Abstract
I
The article focuses on the MSG-induced obesity model, which is produced by subcutaneous injection of MSG at the neonatal stage (2 mg/g body weight MSG from birth to 5 days of age, daily). The authors indicate that MSG appears to be a critical factor in the initiation of obesity, based on the result that restricted calorie intake resulted in the reduction of body weight gain but could not prevent the initiation of obesity.
They also suggest the possibility that MSG used in food as an additive may be involved in the onset of obesity and that the effect of maternal MSG intake on the fetus should be considered.
The MSG-induced obesity model is a well-known animal model, which was first reported by Dr. Olney in 1969. 2 What Dr. Fujimoto et al. reported in their article is almost the same as that reported by Dr. Olney. That is, Dr. Olney reported that subcutaneous injection of MSG at the neonatal stage, daily from 1 to 10 days after birth, induced obesity at a later stage of life (up to 150 days of age) as well as fatty livers, with slightly decreased food consumption. He attributed these symptoms to brain lesions observed within a few hours after the MSG injection.
The joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated the safety of MSG rigorously in 1987, including neurotoxicity followed by endocrinological disturbance. 3 The observed obesity is associated with an impaired pituitary function, which results in atrophy of related target organs such as thyroids and adrenals. The reduced level of prolactin and growth hormone was also reported. 4
JECFA scrutinized the possibility that neurotoxicity might be induced by MSG and the other salts of glutamate used as food additives from various points of view, including metabolism, kinetics, nutritional aspect (intake), and long-term study. Finally, JECFA concluded that the acceptable daily intake should be not specified, because of a very low toxicity.
The following are the key arguments indicating that neurotoxicity followed by obesity is not induced by MSG when used as a food additive.
1. The dose and the route of MSG administration (subcutaneous: 2 g/kg bw) presented in Dr. Fujimoto's article are unrealistic for human intake from foods.
• The LD50 of MSG in mice is 8.2 g/kg bw (s.c.) and 13.0–19.2 g/kg bw (oral). 3 The dose of MSG in the article is one-fourth of the LD50.
• The total intake of glutamate from food in European countries ranges from 5 to 12 g/day (free: ca. 1 g; protein bound: ca. 10 g; added as a flavor enhancer: ca. 0.4 g). In Asian countries, people use MSG more intensively than in Europe. The average intake of MSG in Asian countries ranges from 1.2 to 1.7 g/day. 5
• Rhodes et al. calculated the daily intake of free glutamate in the United Kingdom, measuring the free glutamate content of over 500 MSG-containing food items. The calculated intakes are whole population, 586 mg/day (12 mg/kg/day for an average 50 kg bw); extreme users (97.5th percentile consumers), 2330 mg/day (30 mg/kg/day for an average 70 kg bw); and children (10–11 and 14–15 years old), 1300 mg/day. 6
2. It is reported that the elevation of plasma glutamate level after the injection of MSG is significantly different between oral and subcutaneous administration.
• Glutamate is the single largest contributor to intestinal energy generation, being rapidly metabolized in the intestinal mucosal cells. Therefore, only oral administration of a high dose of glutamate causes elevation of the plasma glutamate level and low doses cannot. 7,8
• The peak plasma glutamate level of neonatal mice (10 days old) after the administration of 0.5 g/kg bw MSG was 62±6 (oral), 278±15 (s.c.) μmol/100 mL, and that of 0.7 g/kg bw MSG was 104±18 (oral), 385±32 (s.c.) μmol/100 mL. 9
• Subcutaneous injection of 2 g/kg bw MSG to neonatal mice caused an increase in plasma glutamate to 270 times the basal level, while the level in the arcuate nucleus increased four to seven times. 10
• Oral administration of 2 or 4 g/kg bw MSG to neonatal or adult rats caused the elevation of plasma glutamate levels 11–12 times as high as the basal level. No appreciable changes in the glutamate level in the lateral thalamus and in the arcuate nucleus were observed. 8
3. There are differences in sensitivity to neuronal injury between species, strain, and age of the animals.
• Neonatal animals are more sensitive than adult animals, due to the immature state of the development of the blood–brain barrier. Regarding the strain-dependent diversity, the order of the sensitivity is mice>rats>guinea pig>primate. 3
• The hypothalamic lesion was found in mice after the subcutaneous injection of MSG at the concentration of 0.5–4 g/kg bw on 2–9 days after birth. For adult mice, a subcutaneous injection of 5–7 g/kg bw MSG was required to cause hypothalamic lesions. 2
• It is reported that MSG oral administration of 250 mg or 1 g/kg daily for 30 days in three infant rhesus monkeys starting at 1 day after birth did not cause necrosis or damage of arcuate nuclei and the median eminence region in the brain. Those three monkeys exhibited normal growth, development, and activity. 11
4. The possibility of neurotoxicity in the fetus by maternal intake of MSG.
• The placenta is a natural barrier that prevents the transfer of glutamate from the maternal into the fetal circulation. The placenta uses glutamate as an energy substrate by extracting it from both maternal and fetal circulations. The fetal liver synthesizes glutamate from glutamine and exports it into the fetal circulation for use by the placenta and the fetal tissues. It is reported that the extraction of glutamate from the fetal circulation is about 90%. 12 From these observations, it is considered to be difficult to raise fetal plasma glutamate levels by elevating maternal plasma levels.
• Infusion of MSG into pregnant rhesus monkeys at a rate of 1 g/h led to a 10–20 times increase in the maternal plasma glutamate level. However, no increase of the fetal plasma level was observed. 13
MSG is a food additive that is orally taken with food. In addition to the above-mentioned standpoints, the kinetics of glutamate is significantly different between intake with or without food. Food containing carbohydrates significantly attenuates peak plasma glutamate levels, by enhancing the metabolism of glutamate in mucosal cells. As a result, less glutamate reaches portal circulation. Stegink reported that the peak plasma glutamate level after ingestion of MSG in water (150 mg/kg) under fasting conditions was seven times higher than that after the ingestion of a liquid meal with added MSG. 14,15
Tsai and Huang reported the circadian variation of plasma glutamate when meals with added 100 mg/kg bw MSG (15, 40, 45 mg/kg bw for breakfast, lunch, and dinner, respectively) were given to healthy adult men. It varied between 33 and 48 μM on days without added MSG, and 32 and 53 μM on days with added MSG. 16
Conclusion
Taken together, it is clearly not appropriate to propose from the result of Dr. Fujimoto's study, the possibility that the MSG used in food as a flavor enhancer may induce neurotoxicity followed by obesity and fatty liver, observed in this research.