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E 621 - Monosodium Glutamate (Mononatriumglutamat)
There is a heated debate about how dangerous it really is, with scientists claiming it's a perfectly natural taste enhancer on the one and and scientists claiming its neural toxicity for both adults and babies on the other, but even if GLU can't cross the blood-brain barrier its unhealthy enough.
There are some foodstuffs which contain it naturally (meat, ageing cheese), but its fairly common in other, non-sweet foodstuffs as well, like soups, crisps, chips, rahmen - just check the stuff in your kitchen. It's in there for the sole purpose of enhancing the taste, but also to make people consume more of the stuff. There is a study from 2005 that deals with GLU, and the outcome of that is fairly alarming:
Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite (M Hermanussen and JAF Tresguerre)
From the article:"... The animals fed 5 g MSG per day increased water uptake by threefold (P<0.01), and food uptake by almost two-fold (P<0.01). The influence of MSG is in general more marked in males than in females." Interpretation: GLU is a widely used nutritional substance that potentially exhibits significant neuronal toxicity. Voracity, and impaired GH secretion are the two major characteristics of parenterally administered GLU-induced neuronal damage. GLU maintains its toxicity in animals even when administered orally. Males appear to be more sensitive than females. The present study for the first time demonstrates, that a widely used nutritional monosubstance – the flavouring agent MSG – at concentrations that only slightly surpass those found in everyday human food, exhibits significant potential for damaging the hypothalamic regulation of appetite, and thereby determines the propensity of world-wide obesity. We suggest to reconsider the recommended daily allowances of amino acids and nutritional protein, and to abstain from the popular protein-rich diets, and particularly from adding the flavouring agents MSG.
Introduction
World-wide obesity has risen to alarming levels (McLellan, 2002). The average weight of German conscripts now increases by almost 400 g/year. Similar data were obtained in Austria, Norway, and the UK. Obesity is not a separate problem of only the obese people but appears to be a characteristic feature of modern populations as a whole (Hermanussen et al., 2001).
Much effort has been spent to understand the pathophysiology of obesity. Apart from the rare monogenic causes for severe disturbances of the eating regulation – genetic alterations of the ob gene (leptin) (Zhang et al., 1996; Strobel et al., 1998), the leptin receptor (Clement et al., 1998), a mutation of the melanocortin 4 receptor (MC4R) gene (Farooqi et al., 2000), and mutations in the pro-opiomelanocortin (POMC) gene (Krude et al., 1998) – obesity appears to show a multifactorial aetiopathogenesis. Disadvantageous dietary habits, such as overconsumption of fat-rich diets, excessive use of modern media, in particular television viewing (Robinson, 2001), a sedentary lifestyle (Votruba et al., 2000), and many other exogenous factors, have been made responsible for the development of obesity already in early childhood. And recently, a new and very challenging hypothesis has been added linking obesity, voracity, and growth hormone (GH) deficiency to the consumption of elevated amounts of the amino-acid glutamate (GLU) (Hermanussen and Tresguerres, 2003a, 2003b). Supraphysiological doses of GLU are toxic for neuronal cells.
The arcuate nucleus is the major site of GLU-induced neuronal damage in the hypothalamus. It is situated close to the bottom of the third ventricle, and is a potent site of leptin action. Leptin is produced in the adipose tissue, crosses the blood-brain barrier by active transport systems, and stimulates a specific signalling cascade (Jequier, 2002): it downregulates the orexigenic neuropeptides NPY, agouti gene-related protein, melanin-concentrating hormone, and orexins, and upregulates POMC and cocaine- and amphetamine-regulated transcript (CART) mRNA (Elmquist, 2001). POMC and its post-translational product, alpha-MSH, stimulate melanocortin receptors (MC3R, MC4R), and thereby downregulate appetite. Arcuate nucleus damage disrupts the signalling cascade of leptin action, thereby impairs the regulation of appetite, and causes voracity (Fan et al., 1997; Lu, 2001).
