Monosodium glutamate: A hidden risk factor for obesity?

Summary

Monosodium glutamate (MSG) has become one of the most widely used food additives in the global food supply. Although it has been classified for decades as a food ingredient that is generally recognized as safe, concerns about the health impacts of chronic MSG use, especially its potential effect on weight, are still ongoing. This comprehensive review summarizes the available human and animal evidence, highlighting potential mechanisms linking MSG use to weight gain or obesity, and discusses challenges and future research directions. Because of MSG intake worldwide as well as hidden MSG in food labeling, there is a pressing need for a mechanistic understanding of the health impacts of MSG use especially on weight. To generate robust scientific evidence and to clarify public concerns, rigorous mechanistic studies and randomized controlled clinical trials are warranted.

1 |. BACKGROUND

Monosodium glutamate (MSG), the sodium salt of glutamic acid, is a common food additive and flavoring agent. MSG was developed 100 years ago by the Japanese biochemist Kikunae Ikeda from edible seaweed, a food widely used in Japanese soups.¹ Today, MSG is often made from corn sugar, sugar cane, or sugar beets through a fermentation process.¹ It is added in commercially processed foods or during food preparation to enhance taste, in particular umami, the fifth taste.

1.1 |. MSG in food supply

MSG has become one of the most widely used additives, not only in Asian cuisine but in the global food supply. It is found in many restaurants and commercially processed foods, seasonings, and even in infant formulas.^2–5 According to the Information Handling Services (IHS) Chemical Economics Handbook, in 2014, world demand for man-made MSG was estimated at 3 + million metric tons, sold to more than 100 countries including the USA.⁶ Survey data in 1990s–2000s that were recently published have estimated that individual average daily MSG intake was near 1 g in Western countries and approximately 2 g in Asian countries, with extreme users consuming up to 10 g per day.^7–9 Of note, those survey data were likely underestimates due to missing information about MSG in commercially processed foods and/or seasonings.

1.2 |. Natural glutamate vs. man-made MSG

Glutamate occurs naturally in protein-containing foods. Notably, natural food vs. MSG sources of glutamic acids may be biologically different. For example, MSG is a single molecule, which can be absorbed directly into the circulation and pass the blood–brain barrier (BBB).^10–12 By contrast, glutamic acid in natural or unprocessed foods predominantly exists as a part of proteins or polypeptides, which need to be broken down in the digestive system before absorption into circulation.¹² In addition, there are two chiral forms of glutamic acids (L- and D-glutamic acid) that are fundamentally different. For example, D-amino acids can impede protein biosynthesis because the incorporation of D-amino acids into protein is inefficient.^13–15 The free glutamic acids in higher organisms are composed predominantly (if not exclusively) of the L-glutamic acid enantiomer, while MSG or processed free glutamic acid always contains some D-glutamic acid.^16–19

1.3 |. FDA’s regulation and concerns about MSG use

The US Food and Drug Administration (FDA) has classified MSG as a food ingredient that is “generally recognized as safe” (GRAS), and the FDA requires that MSG be listed on the food label.²⁰ However, MSG may also be hidden in ingredient labels when listed under other names.^3,21,22 For example, if a seasoning contains <99% sodium salt of glutamic acid, MSG may be listed as hydrolyzed protein, gelatin, hydrolyzed corn gluten, autolyzed yeast, textured protein, sodium caseinate, or yeast extract.^3,22

Concerns about MSG use have been raised for many years. In 1968, a Letter to the Editor in the New England Journal of Medicine first identified “Chinese restaurant syndrome”, attributing the symptoms to MSG intake.²³ Ever since, the FDA has received numerous reports of short-term adverse reactions with regard to MSG consumption such as headache and nausea. However, no clear causal link has been established between MSG consumption and those reported symptoms.²⁴ The last detailed FDA review of MSG and its health effects was in 1995, when the FDA endorsed a Federation of American Societies for Experimental Biology report that MSG as a food additive was generally safe.²⁵ However, scientific and public concerns about the potential health impacts of chronic MSG use persist. This includes, in particular, debates about MSG as a risk factor for obesity, a question first raised by Olney in 1969.²⁶

