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Cited by 131Neuroinflammation and Neurodegeneration MechanismsRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

Dietary sugars, not lipids, drive hypothalamic inflammation

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Gao, Yuanqing, Bielohuby, Maximilian, Fleming, Thomas, Grabner, Gernot F., Foppen, Ewout, Bernhard, Wagner, Guzmán-Ruiz, Mara, Layritz, Clarita, Legutko, Beata, Zinser, Erwin, García-Cáceres, Cristina, Buijs, Ruud M., Woods, Stephen C., Kalsbeek, Andries, Seeley, Randy J., Nawroth, Peter P., Bidlingmaier, Martin, Tschöp, Matthias H., Yi, Chun-Xia·2017·Molecular Metabolism
DOI 10.1016/j.molmet.2017.06.008PMC PMC5518723
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Abstract

OBJECTIVE: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. METHODS: We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM). RESULTS: We found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet. CONCLUSIONS: , leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.

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Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 High carbohydrate, high fat diets, but not low-carbohydrate, high-fat diets, increase hypothalamic microglial reactivity and neuronal CML content. (A) Daily calorie intake of chow, HCHF1, HCHF2, LCHF1, and LCHF2 diet groups (n = 13 for each group, F(1,60) = 80.26, P < 0.0001). (B & C) Independent of daily calorie intake, the HCHF1 and HCHF2 groups had the most profound impact on BW gain (n = 13 for each group). (D) Fat mass proportion of total BW of each diet group (n = 13 for each group). (E) Quantification of the number of iba1-ir microglia in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in I) from each diet group (n = 6 for each group). (F) Quantification of the cell coverage of iba1-ir microglia. (G) Quantification of the area covered by GFAP-ir astrocytes in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in I) from each diet group (n = 6 for each group). (H) Quantification of the integrative intensity of CML-ir in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in J) from each diet group (n = 6 for each group). (I) Illustration of iba1-ir microglia in the ARC of each diet group; dark arrow pointed cells are magnified in the left upper corner. (J) Illustration of GFAP-ir astrocytes in the ARC of each diet group. (K) Illustration of CML-ir cells in the ARC of each diet group. III: third cerebral ventricle; Scale bar: 50 μm in I and K, and 100 μm in J. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as means ± s.e.m. P values for 5-diet group-effects were analyzed by One-way ANOVA, followed by Student's t test for post-hoc analysis.
Figure 1 High carbohydrate, high fat diets, but not low-carbohydrate, high-fat diets, increase hypothalamic microglial reactivity and neuronal CML content. (A) Daily calorie intake of chow, HCHF1, HCHF2, LCHF1, and LCHF2 diet groups (n = 13 for each group, F(1,60) = 80.26, P < 0.0001). (B & C) Independent of daily calorie intake, the HCHF1 and HCHF2 groups had the most profound impact on BW gain (n = 13 for each group). (D) Fat mass proportion of total BW of each diet group (n = 13 for each group). (E) Quantification of the number of iba1-ir microglia in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in I) from each diet group (n = 6 for each group). (F) Quantification of the cell coverage of iba1-ir microglia. (G) Quantification of the area covered by GFAP-ir astrocytes in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in I) from each diet group (n = 6 for each group). (H) Quantification of the integrative intensity of CML-ir in a frame of 0.2 mm × 0.2 mm in the ARC (illustrated in J) from each diet group (n = 6 for each group). (I) Illustration of iba1-ir microglia in the ARC of each diet group; dark arrow pointed cells are magnified in the left upper corner. (J) Illustration of GFAP-ir astrocytes in the ARC of each diet group. (K) Illustration of CML-ir cells in the ARC of each diet group. III: third cerebral ventricle; Scale bar: 50 μm in I and K, and 100 μm in J. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as means ± s.e.m. P values for 5-diet group-effects were analyzed by One-way ANOVA, followed by Student's t test for post-hoc analysis.CC BY-NC-ND · PubMed Central