GLU toxicity is mediated either by inhibiting cystine uptake (Murphy et al., 1990) or receptor-mediated. The N-methyl-D-aspartate receptor (NMDA-R) is fully functional in the rat early in embryogenesis. Xue et al. (1997) found that GLU- and aspartate-immunoreactive neurones were completely absent in the monosodium glutamate (MSG)-lesioned arcuate nucleus as well as the ventromedial nucleus lateral to the arcuate nucleus, in mice treated neonatally with MSG. Similarly, NMDA-R1-immunoreactive neurones were mostly absent in the MSG-lesioned arcuate nucleus but remained intact in the ventromedial nucleus. There was also a substantial loss of NMDA-R2 immunoreactivity within the arcuate nucleus. Beas-Zarate et al. (2001) measured changes in gene expression of the NMDA-R subunits: NMDA-R1, NMDA-R 2A, and NMDA-R 2B in the cerebral cortex, striatum and hippocampus in the brains of rats treated neonatally with MSG. The authors showed increases in GLU levels and activation of GLU-receptors after neonatal s.c. administration of MSG at doses of 4 mg/g body weight and an increase in glial cell reactivity and important changes in NMDA-R molecular composition, with signs of neuronal damage. Kaufhold et al. (2002) were able to prevent the adverse effects of neonatal MSG treatment by concurrent administration of a selective and highly potent noncompetitive NMDA-R antagonist of GLU.
Administering GLU to newborn rodents not only destroys arcuate nucleus neurones, it also damages other hypothalamic areas. Bloch et al. (1984) showed that MSG treatment results in the complete loss of growth hormone releasing factor (GRF)-immunoreactive cell bodies within this nucleus and provokes a selective disappearance of GRF-immunoreactive fibres in the median eminence of rats. This technique has routinely been practised to produce functionally hypopituitary animals (Lima et al., 1993) for studies of short-term growth (Hermanussen et al., 1996).
That is, GLU-induced neuronal damage results in voracity and subsequent excessive weight gain, and impaired GH secretion, the two major characteristics of human obesity.
The present study was undertaken to further investigate the links between obesity, voracity, and GH deficiency. We present novel human data supporting evidence that morbid obesity not only associates with GH secretory dysfunction, but also with short stature, and animal data supporting evidence that GLU toxicity is not limited to parenteral administration of this amino acid, but that oral administration of GLU also causes voracity and GH deficiency. The similarity between clinical findings in human obesity, and effects of oral administration of MSG in laboratory animals strongly support the view that supraphysiological oral loads of the amino-acid GLU play a key role in human obesity.
Skipping Methods and Material.
Results
Human data
Morbid obesity associates with short stature. Regardless of school education, average stature of conscripts progressively declines when BMI increases above 38 kg/m2. The same applies for fertile women. Morbidly, obese young women are shorter than average (Figure 1) though to a lesser extent than conscripts.
Figure 1.
Average body height of 807 592 German conscripts born between 1974 and 1978, aged 19 years, and 1 432 368 young German women at the beginning of pregnancy (deutsche Perinatalerhebung) 1995–1997 (Voigt et al., 2001), vs BMI.
Full figure and legend (21K)Animal data
Oral administration of MSG to pregnant Wistar rats affects birth weight of the offspring (Figure 2a). Maternal feeding with 2.5 g MSG per day (group 2) results in no birth weight modification as compared to controls, whereas maternal feeding with 5 g MSG per day (group 3) results in severe birth weight reduction (P<0.01). Weight increments remain subnormal when MSG feeding to the mothers is maintained during weaning (Figure 2b) (P<0.01).
Figure 2.
Mean (
s.e.m.) birth weight (a) and weaning body weight (b) in normal rats (control), neonatally MSG-treated rats (injection) and 2.5 g (2.5 g MSG) and 5 g (5 g MSG) MSG oral administered rats (n=12–18). Each group includes male and female data since statistical analysis showed no gender differences. **P<0.01 vs other groups (a), **P<0.01 vs CONTROL + INJECTION groups and #P<0.05 vs 2.5 g MSG group (b).
Figure 3a, b shows GH plasma levels of the offspring. As expected, GH plasma levels were low in animals that were neonatally injected with MSG, both at day 30 and at day 90 of life (P<0.05). However, GH serum levels were also affected in animals that had received MSG during prenatal life via maternal feeding. Figure 3b illustrates that animals kept on high MSG diet (5 g MSG per day) show serum GH levels that are as low or even lower than those of MSG injected animals (P<0.05), both at day 30 and at day 90 of life. The influence of MSG is in general more marked in males than in females.
Figure 3.
Mean ( s.e.m.) plasma concentration of GH at 30 days (a), and at 90 days (b) of life in normal rats (control), neonatally MSG-treated rats (injection) and 2.5 g (2.5 g MSG) and 5 g (5 g MSG) MSG oral administered rats (n=12–18 (a), n=6–9 (b)). Each group includes male and female data since statistical analysis showed no gender differences. **P<0.01 vs CONTROL group and *P<0.05 vs CONTROL group (a), *P<0.05 vs CONTROL + 2.5 g MSG and ##P<0.01 vs the corresponding FEMALE group (b).