1.4 |. MSG dose, route of administration, and assessment in research

For decades, MSG has been used to induce obesity in animals, e.g., rodents, to study obesity or other metabolic disorders.^27–32 Of note, MSG data from most animal studies were generated by using relatively large doses of MSG and parenteral injection (e.g., 4 mg/g body weight, subcutaneously).³³ While debates on the health impacts of different MSG doses and routes continue, some studies have found that oral MSG use (e.g., 2.5 g/d) at a level similar to the amount typically added to food has a significant effect on weight, possibly by damaging hypothalamic regulation of appetite.^4,34 Such data from animal studies can serve as the foundation for translational research.

In observational human studies, MSG consumption has been usually assessed by multiple 24-hour recalls. Similar to other observational nutrition studies, dietary assessments are notoriously of poor accuracy, and measurement error seems inevitable.³⁵ In particular, information about added MSG in a variety of seasonings and/or commercially processed foods is often missing, which likely causes underestimation and differential misclassification of MSG intake.

In addition, the relationship between MSG intake and blood glutamate concentration is unclear. A few studies from the same lab indicate that a single test meal can increase plasma glutamate up to 5-fold within a few hours of consuming different doses (e.g., 34 mg/kg to 150 mg/kg),^36–39 but others⁴⁰ show no significant rise in plasma glutamate concentrations, presumably, due to the extraordinary ability of intestinal cells to metabolize glutamate.^41,42

2 |. STUDIES LINKED MSG TO OBESITY OR ADIPOSITY

Because of substantial heterogeneities of the existing literature in study design, study subject, animal model, and MSG dose, duration, and route of administration, we conducted this study as a comprehensive review with a systematical literature search. We aimed to reveal a big picture of the existing literature and present a deeper understanding of the historical studies, the underlying mechanisms, and the challenges of this research area.

We systematically searched PubMed, and Web of Science (WOS) for relevant studies published until August, 2024. Google Scholar was used to complement the database searches. The detailed search strategy can be found in Supplementary Table 1a and b. Briefly, the broad search string included the combination of 1) (monosodium glutamate) OR (glutamate) OR (Ajinomoto); and 2) (obesity) OR (overweight) OR (adiposity). The reference list of studies identified from aforementioned databases were also reviewed for any relevant studies. Search results from PubMed (N = 2514) and WOS (N = 1405) were imported to Covidence for screening. After removing 770 replicates by Covidence, a total of 3149 articles were screened for relevancy based on title and abstract. Figure 1 presents the flow diagram of literature search and screening adapted from the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline.⁴³ KK and YZ independently reviewed the full-text articles (N = 43) and determined the eligibility based on the Population, Intervention, Comparison, Outcomes, and Study (PICOS) inclusion and exclusion criteria (Supplementary Table 2).

FIGURE 1.

PRISMA flow diagram of study selection.

2.1 |. Laboratory studies

As early as the 1960s, Olney found that adult mice treated parenterally with MSG (0.5 to 4 mg/g, subcutaneous injection) developed marked obesity (Table 1).²⁶ The finding was confirmed or supported by numerous other animal studies with MSG doses ranging from 1 to 5.8 mg/g through subcutaneous or intraperitoneal injection,^44–55 though three studies reported that MSG injection at a similar dose did not significantly affect weight or adiposity in mice and/or rats.^46,56,57 Additionally, studies investigated the effects of MSG oral administration with contradictory findings. In a one-week feeding study with a formula diet comprised of 30 g/kg MSG, no significant changes in weight were observed among gerbils.⁵⁸ However, two other feeding studies in rats or cats with lower amounts of MSG in a controlled diet found significant weight gain in the MSG-treated group.^59,60 In animal models fed with food ad libitum, one study,⁶¹ but not others,^46,62–64 found that MSG intake caused high abdominal fat or weight gain. A few studies provided animals with free access to MSG-added drinking water. Some,^65,66 but not all,^46,63,67,68 found effect of MSG on weight or adiposity. Notably, the doses of MSG in these studies were much lower than the injected dose used to induce obesity in rodent models.^69–71

TABLE 1.

