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Cited by 194Advanced Glycation End Products researchPotato Plant ResearchAdipokines, Inflammation, and Metabolic Diseases

The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction

Open access
Sergi, Domenico, Boulestin, Hakim, Campbell, Fiona M., Williams, Lynda M.·2021·Molecular Nutrition & Food Research
DOI 10.1002/mnfr.201900934
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Abstract

Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non‐enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β‐cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β‐cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes mechanisms by which dietary advanced glycation end products (AGEs) contribute to metabolic dysfunction, including insulin resistance, pancreatic β-cell dysfunction, hypothalamic inflammation, obesity, and type 2 diabetes mellitus. It covers AGE formation, absorption, receptor signaling, detoxification, and evidence from cell, animal, and human studies while noting measurement and dietary AGE controversies.

Key findings

  • Dietary AGEs are formed via the Maillard reaction during cooking and processing; around 10–30% are absorbed depending on chemical characteristics, with free low-molecular-weight AGEs absorbed more efficiently than protein-bound AGEs. Foods such as peanuts, biscuits, cereals, toast, and heat-processed meats have the highest measured CML, CEL, and MG-H1 levels (2–5 mg, 2–7 mg, and 15–60 mg per 100 g, respectively), whereas coffee, fruits, vegetables, butter, olive oil, and red wine contain negligible amounts.
  • AGEs activate RAGE and downstream pathways including JNK, IKK/NF-κB, and NADPH oxidase/ROS, promoting inflammation and oxidative stress that impair insulin signaling, downregulate GLUT4, and contribute to β-cell cytotoxicity, apoptosis, and impaired glucose-induced insulin secretion.
  • In animal models, a high-AGE diet containing synthetic MG-BSA at 1 mg per g of diet decreased insulin receptor and IRS phosphorylation and defective AKT activation in skeletal muscle, adipose tissue, and liver. In humans, an AGE-restricted diet improved insulin sensitivity in T2DM and normalized AGER1 and sirtuin1 while decreasing NF-κB acetylation, circulating TNFα, serum AGEs, and leptin; hyperinsulinemic-euglycemic clamp studies showed a low AGE diet improved insulin sensitivity versus a high AGE diet decreasing it.
  • AGEs may promote obesity via hypothalamic inflammation and disrupted central energy balance; a high-fat/high-carbohydrate diet increased CML immunoreactivity in POMC and NPY neurons, and RAGE/ALCAM knockdown improved metabolic phenotype and decreased microglial reactivity. A 5-year follow-up study associated AGEs with increased body weight after adjusting for total energy intake and other confounders.

Methods

  • Narrative review; no primary experimental data are reported. The paper synthesizes published literature on AGE formation, dietary sources and absorption, receptors, detoxification, and metabolic effects.
  • Evidence discussed includes cell culture studies, animal models, human feeding trials, hyperinsulinemic-euglycemic clamps, and cohort follow-up data.
  • Main analysis is a qualitative synthesis of mechanisms and cited findings; no systematic search strategy, meta-analysis, or quantitative pooling is described.

Limitations

  • The paper states there is debate about the relative importance of dietary AGEs because of limited digestion and absorption, particularly of high-molecular-weight AGEs, while low-molecular dietary AGEs appear to be efficiently disposed of by the kidneys.
  • The paper notes intrinsic problems in comparing AGE concentrations across studies due to different measurement techniques and food matrix effects; immunoassays do not give absolute values, whereas mass spectrometry gives absolute concentrations for AGEs such as CML.
  • The paper reports conflicting human feeding studies: some show AGE restriction reduces inflammation and improves vascular function, but two feeding studies showed no effect of dietary AGEs on inflammatory and cardiovascular profiles. Evident from the text: as a narrative review, it lacks systematic search, risk-of-bias assessment, and quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/mnfr.201900934

Cites

143 of 143 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Dicarbonyls can also be generated from glucose autoxidation, lipid peroxidation, and the polyol pathway.

    “These molecules can also be generated from glucose autoxidation, lipid peroxidation, and the polyol pathway.[18]”
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  • Premisecitation

    Glucose is a poor glycating agent compared to dicarbonyls such as methylglyoxal.

    “Despite its ability to react with free amino groups, glucose is a poor glycating agent compared to dicarbonyls such as methylglyoxal.[16]”
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  • Premisecitation

    Excessive AGE formation is particularly associated with cross-linking of matrix proteins such as collagen, vitronectin, and laminin.

    “Excessive AGE formation is particularly associated with cross-linking of matrix proteins such as collagen, vitronectin, and laminin.[2,10,11]”
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  • Premisecitation

    Fructose can increase AGE formation independently of glucose by increasing alpha-oxoaldehyde levels.