Animals that were kept on medium MSG diet (2.5 g MSG per day) showed low-serum GH levels at day 30 of life (P<0.01), but seemed to partially recover before day 90. Almost identical results were observed in IGF-1 serum levels (Figure 4a, b).
Figure 4.
Mean ( s.e.m.) IGF-1 plasma concentration at 30 days (a) and at 90 days (b) of life in normal rats (control), neonatally MSG-treated rats (injection) and 2.5 g (2.5 g MSG) and 5 g (5 g MSG) MSG oral administered rats (n=12–18 (a), n=6–9 (b)). Each group includes male and female data since statistical analysis showed no gender differences. **P<0.01 vs CONTROL group (a), **P<0.01 vs CONTROL + 2.5 g MSG and ##P<0.01 vs the corresponding FEMALE group (b).
Figure 5a, b shows the influence of MSG on appetite. Whereas – in contrast to previous findings (Fan et al., 1997) – MSG-injected animals of this investigation did not show significantly increased appetite compared to controls, the animals kept on medium MSG diet (2.5 g MSG per day), and particularly those kept on high MSG diet (5 g MSG per day) demonstrated marked voracity. The animals fed 5 g MSG per day increased water uptake by threefold (P<0.01), and food uptake by almost two-fold (P<0.01). Voracity seems to be MSG-dose-dependent and the increase was identical in both genders.
Figure 5.
Mean ( s.e.m.) water (a) and food (b) uptake at 90 days of life in normal rats (control), neonatally MSG-treated rats (injection) and 2.5 g (2.5 g MSG) and 5 g (5 g MSG) MSG oral administered rats (n=6–9). **P<0.05 vs CONTROL + INJECTION groups; †P<0.05 vs INJECTION group; ‡‡P<0.01 vs 2.5 g MSG group and ##P<0.01 vs the corresponding FEMALE group (a), **P<0.01 vs CONTROL + INJECTION group (b).
Leptin values were significantly increased in animals that were neonatally injected with MSG, both at day 30 and at day 90 of life (P<0.05), we found reduced leptin levels in the two orally treated groups.
Rats orally treated with MSG are smaller and have lower body weight, than control animals. The gravity index (specific weight, measured in air and water) that provides a relative information about the fat content of animal carcasses, however, indicated that MSG fed animals contained significantly more body fat both at day 30 and at day 90 than controls (P<0.05).
Discussion
Glutamic acid (GLU) is the most common amino acid in animal protein, and accounts for some 16% of meat protein, and some 20% of milk protein weight. That is, infants who daily consume up to 5 g/kg body weight of protein (Koletzko, 2002), consume as much as 1 g/kg body weight of GLU. GLU is also the physiological ligand of the taste receptor umami, the dominant taste of food containing L-GLU, like chicken broth, meat extracts, ageing cheese. Umami is responsible for the immediate sensory effect of MSG on the palatability of food. MSG is used as flavouring agent.
However, it has long been known that MSG can also intoxicate arcuate nucleus neurones. In 1969, Olney and Sharpe reported on brain lesions, obesity, and other disturbances in mice (Olney, 1969), and in an infant rhesus monkey (Olney and Sharpe, 1969) treated with MSG. In 1976, Holzwarth-McBride et al. (1976) investigated the effect of the MSG induced lesion of the arcuate nucleus by measuring catecholamine content in this nucleus and the median eminence of the mouse hypothalamus. The two major characteristics of MSG-induced arcuate nucleus damage hitherto described, are voracity, and impaired GH secretion. However, all of these studies focussed on parenterally administered MSG. We demonstrated that MSG maintains its toxicity even when administered orally.
The influence of MSG is in general more marked in males than in females. Since MSG has excitotoxic activities and implies oxidative stress, the gender difference may be explained by to the antioxidant activity of estrogens (Ruiz-Larrea et al., 1997; Cuzzocrea et al., 2001). Estrogens have a very important neuroprotective activity (Azcoitia et al., 1999).