Animal studies related MSG to obesity or body weight.

Author/year	Animal model	Route of administration	MSG dose	Follow-up or duration	Increased risk of obesity or weight		Funded by and/or collaborated with MSG industry or associated organization†
					Yes	No
MSG injection
Olney26/1969	Swiss albino mice	Subcutaneous injection	0.5 to 4 mg/g	Birth to 9 months	√		No
Redding44 1971	Sprague-Dawley rats	Subcutaneous injection	2.2 to 4.2 mg/g	Birth to 110 days	√*		No
Pizzi45/1976	Albino mice	Subcutaneous injection	2.2 to 5.8 mg/g	At least 150 days	√		No
Bunyan46/1976	CFLP mice	Subcutaneous injection	3 mg/g	20 to 30 weeks	√		No
	CFLP mice	Intraperitoneal injection	5 mg/g	23 weeks	√
	CFY rats	Intraperitoneal injection	5 mg/g	17 weeks		√
Nemeroff47/1977	Sprague-Dawley rats	Intraperitoneal injection	4 mg/g	31 weeks	√		No
Pizzi48/1977	BLU:Ha (ICR) mice	Subcutaneous injection	2.2 to 4.2 mg/g	302 days	√		No
Tanaka49/1978	ICR-JCL mice	Subcutaneous injection	2 mg/g	Birth to 15 weeks	√		No
Kanarek50/1979	Sprague-Dawley rats	Subcutaneous injection	2 or 4 mg/g	130 days	√		No
Komeda56/1980	Hamster	Subcutaneous injection	4 mg/g	30 weeks		√	No
Lorden57/1986	CF-1 albino mice	Subcutaneous injection	1 to 4 mg/g	150 days		√	No
Hriscu51/1997	Newborn mice	Intramuscular injection	2 mg/g	30 days	√		No
Miśkowiak52/1999	Female Wistar rats	Subcutaneous injection	4 mg/g	18 months	√		No
Tsuneyama53/2014	DIAR mice	Subcutaneous injection	4 mg/g	54 weeks	√		No
Savcheniuk54/2014	Wistar rats	Subcutaneous injection	3 to 4 mg/g	4 months	√		No
Fujimoto55/2014	ICR mice	Subcutaneous injection	2 mg/g	12 months	√		No
Feeding studies
Bazzano58 1970	Gerbils	Formula food	30 g/kg per day	1 week		√	No
Bunyan46/1976	CFLP mice and CFY rats	Drinking water or food ad libitum	20 g/l or 20 g/kg	14 or 23 weeks		√	No
Collison59/2011	Domestic cats	Controlled diet	1.125% MSG (average 201.4 mg/kg) twice a day	9 months	√		No
Ren67/2011	C57BL6/J mice	Drinking water free access	1% MSG solution	15 weeks		√	Yes
Afifi61/2011	Albino rats	Food ad libitum	0.1 g/g	20 days	√		NA
Boutry62/2011	Wistar rats	Normoenergetic diet	2% MSG w/w	15 days		√	Yes
Tordoff63/2012	Sprague Dawley rats and C57BL/6 J mice	Drinking water or food ad libitum	1% MSG solution or 1 to 3% MSG w/v.	8 to 26 weeks		√	Yes
Nakamura68/2013	C57BL/6 J mice	Drinking water free access	0.064% MSG solution	32 weeks		√	Yes
Abd El-Aziz64/2014	Sprague Dawley rats	Food ad libitum	395 mg/kg daily	6 weeks		√	NA
Nusaiba60/2018	Wistar rats	Controlled diet	3, 6 or 9 g MSG mixed with 300 g feed	14 days	√		NA
Othman65/2019	Albino mice	Drinking water free access	360 mg/kg in water daily	1 month	√		No
Andres- Hernando66/2021	AMPD2 knockout Mice	Drinking water free access	60 to 300mM (1 to 5% w/v)	2 weeks	√		No

^*The MSG-treated rats appeared to be obese based on the Lee obesity index (weight^0.33/Naso-Anal Length).