    “Additionally, fructose can increase AGE formation independently of glucose by increasing 𝛼-oxoaldehydes levels.[5]”
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  • Interpretationreasoning

    AGEs may contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance.

    “Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance.”
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    Premisecitation

    Free-AGEs are a good marker for dietary AGE intake, while plasma protein-bound AGEs better represent endogenously produced AGEs.

    “making free-AGEs a good marker for dietary AGE intake while plasma protein-bound AGEs better represent endogenously produced AGEs.[31]”
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    Premisecitation

    Absorption of AGEs as single amino acids or dipeptides occurs more efficiently than protein-bound AGEs, evidenced by higher levels of CML in faeces when protein-bound CML is ingested.

    “Thus, the absorption of AGEs as single amino acids or dipeptides occurs more efficiently than protein-bound AGEs, evidenced by higher levels of CML in the faeces when protein-bound CML is ingested.[36]”
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    Premisecitation

    Dietary AGEs are absorbed by the gastrointestinal tract, and dietary and circulating free-AGE concentrations are highly correlated.

    “Dietary AGEs are absorbed by the gastrointestinal tract to exert their effects on health with dietary and circulating free-AGEs concentrations highly correlated, [28][29][30]”
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    Premisecitation

    AGEs are produced endogenously as part of normal metabolism and during cooking and processing of food, and a significant proportion is absorbed in the gastrointestinal tract.

    “AGEs are produced both naturally in the body, as part of normal metabolism, and during the cooking and processing of food with a significant proportion being absorbed in the gastrointestinal tract.”
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    Premisecitation

    Free CML is absorbed by simple diffusion, while dipeptides require peptide transporter 1, which also transports pyrraline dipeptides.

    “Free CML is absorbed by simple diffusion, [33] with dipeptides requiring the peptide transporter 1, [34] which also transports pyrraline dipeptides.[35]”
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    Premisecitation

    AGE modification inhibits proteolytic digestion, so low molecular weight AGEs are absorbed more efficiently than protein-bound AGEs.

    “AGE modification inhibits proteolytic digestion [32,38] thus, low molecular weight AGEs are absorbed more efficiently than protein-bound AGEs.[39]”
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    Premisecitation

    Increased presence of AGEs in collagen across eight mammalian species is associated with reduced lifespan, indicating that AGE levels determine lifespan and rate of ageing.

    “Also, the increased presence of AGEs in collagen across eight mammalian species has been shown to be associated with reduced lifespan, indicating that AGE levels determine lifespan and rate of ageing.[14]”
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    Premisecitation

    The Western diet contains large amounts of AGEs due to high levels of food processing and is high in fat and sugar, particularly fructose, which increases AGE production in the body partly by increasing circulating glucose levels via enhanced hepatic glucose production and insulin resistance.

    “Furthermore, the Western diet not only contains large amounts of AGEs, due to high levels of food processing, but is also high in fat and sugar, particularly fructose, which increases AGE production in the body, in part, by increasing circulating glucose levels via enhanced hepatic glucose production and insulin resistance.[4]”
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    Premisecitation

    The most prevalent hydroimidazolone in human tissues is formed from the interaction of methylglyoxal with arginine residues.

    “Some of the most commonly formed AGEs include the hydroimidazolones, the most prevalent of these in human tissues is formed from the interaction of methylglyoxal with arginine residues.[23]”
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    Premisecitation

    AGEs are implicated in the development of numerous chronic diseases including diabetes-related complications, cardiovascular, renal, and neurodegenerative disease, and have recently been implicated in hypothalamic inflammation and obesity.

    “Advanced glycation end products (AGEs) are a complex and heterogeneous group of protein, lipid, and DNA adducts implicated in the development of numerous chronic diseases including diabetes related complications, cardiovascular, renal, and neurodegenerative disease, and have recently also been implicated in hypothalamic inflammation and obesity.[1]”
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    Premisecitation

    Activity of glyoxalase is upregulated in diabetes to prevent build-up of reactive dicarbonyls, thereby suppressing AGE formation.

    “Activity of the glyoxolase is upregulated in diabetes to prevent the build-up of reactive dicarbonyls thereby suppressing AGE formation.[69]”
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    Interpretationcitation

    MG-H1 does not require attachment to a peptide carrier to exert its effect, and because MG-H1 content of foods is much higher than CML or CEL, free MG-H1 absorbed from the diet is likely to be a significant activator of mRAGE.

