation, while the rest is used as an oxidative substrate by the intestinal mucosa (Smriga. 2007), the difference between thhe orally consumed 33mg/kg MSG that helped the rodents in the study by Kondoh and Torii to lean out and the intraperitoneally injected 4,000mg/kg that were necessary to induce the touted hepatic side effects in the study by Faromby and Onyema are way above the average intake even the worst offenders among the MSG abusers are exposed to (cf. figure 2):

Figure 1: Average per capita daily MSG intake in different countries (adapted from Löliger. 2000)

Even if we discard the oxidative loss within the intestine, those 4,000mg/kg for a rodent (in previous studies Onyema et al. had even used 6,000mg/kg to elicit the hepatic damage; Onyema. 2006) would translate to ~650mg/kg in humans and would mean that you would have to shovel down anywhere between 32g and 64g of pure MSG (depending on whether you weigh 50 or 100kg), i.e. 20-40x more than the average daily intake of a Korean (note: The "rodent model of MSG induced obesity" is induced by injection of 10,000mg/kg body weight; cf. Bunyan. 1976) and the whopping MSG equivalent of 400-800ml of soy sauce (avg. MSG content 80mg/ml), which is probably the worst offender in the E-number-laden ingredient arsenal of the Asian cuisine.

Figure 3: Protein-bound and free glutamate content of "high" glutamate foods (left) and total glutamate content of selected plant proteins (right; data adapted from Loliger. 2000)

Your best bet to ingest similar amounts of free glutamate from real foods is, as the data from a review by Loliger suggests (cf. figure 3), would be parmesan cheeese, but in all honesty, in view of the fact that you would have to consume 2.6kg of the Italian delicacy, it is pretty unlikely that the glutamate and not the sheer amount of pure energy in the cheese would be the underlying reason for subsequent weight gain. Against that background it should not be surprising that negative side-effects as they occur as a result of high to unrealistically high MSG intakes and or in especially susceptible individuals, are not exactly common in people who don't eat out and/or consume pre-packaged convenient foods on a regular, if not daily basis.

Too much of a vitally important thing at the wrong time and as part of the wrong foods...

The mere presence of non-negligible amounts of glutamate in all sorts of "real" foods, should yet remind you that glutamate is not a toxin, or a "foreign substance" we are not evolutionary adapted to, but an amino acid that is of utmost importance for the health of your central nervous system (Platt. 2005). So that at the end of this analysis we may not be back at square one, but still have to concede that it brought us back to a set of very common motifs here at the SuppVersity:

• When consumed in excess, substances that are good, healthy, beneficial and even "vitally" (=vitamin ;-) important can easily turn against you
• When substances do not have to pass the gut, the dose-response relationship can differ so substantially that results that are acquired using route A (e.g. intraperitoneal injection) cannot simply be transfered to scenarios employing different administration routes (e.g. oral ingestion)
• Inter-individual/-species differences and differences between healthy and unhealthy individuals / animals, warrant utmost caution, when it comes to interpreting data - the "Chinese Restaurant Syndrome", for example, could be a result of increased gut and blood-brain-barrier permeability that would lead to an increased absorption of glutamate from the intestine into the blood and from there across the blood-brain-barrier right into the brain.
• Oftentimes, differences due to the aforementioned factors are not of simple quantitative, but of qualitative nature, in the case of MSG this would be the difference between the metabolic activation in response to the local activation of glutamate receptors in the gut that are connected to the vagus nerve, on the one hand, and the systemic / central obesogenic (fattening) effects of glutamate that leaks from the gut into the blood and from there into the brain.

And lastly, to eventually come full circle and remind you of the results of Collison et al., we cannot ignore that MSG is one of those substances that is usually found in foods with a whole host of other nutrient-poor ingredients, anti-nutrients and proven obesogenic, pro-inflammatory and otherwise unhealthy substances and food additives. They are wrapped in plastics have an extended shelf life due to tons of preservatives and highly adorned with stickers and labels saying "low this", "extra that", "only X amounts of calories", etc. - as long as you avoid those foods on 360+ days of the year, prepare your meals from whole foods, don't dine at cheap restaurants, fast-food outlets and snack bars too often or try to find the "optimal amount of supplemental MSG to stimulate your vagus nerve and help you shed fat" *lol*, you can calmly watch the ever-recurring MSG scares on the Internet and other mass media ;-)

References:

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