^†Information derived from disclosure/acknowledgment and authorship. NA: no information is available.

A feeding study in pregnant rats found that MSG (Purina rat chow ad libitum supplemented with 0.1 g/g) caused a substantial increase in maternal abdominal fat and fat/body weight ratio through leptin resistance, as well as dyslipidemia and perturbation of the expression of both leptin and its receptor.⁶¹ Consistently, subcutaneous administration of MSG (4 mg/g) to newborn rats caused obesity, decreased adiponectin, and increased leptin in adulthood.⁵⁴ In a rodent model of MSG-induced obesity and non-alcoholic steatohepatitis (NASH), caloric restriction modulated NASH progression but was unable to prevent its development, highlighting the critical role of MSG to trigger obesity.⁵⁵ Moreover, a feeding study in adult rats revealed a significant dose-dependent increase in body weight across groups treated with different doses of MSG (3, 6, and 9 g per day) compared to the control group (no MSG); body weight correlated positively with the duration of MSG consumption.⁶⁰ Notably, the majority of studies reporting either no effect or favorable effect of MSG consumption on weight or body composition was either conducted or funded by MSG manufacturers or associated organizations.

In sum, findings from the available laboratory studies conducted across a few decades are inconsistent. Several lines of evidence suggest a link between MSG use and weight gain. Presumably, the inconsistent results might be explained by the heterogeneities in animal models and MSG dose, duration, and route of administration in the studies.

2.2 |. Human studies

Although concern for MSG as a risk factor for obesity has been proposed for decades,^4,72 human data directly relating MSG intake to body weight or obesity are limited, and findings are inconsistent (Table 2). In the early 1970s, a feeding study with large amounts of MSG (25 to 147 g/day) in a formula diet given to 14 adult men for 2 to 6 weeks (mean ~3 weeks) did not find any significant effect on body weight. Presumably, the absence of reported effect of MSG on weight was due to the study design with isocaloric formula diet (the composition was not provided) to maintain energy balance.⁵⁸ Also, a single-blind randomized trial was conducted in the Netherlands among 97 elderly women and men.⁷³ MSG treatment group was provided meal with 0.3 g MSG and 0.7 g maltodextrine, and the control group was provided meal with 1 g maltodextrine. After 16-week intervention, no significant effect on weight was observed. The average body weight in the MSG group was decreased by 0.7 kg, while it was increased by 0.1 kg in the control group. The loss to follow-up rate was 8% for the control group and 21% for the MSG group, respectively. In addition, a crossover trial was conducted in France among 13 healthy adults.⁷⁴ Two grams of MSG supplementation or sodium chloride (NaCl) was given for 6 days. While the total protein intake had no change, intakes of a number of indispensable amino acids were significantly increased. However, the body weight of the participants remained stable over the intervention period.

TABLE 2.

Human studies related MSG to weight/obesity.