    “In contrast to CML or CEL, the hydroimidazolone MG-H1 does not require attachment to a peptide carrier to exert its effect [47] and as the MG-H1 content of foods is much higher than either CML or CEL, free MG-H1 absorbed from the diet is likely to be a significant activator of mRAGE. [27,48]”
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    Premisecitation

    AGER1 can counteract AGE-induced oxidative stress and inhibit activation of NF-kB by promoting sirtuin1-dependent deacetylation and suppression of NF-kB.

    “AGER1 can counteract AGE-induced oxidative stress [61,62] as well as inhibit the activation of NF-𝜅B by promoting a sirtuin1-dependent deacetylation and suppression of NF-𝜅B.[63,64]”
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    Premisecitation

    AGER1 is present in almost all cells and tissues, is upregulated by AGEs, and increases their uptake and removal.

    “AGER1 is present in almost all cells and tissues, is upregulated by AGEs and increases their uptake and removal.[18]”
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    Premisecitation

    Around 99% of all methylglyoxal is broken down via the glyoxalase pathway.

    “It has been estimated that around 99% of all methylglyoxal is broken down via the glyoxalase pathway [67] detailed below.”
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    Premisecitation

    High levels of AGEs lead to downregulation of both AGER1 and sirtuin1, causing the protective mechanism to fail.

    “Nonetheless, this protective mechanism begins to fail as the concentration of AGEs increases, with high levels of AGEs leading to a downregulation of both AGER1 and sirtuin1.[64]”
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    Premisecitation

    Mass spectrometry techniques now give absolute concentrations for AGEs such as CML, meaning values can be compared between studies using this methodology.

    “However, the mass spectrometry techniques used now give absolute concentrations for AGEs such as CML meaning that values can be compared between studies carried out using this methodology.[27,48,110]”
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    Premisecitation

    ROS potentiate the inflammatory response by activating NF-kB, which induces inflammatory mediators and upregulates RAGE, establishing a positive feedback loop.

    “Moreover, ROS potentiate the inflammatory response by activating NF-𝜅B, which, once activated, migrates to the nucleus and induces not only the expression of inflammatory mediators, but also upregulates RAGE, thus establishing a positive feedback loop.[55,56]”
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    Premisecitation

    Restriction of dietary AGEs is associated with reductions in inflammation and an increase in vascular function in humans.

    “Nonetheless the restriction of dietary AGEs has been associated with reductions in inflammation and an increase in vascular function in humans, [96,97]”
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    Premisecitation

    CML and CEL bind to the V domain of mRAGE to trigger an immunoinflammatory response, but can only bind if incorporated into larger peptide structures.

    “mRAGE interacts with AGEs, such as CML, CEL, which bind to the V domain of mRAGE to trigger an immunoinflammatory response.CML and CEL can only bind to mRAGE if they are incorporated into larger peptide structures.[45,46]”
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    Premisecitation

    AGEs have been implicated in the pathogenesis of insulin resistance and type 2 diabetes mellitus as well as obesity.

    “Indeed, apart from playing a pivotal role in diabetic complications, including cardiovascular, kidney and neurodegenerative diseases such as Alzheimer's and Parkinson's disease, AGEs have also been implicated in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM) as well as obesity.[1,18,[114][115][116][117][118]”
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    Premisecitation

    High loads of dietary AGEs are associated with premature cognitive decline in humans and in animal models fed a high MG diet equivalent to 19 μmol per day.

    “while high loads of dietary AGEs have been associated with premature cognitive decline in humans [98] and in animal models fed a high MG diet equivalent to 19 𝜇mol per day.[99]”
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    Premisecitation

    In humans, a low AGE diet induces an improvement in insulin sensitivity compared to a high AGE diet, which decreases insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps.

    “The impact of AGEs on insulin resistance in humans has also been confirmed using hyperinsulinemic-euglycemic clamps, the gold standard for the assessment of insulin sensitivity [48] with a low AGE diet inducing an improvement in insulin sensitivity compared to a diet high in AGEs, which decreases insulin sensitivity.[48]”
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    Premisecitation

    PGC-1α regulates mitochondrial energy metabolism and biogenesis and is pivotal in modulating mitochondrial bioenergetics, which is impaired in individuals with T2DM.

    “PGC 1𝛼 regulates mitochondrial energy metabolism and biogenesis, thus playing a pivotal role in modulating mitochondria bioenergetics, which has been reported to be impaired in individuals affected by T2DM.[128,129]”
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    Premisecitation

    Mice fed a high-AGE diet containing synthetic MG-BSA at 1 mg per g of diet showed a decrease in insulin receptor and IRS phosphorylation, and defective downstream activation of AKT in skeletal muscle, adipose tissue, and liver.

