Saturday, June 9, 2012

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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