Author/year/country	Study design	Sample size	Participant age	MSG dose/intake range	MSG assessment	Study period	Main findings	Funded by and/or collaborated with MSG industry or associated organization†
Feeding study or trial
Bazzano58/1970/USA	Feeding study	14	NA (adults)	25–147 g/d added to a formula diet	NA	14 to 42 days	No effect on weight	No
Essed73/2007/Netherlands	Single blind randomized trial	97	65 + years	0.3 g MSG + 0.7 g maltodextrine vs. 1 g maltodextrine (placebo) per meal	NA	105 to 112 days	No effect on energy intake and weight	Yes
Boutry74/2011/France	Crossover trial	13	30–50 years	2 g/d MSG vs. NaCI (placebo)	NA	6 days	No effect on weight	Yes
Observational study
He77/2008/China	Cross-sectional	752	40–59 years	Men: 0.36 g/d Women: 0.30 g/d	24-hour recalls + weighing	N/A	MSG intake is positively associated with BMI and risk of overweight	No
Shi79/2010/China	Prospective study	1227	20 + years	3.8 g/d	Questionnaire	5 years	MSG intake is inversely associated with weight gain. The inverse association becomes non-significant after adjustment for rice intake or food patterns.	No
He8/2011/China	Prospective study	10,095	18–65 years	2.2 g/d	24-hour recalls + weighed food inventory	5.5 years	MSG consumption is positively associated with BMI and incidence of overweight	No
Insawang76/2012/Thailand	Cross-sectional	349	35–55 years	3.6 g/d	MSG is provided for food preparation for 10 days and the amount utilized is assessed at the end of the 10-day period.	N/A	MSG consumption are associated with risk of overweight and metabolic syndrome.	No
Hien77/2013/Vietnam	Cross-sectional	1528	20 + years	2.2 g/d	24-hour recalls + weighing	N/A	MSG intake is not associated with risk of overweight	Yes
Zou78/2015/China	Cross-sectional	5577	49–58 years	Median 1.6 to 3.4 g/d	24-hour recalls	N/A	MSG intake is positively correlated with BMI in town residents, but not among residents in urban and rural areas.	No

^†Information derived from disclosure/acknowledgment and authorship.

N/A: not applicable.

As for observational studies, a cross-sectional analysis among 752 generally healthy Chinese adults found that MSG consumption was associated with increased prevalence of overweight after controlling for physical activity, energy intake, and additional factors (adjusted odds ratio [OR]: 2.75, 95% confidence interval [CI]: 1.28–5.95, p for trend = 0.04).⁷⁵ A positive cross-sectional association between MSG intake and overweight was also observed in a study of 349 Thai adults from 324 families in a rural area of Thailand (OR: 1.16, 95% CI: 1.04–1.29, p for trend <0.01) with adjustment for sex, age, physical activity, smoking, history of diabetes and calorie intake.⁷⁶ However, a cross-sectional study of 1528 adults, conducted by a MSG industry-funded institute in Vietnam, reported no association between MSG and overweight with adjustment for education and smoking.⁷⁷ In another cross-sectional analysis of 5577 adults randomly selected in China, a significant positive correlation was found in town residents (correlation coefficient between MSG and BMI: 0.087, p < 0.05), but not among residents in urban and rural areas.⁷⁸ While these studies may help generate hypotheses, cross-sectional study designs can be biased by reverse causation, preventing the establishment of temporality. In a prospective study among 10,095 adults from 9 Chinese provinces, MSG consumption was positively associated with overweight development after adjusting for age, sex, urban residence, region, smoking status, alcohol consumption, individual income, education, physical activity, and dietary intakes of total energy, sodium, potassium, and calcium (OR: 1.28, 95% CI: 1.12–1.45, p for trend <0.01).⁸ However, prospective data from 1282 Chinese adults in the Jiangsu Nutrition Study found a significant inverse association between MSG intake and weight gain with adjustment for age, sex, smoking, drinking, eating out, active commuting, leisure time physical activity, sedentary activity, education, occupation, and total energy and glutamate intake (OR: 0.47, 95% CI: 0.27–0.84, p for trend = 0.028).⁷⁹ This inverse association was attenuated and became non-significant after further adjustment for rice intake and patterns of food consumption. Similarly, a randomized two-way cross-over design experimental study conducted by a MSG manufacturer reported that energy intake was significantly less during lunch and before mid-afternoon snacks with an MSG (total 1 g) soup preload compared with a control soup preload in 68 overweight or obese women (BMI range: 25.0–39.9 kg/m²) tested once a week for 3 weeks in an industry research laboratory.⁸⁰ Thus, overall findings on MSG and adiposity in humans have been limited and mixed. A definitive conclusion is premature based on the existing human data.