    “In these studies mice fed a high-AGE diet containing synthetic MG-BSA at 1 mg per g of diet showed a decrease in insulin receptor and IRS phosphorylation, and defective downstream activation of AKT in skeletal muscle, adipose tissue, and liver.[64]”
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    Premisecitation

    In skeletal muscle, AGEs downregulate GLUT4 and promote activation of inflammatory pathways and endoplasmic reticulum stress as indicated by upregulation of NF-kappa-B p50 subunit and 78 kDa glucose-regulated protein.

    “In skeletal muscle, a tissue pivotal for the control of glucose homeostasis, AGEs downregulate GLUT4 and promote the activation of inflammatory pathways as well as endoplasmic reticulum stress as indicated by the upregulation of nuclear factor NF-kappa-B p50 subunit and 78 kDa glucose-regulated protein.[124]”
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    Premisecitation

    PGC-1α is instrumental in this process: genes under its control are downregulated in individuals with T2DM, and its upregulation has insulin-sensitizing effects in vitro and in animal models.

    “Importantly, PGC 1𝛼 appears to be instrumental in this process as genes under its control are downregulated in individuals suffering from T2DM and its upregulation has also been shown to have insulin sensitizing effects in vitro as well as in animal models.[129,132,133,134]”
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    Premisecitation

    An AGE-restricted diet improves insulin sensitivity in T2DM with normalization of AGER1 and sirtuin1 expression and a decrease in NF-kB acetylation, circulating TNFα, serum AGEs, and leptin.

    “with an AGE-restricted diet improving insulin sensitivity in T2DM with a normalization of the expression of AGER1 and sir-tuin1 as well as a decrease in NF-𝜅B acetylation circulating TNF𝛼, serum AGEs, and leptin.[63]”
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    Interpretationreasoning

    AGEs activate both JNK and IKK/NF-kB signaling pathway, supporting the relationship between AGEs and insulin resistance.

    “Importantly, AGEs activate both JNK as well as the IKK/NF-𝜅B signaling pathway supporting the relationship between AGEs and insulin resistance.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The molecular mechanism responsible for AGE-induced oxidative stress relies on increased mitochondrial ROS production and activation of JNK, which in turn activates NADPH oxidase, further fueling oxidative stress.

    “Cell culture studies also showed that the molecular mechanism responsible for AGE-induced oxidative stress relies on increased mitochondrial ROS production as well as the activation of JNK which, in turn, activates NADPH oxidase further fueling oxidative stress.[136]”
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    Premisecitation

    Energy balance is controlled by an intricate, finely-tuned neuroendocrine system.

    “Energy balance is controlled by an intricate, finely-tuned neuroendocrine system.[141,142]”
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    Premisecitation

    AGEs exert a cytotoxic effect on β-cells and induce apoptosis, which may be dependent on ROS production.

    “AGEs exert cytotoxic effect on 𝛽-cells and induce apoptosis, which may be dependent on ROS production.”
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    Premisecitation

    The AGE-RAGE axis triggers oxidative stress, which is associated with the development of insulin resistance.

    “In addition to inflammation, the AGE-RAGE axis also triggers oxidative stress, which is associated with the development of insulin resistance.[122,123]”
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    Premisecitation

    AGEs, by inhibiting mitochondrial cytochrome oxidase, compromise β-cell ATP synthesis capacity, causing impairment in ATP-induced shutdown of K+ channels, β-cell depolarization, and consequently Ca2+ influx, thereby preventing exocytosis of insulin-containing granules.

    “AGEs, by inhibiting mitochondrial cytochrome oxidase, [137] compromise 𝛽-cell ATP synthesis capacity causing an impairment in ATP-induced shutdown of K + channels, 𝛽-cell depolarization and consequently the influx of Ca 2+ thereby preventing the exocytosis of insulin-containing granules.[138]”
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    Premisecitation

    AGEs can activate pro-inflammatory pathways; JNK and IKK/NF-κB have been implicated in mediating high-fat diet-induced hypothalamic insulin and leptin resistance leading to hypothalamic dysfunction.

    “AGEs can also activate pro-inflammatory pathways; JNK and IKK/NF-𝜅B both of which have been implicated in mediating high-fat diet induced hypothalamic insulin and leptin resistance leading to hypothalamic dysfunction.[145][146][147][148][149]”
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  • May combine two claims.

    Interpretationreasoning

    The Western diet contains elevated levels of highly processed foods and as such represents a source of AGEs, which contributes to promoting obesity, insulin resistance, and deterioration in metabolic health.