The present investigation was performed in animals not older than 90 days. Although at this age, the animals are still too young to exhibit obvious signs of obesity, MSG fed animals contain more body fat than controls, and show impaired glucose tolerance and insulin resistance (Hirata et al., 1997). Macho et al. (2000) found a shift in glucose metabolism towards lipid synthesis in fat tissue, in 3-month-old rats treated with MSG during the postnatal period, and demonstrated an attenuation of insulin effect on glucose transport due to a lower insulin binding and lower content of GLUT4 protein. They concluded that early postnatal administration of MSG exerts an important effect on glucose metabolism and insulin action in adipocytes of adult animals, indicating that apart from excitotoxic effects in the central nervous system, MSG treatment appears to also exert peripheral metabolic effects.
The present findings are alarming, and throw doubts upon the unscrupulousness of current use of the flavouring agent MSG. L-Glutamic acid was evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1988. The JECFA allocated an 'acceptable daily intake not specified' to glutamic acid and its salts with no additional risk to infants. The Scientific Committee for Food (SCF) of the European Commission reached a similar evaluation in 1991. The conclusions of a subsequent review by the Federation of American Societies for Experimental Biology (FASEB) and the Federal Drug Administration concurred with the safety evaluation of JECFA and the SCF (Walker and Lupien, 2000). MSG can be added at concentrations of up to 10 g per kg food (European Parliament and Council Directive 95/2/EC). Ca. 3 g MSG are added per kg potato chips (Greiff, Bahlsen-Lorenz company, personal communication, 2002), ca. 3–6 g are added per kg meat products (Kasch, Dölling company, 2002, personal communication).
We used a medium (2.5 g per day per adult animal) and a high (5 g per day per adult animal) MSG diet, accounting for some 10%, respectively, some 20% of the daily amount of food. Yet, rat chow is dried food. Assuming a water content of some 70% in an ordinary breakfast sausage, 6 g MSG per kg meat product equals some 2% MSG in the dry product. That is, the medium concentrations of GLU used in our animals, surpassed the concentration that is currently added to modern industrial food, by only the factor five!
The present study for the first time demonstrates, that a widely used nutritional monosubstance – the flavouring agent MSG – at concentrations that only slightly surpass those found in everyday human food, exhibits significant potential for damaging the hypothalamic regulation of appetite. Although the experimental part of this study was performed in rodents, and though it remains to be elucidated whether rodents are more sensitive to MSG than humans, uneasiness remains when considering that world-wide MSG production has increased from 200 000 (1969), to 270 000 (1979), to 800 000 tons/year in 2001 (Schmid, 2002) (Schmid, 2002, personal communication). First, clinical evidence in the treatment of very obese subjects further stresses the importance of GLU in the regulation of appetite: Blocking GLU action by antagonising GLU-gated Ca2+ ion channels with memantine normalises binge-eating disorders within a few hours (Hermanussen and Tresguerres, 2005).
Other questions remain: is obesity the disease that we are interested in? Obesity results from a nutritional imbalance. That is, in view of the present findings, we rather have to consider if not voracity is the disease that needs to be addressed in the first place. It has been shown that obesity associates with GH secretory dysfunction. A 24 h integrated concentrations of GH were lower in young, obese subjects than in young subjects who were lean (Meistas et al., 1982). Veldhuis et al. (1991) examined the mechanisms underlying the reduced circulating GH concentrations in obese subjects. Obese men had fewer GH secretory bursts, and both GH secretion rate and GH burst frequency were negatively correlated with the degree of obesity (Veldhuis et al., 1991). However, since obesity results from a nutritional imbalance, that is, obesity results from voracity – we are now concerned that both the damage in the regulation of appetite, and the impaired GH secretion, result from world-wide supraphysiological GLU consumption. The fact that large BMI associates with short stature, indicates towards the possibility that both excessive appetite and growth failure, may have a common cause.
If this be the case, many more questions arise: Do other amino acids metabolise into GLU, do other amino acids lead to similar toxic effects when fed at supraphysiological doses? Is GLU the only ligand that causes NMDA-R-mediated neuronal damage, or do elevated levels of glycine produce similarly deleterious effects when binding to the glycine site of the NMDA-R (the NMDA-R has a glycine-binding site (Huggins and Grant, 2005))? Is the NMDA-R the only receptor that mediates arcuate nucleus damages? Do oral loads of GLU exhibit the same effects than parenteral loads of this amino acid? Much work is still to be performed, but good reasons have already been accumulated to reconsider the recommended daily allowances of amino acids and nutritional protein, and to abstain from the popular protein-rich diets, and particularly from adding the flavouring agents MSG.
Ok, European Court, toxic or not, why is it allowed to add this stuff to food at all?