3 |. POTENTIAL MECHANISMS LINKING MSG TO OBESITY

Although findings from both animal and human studies are controversial and the biological mechanisms are not completely understood, there are a few suggested pathways linking MSG use to weight gain or obesity (Figure 2).

FIGURE 2.

Potential mechanisms linking MSG and obesity (created with BioRender.com).

3.1 |. Increased food intake

Added MSG flavoring, which enhances the taste or provides umami, increases food palatability, and may increase food intake. For instance, an animal study found that food intake was higher in rats fed the standard diet supplemented with MSG (100 g/kg) than in those fed the control diet.⁸¹ The findings are supported by another feeding study indicating that oral MSG (5 g/d) resulted in an almost two-fold increase in food uptake (p < 0.01) in rats.⁴ In human observation studies, MSG increases palatability, stimulates appetite, and consequently increases energy intake which may cause weight gain.^82–84

3.2 |. Leptin resistance

An MSG-leptin resistance-obesity pathway has been proposed based on findings from animal studies, but has not been tested in human studies. Leptin, the adipokine produced by adipocytes, crosses the BBB via active transport and regulates energy intake via a specific signaling cascade implicating the neuropeptide Y (NPY)/agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, where leptin receptors are present.^85,86 Leptin’s key role in regulating food intake and energy balance was established in seminal studies.^87,88 Individuals with obesity have leptin resistance, which prevents normal physiologic responses and appetite suppression.⁸⁹

Some studies indicate that MSG may cause leptin resistance.^{34,54,61,66,90,91} For example, leptin administration suppressed body weight gain in controls but had no such effect in MSG-treated Sprague–Dawley rats (4 mg/g, subcutaneous injection).⁹⁰ This finding was verified by another study in Wistar rats showing that leptin administration significantly inhibited food intake and caused weight loss in control rats, whereas MSG-treated (4 mg/g, subcutaneous injection) rats did not respond to leptin administration.⁹¹ In a rat model, oral administration of MSG (2.5 or 5 g/d) during gestation and development damaged the arcuate nucleus, decreased leptin, and increased food intake.³⁴ Additionally, a recent study found that oral MSG consumption (60 to 300mM in drinking water) caused hypothalamic inflammation, central leptin resistance, and obesity in adenosine monophosphate deaminase-2 (AMPD2) knockout mice.⁶⁶ These studies suggest that rats treated with MSG may develop leptin resistance, although the MSG doses used in most animal studies are supraphysiologic.

Nevertheless, leptin resistance could be related to hypothalamic damage. For example, neonatal subcutaneous administration of MSG (e.g., 0.5 to 4 mg/g) to rodents (e.g., Swiss albino mice) results in hypothalamic damage⁹² and obesity,^26,93,94 similar to models of obesity caused by hypothalamic tumors.^95,96 Notably, most of the evidence on hypothalamic lesions and resulting increased appetite derives from laboratory animals injected parenterally with MSG. Yet, a few animal studies from different laboratories have demonstrated that oral administration of MSG at relatively low doses (e.g., 5 g/d, similar to the amount in the human diet) also results in hypothalamic damage.^{4,34,97–102} Those findings suggest that the potential toxicity of MSG on hypothalamic neurons may interrupt or attenuate the actions of leptin on the arcuate nucleus, which is necessary for maintaining energy balance. Thus, MSG intake may cause leptin resistance resulting in overweight or obesity by impairing the hypothalamic leptin signaling cascade.^72,103 This hypothesis is supported by a number of laboratory studies.^4,104–110 In these studies, MSG administration in various animal models leads to significant neuronal damage, centered on the hypothalamus, alterations in key neurotransmitter systems, and disruptions in growth hormone secretion and metabolic processes.