    “The Western diet contains elevated levels of highly processed foods and as such represents a source of AGEs, which contributes to promoting obesity, insulin resistance, and deterioration in metabolic health.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mechanisms observed in cell culture and animal models of AGE exposure translate to human metabolic dysfunction.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Insulin and leptin are the main anorexigenic hormones and inform the hypothalamus, particularly the arcuate nucleus, about long- and short-term energy status.

    “Insulin and leptin are the main anorexigenic hormones and inform the hypothalamus, particularly the arcuate nucleus of the hypothalamus (ARC), the master regulator of energy balance, about longand short-term energy status.[143,144]”
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    Premisecitation

    The role of AGEs in promoting hypothalamic inflammation was confirmed in animals lacking RAGE and ALCAM, which have an improved metabolic phenotype and decreased microglial reactivity on a high-fat diet.

    “The role of AGEs in promoting hypothalamic inflammation was confirmed in animals lacking RAGE and ALCAM which have an improved metabolic phenotype and decreased microglial reactivity on a high-fat diet.[1]”
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    Premisecitation

    The hypothalamus receives and integrates central and peripheral information related to nutritional status and responds by triggering orexigenic and anorexigenic responses to preserve energy homeostasis and maintain body weight within a tight range.

    “The hypothalamus receives and integrates central and peripheral information related to the nutritional status of the individual and responds to these neural, nutritional, and hormonal cues by triggering orexigenic and anorexigenic responses in order to preserve energy homeostasis and maintain body weight within a tight range.[142]”
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  • The paper relies on this without support.

    The association between AGEs and increased body weight after adjusting for total energy intake and other confounders is not due to residual confounding.

    “Importantly, the ability of AGEs to increase body weight was retained after adjusting for total energy intake and other cofounders, suggesting AGEs directly affect energy balance.”

  • The paper relies on this without support.

    Mechanisms observed in cell culture and animal models of AGE exposure translate to human metabolic dysfunction.

    “Studies using primary 𝛽-cells and cell lines demonstrate that inhibition of RAGE or antioxidant treatment prevents AGE-induced cell toxicity.[135]”
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Research works printed but not linked: 10

  1. Maillard L., 1912, C. R. Seances Acad. Sci., 154, 66
  2. Hammes H. P., 1996, Lab. Invest., 75, 325
  3. Monnier V. M., 1989, Prog. Clin. Biol. Res., 304, 1
  4. Liang Z., 2019, Crit. Rev. Food Sci. Nutr., 1
  5. Lue L., 2009, Funct. Neurol., 4, 167
  6. Shewfelt R. L., 2016, Defense of Processed Food: It's Not Nearly as Bad as You Think
  7. Cordova R., 2019, Eur. J. Nutr., 1
  8. Zick Y., 2005, Sci. Signaling, 268, pe4
  9. Brobeck J. R., 1943, Yale J. Biol. Med., 15, 831
  10. Sergi D., 2019, Nutr. Rev.

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Authors
Sergi, D., Boulestin, H., Campbell, F. M., & Williams, L. M.
Affiliations
  • Commonwealth Scientific and Industrial Research Organisation (AU)
  • University of Aberdeen (GB)
Corresponding author
Williams, Lynda M.
ORCID
Venue
Molecular Nutrition & Food Research
Publisher
Wiley
Published
2020-04-20
Volume
65
Issue
1
Pages
e1900934-e1900934
ISSN
  • 1613-4125 (ISSN-L)
  • 1613-4133
DOI
10.1002/mnfr.201900934
OpenAlex
W3014454708
Semantic Scholar
97ca7e276f92fd6912c3817577b53faabeec219d
Cited by
194
References
147
Citations by year
2026: 20 · 2025: 40 · 2024: 42 · 2023: 30 · 2022: 34 · 2021: 24 · 2020: 4
FWCI
2.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Nutrition & Food Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, cc-by)
Funders
  • Rural and Environment Science and Analytical Services Division
  • Commonwealth Scientific and Industrial Research Organisation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Potato Plant Research
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
advanced glycation end products, dietary AGEs, metabolic dysfunction, type 2 diabetes, insulin resistance, beta-cell dysfunction, hypothalamic inflammation, energy balance, Western diet, obesity, hyperglycemia, diabetes complications, signaling pathways
MeSH terms
Antigens, Neoplasm, Cooking, Diabetes Mellitus, Type 2, Diet, Enzymes, Humans, Inflammation, Obesity, Glycation End Products, Advanced, Mitogen-Activated Protein Kinases, Insulin-Secreting Cells, Diet, Western

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