3.3 |. Effects on gut microbiota

MSG may also affect gut microbiome composition and function, both critical factors contributing to obesity by altering host energy harvest, storage, and hormonal responses.^111–115 In a cohort comparing young Chinese individuals with and without obesity, investigators identified that abundance of gut microbiota L Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in participants with obesity and was also inversely correlated with serum glutamate concentration.¹¹⁶ In mice, gavage with B. thetaiotaomicron reduced plasma glutamate and alleviated diet-induced body-weight gain and adiposity. In addition, weight-loss intervention by bariatric surgery in humans with obesity reversed obesity-associated microbial and metabolic alterations, leading to a more normal abundance of B. thetaiotaomicron and lower levels of serum glutamate.¹¹⁶ The effects of MSG ingestion on the microbiota have not been well investigated. A short-term (4 weeks), small-scale (n = 12), non-randomized human study showed limited effect of low doses of MSG administration (2 g/d) on stool microbial composition in lean individuals.¹¹⁷ However, in a rodent model, chronic consumption of MSG combined with high-fat and high-fructose (HFF) diets induced gut dysbiosis compared to feeding MSG or HFF diet alone.¹¹⁸ Also, a recent experiment in mice found that obesity was associated with elevated stool L-glutamic acid.¹¹⁹ Additionally, previous studies have indicated that the risk of obesity and metabolic phenotypes can be influenced by transferring the microbiota from obese donors regardless the microbiota source is murine or human.^113,120,121

3.4 |. Purine nucleotide degradation

MSG could influence biological pathways involved in sugar and salt consumption. Higher consumption of sugar or sweet foods or beverages has been associated with increased visceral adiposity in some studies.^122,123 Additionally, salt intake has been observationally linked to weight gain and obesity.^124,125 A recent study, in wild-type mice supplied with MSG-laced drinking water (from 60 to 300mM, 1 to 5% w/v), suggests that MSG consumption may induce obesity through the purine nucleotide degradation pathway, a pathway that is also activated by fructose or sugar and salt consumption.⁶⁶ In particular, MSG intake activates purine nucleotide production, lowers adenosine triphosphate (ATP) levels, and stimulates the enzyme AMPD2. Depleted ATP, together with uric acid-dependent oxidative and inflammatory conditions, can decrease the sensitivity of the hypothalamus to leptin; it can also promote food and caloric intake, ultimately increasing adipose tissue mass and causing ectopic fat accumulation in the liver. Notably, MSG, salt, and sugar might all engage a common pathway, necessary for survival by ancestral humans, but which increases the risk for metabolic disorders today.⁶⁶ In sum, while more studies are surely needed to better understand the underlying mechanisms, preliminary evidence suggests that MSG may influence pathways and/or have joint effects with sugar and salt intake resulting in perturbation of energy balance. This is of public health significance as food manufacturers often add MSG to enhance the taste and palatability of processed food.

4 |. CHALLENGES IN STUDYING MSG AND FUTURE RESEARCH

The compelling results from animal experiments, combined with limited and conflicting evidence from human studies, has raised controversy about the potential effect of MSG consumption on adiposity, as reflected by several narrative reviews,^31,126–130 letters to the editor,^131–133 and an editorial¹³⁴ that have reached conflicting conclusions.

The contradictory evidence in observational studies likely relates, at least in part, to the methodological challenge of assessing MSG intake. In most of these studies, MSG consumption was estimated from types of foods reported in multiple 24-hour recalls, although some studies also employed home visits to weigh MSG containers used in cooking. Such information can be reasonable to broadly rank participants by MSG intake (e.g., users vs. non-users or higher vs. lower), but is less accurate for quantitative assessments of MSG consumption, due to the relatively small amounts added during food preparation, potential for intra-person variation in intake over time, and presence of hidden MSG in seasonings, commercially processed foods, and/or restaurant foods. Also, measurement error for MSG consumption could be systematic, i.e., related to other risk factors for obesity, which may bias the observed associations in unpredictable ways.

Currently, there are no known available biomarkers to assess MSG consumption. Circulating glutamic acids, for example, cannot distinguish MSG as a source vs. glutamic acids derived from natural foods such as fish or tomato juice. An alternative approach is to use adherence biomarkers. For instance, in a pilot study,⁸ riboflavin was physically mixed with MSG. Healthy individuals are easily saturated with riboflavin and extra intake is almost exclusively excreted through urine. Thus, investigators assessed total household MSG consumption by weighing the MSG container before and after the 24-hour recall, and then estimating the proportion of food consumption, including MSG, by measuring urinary riboflavin among household members. A drawback is that this approach can only be used in intervention or controlled feeding studies in which MSG or foods, mixed with a certain amount riboflavin, are provided by the investigators. Theoretically, MSG can also be isotopically labeled and tracked, but the practical feasibility of this method in a human study has yet to be established. Thus, to overcome the limitations of observational studies such as bias or confounding from unknown or unmeasured factors, and to generate more rigorous scientific evidence, randomized placebo-controlled trials are required.

In addition, most of the human studies were conducted in Asia where MSG is commonly added during food preparation in addition to consumption from commercially processed and/or restaurant foods. Thus, the possibility of confounding by “Nutrition Transition” cannot be excluded due to the shift in dietary consumption and energy expenditure that coincides with economic, demographic, and epidemiological changes in the past decades.¹³⁵

Moreover, clinical trials funded by for-profit vs. not-for-profit organizations tend to report different results.¹³⁶ In reviewing the MSG literature, we observed a similar phenomenon. For instance, MSG increases food palatability, which should stimulate appetite and increase food intake. However, some human studies conducted or supported by the MSG industry or associated organizations report increased satiety,¹³⁷ and decreased energy intake in an ad libitum meal with added MSG.^80,138 This paradoxical literature further highlights the need for rigorous independently funded studies.

Notably, the technology to enable precision nutrition has advanced in recent years.¹³⁹ To better understand the potential effect of MSG on weight, future research should consider individual differences in the metabolome and the microbiome such as the exposome. To identify potential metabolic pathways that may contribute to the role of MSG in obesity, global, non-targeted metabolomic profiling (i.e., the unbiased examination of hundreds or thousands of small metabolites in a biological sample using a high-throughput platform) may be useful.^140–142 Studies of effects of MSG consumption on the microbiome in humans, such as effects on the abundance of B. thetaiotaomicron, are needed. In addition, the hypothalamus consists of several nuclei with distinct functions, some of which involve regulation of food intake or energy balance. Recent advances in molecular techniques have allowed researchers to define the neurocircuitry of a number of important centrally controlled homeostatic processes, e.g., energy balance.¹⁴³ Additionally, functional magnetic resonance imaging has been established as the gold standard in the assessment of neuronal functions related to nutrition.¹⁴⁴ It has been used to delineate brain regions that show altered activity in obese individuals.¹⁴⁵ Together, these advanced techniques may help us better discover the health impact of MSG use and the underlying neuronal mechanisms in relation to obesity.

5 |. SUMMARY

The consumption of MSG has steadily increased worldwide based on data from the glutamate industry. While MSG is listed in the GRAS as a safe ingredient by the FDA, questions and debates about its effects on human health have been ongoing since the mid-20th century. The existing literature from both animal and human studies are inconsistent, which may be explained by the substantial heterogeneities in study design, study subject, animal model, and MSG dose, duration, and route of administration. Despite the discussed limitations and challenges, several lines of evidence suggest potential for concern that MSG use may be an added risk factor of obesity. There is a pressing need for more mechanistic and interventional studies on the health impact of MSG in humans, and well-designed randomized placebo-controlled trials are warranted.

Abbreviations:

MSG

monosodium glutamate

IHS

Information Handling Services

BBB

blood–brain barrier

FDA

Food and Drug Administration

GRAS

generally recognized as safe

WOS

web of Science

PICOS

Population, Intervention, Comparison, Outcomes, and Study

NASH

non-alcoholic steatohepatitis

OR

odds ratio

BMI

body mass index

NPY

neuropeptide Y

AgRP

agouti-related protein

POMC

proopiomelanocortin

AMPD2

adenosine monophosphate deaminase-2

HFF

high-fat and high-fructose

ATP

adenosine triphosphate.