Figure 2 High carbohydrate, high fat diets increase CML production and secretion from hypothalamic neurons. (A & B) CML-ir POMC neurons in the ARC of mice on chow or HCHF diet. (C & D) CML-ir NPY neurons in the ARC of mice on chow or HCHF diet. (E) Quantification of the number of CML-ir POMC or NPY neurons (identified by Pomc- or Npy-driven eGFP labeling) in the ARC of mice on chow or HCHF (n = 6 mice for POMCeGFP or for NPYeGFP on each diet, P < 0.001 for POMC, P = 0.007 for NPY). Scale bar: 30 μm. Data are presented as means ± s.e.m. **P < 0.01, ***P < 0.001. P values for unpaired comparisons in were analyzed by two-tailed Student's t test.
Figure 2 High carbohydrate, high fat diets increase CML production and secretion from hypothalamic neurons. (A & B) CML-ir POMC neurons in the ARC of mice on chow or HCHF diet. (C & D) CML-ir NPY neurons in the ARC of mice on chow or HCHF diet. (E) Quantification of the number of CML-ir POMC or NPY neurons (identified by Pomc- or Npy-driven eGFP labeling) in the ARC of mice on chow or HCHF (n = 6 mice for POMCeGFP or for NPYeGFP on each diet, P < 0.001 for POMC, P = 0.007 for NPY). Scale bar: 30 μm. Data are presented as means ± s.e.m. **P < 0.01, ***P < 0.001. P values for unpaired comparisons in were analyzed by two-tailed Student's t test.CC BY-NC-ND · PubMed Central
Figure 3 RAGE and ALCAM are expressed on non-neuronal cell populations. (A) CML binds to proteins of RAGE (molecular weight ≈ 75 KDa) and ALCAM (molecular weight ≈ 105 KDa); the vehicle does not bind to protein of either receptor, as illustrated by no band detected in binding of ALCAM. (B) RAGE and ALCAM gene expression in mediobasal hypothalami of chow or HCHF mice (n = 6 for chow or for HCHF, P = 0.019 for RAGE, P = 0.006 for ALCAM). (C) RAGE is intensely expressed by microglia (iba1-ir, indicated by white arrowheads). Higher magnifications of the areas framed by dashed lines are presented in D. (E) RAGE is intensely expressed on endothelial cells (laminin-ir, indicated by white arrows). Higher magnifications of the areas framed by dashed lines are presented in F. (G) CML stimulates TNFα, but not PDGF-B, gene expression in cultured primary microglia (n = 6 wells of cells for vehicle, n = 5 for TNFα treatments, P = 0.04 for TNFα). (H & I) CML stimulates microglial reactivity in the mediobasal hypothalamic area, arrowheads point to the areas where the tip of the infusion probes located. (J) Iba1-ir cell number and cell coverage in H & I (n = 4 mice for vehicle, n = 5 for CML). (K) ALCAM is expressed on part of the vasculature (laminin-ir, indicated by white arrows, two pericytes are indicated by white arrowheads); higher magnifications of the areas framed by dashed lines are presented in L. (M) ALCAM is expressed on pericytes (PDGFRβ-ir, white arrowheads). Higher magnifications of the areas framed by dashed lines are presented in N. Scale bar: 30 μm in C, E, K and M, 7.5um in D, F, L and N. Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01. P values for unpaired comparisons were analyzed by two-tailed Student's t test.
Figure 3 RAGE and ALCAM are expressed on non-neuronal cell populations. (A) CML binds to proteins of RAGE (molecular weight ≈ 75 KDa) and ALCAM (molecular weight ≈ 105 KDa); the vehicle does not bind to protein of either receptor, as illustrated by no band detected in binding of ALCAM. (B) RAGE and ALCAM gene expression in mediobasal hypothalami of chow or HCHF mice (n = 6 for chow or for HCHF, P = 0.019 for RAGE, P = 0.006 for ALCAM). (C) RAGE is intensely expressed by microglia (iba1-ir, indicated by white arrowheads). Higher magnifications of the areas framed by dashed lines are presented in D. (E) RAGE is intensely expressed on endothelial cells (laminin-ir, indicated by white arrows). Higher magnifications of the areas framed by dashed lines are presented in F. (G) CML stimulates TNFα, but not PDGF-B, gene expression in cultured primary microglia (n = 6 wells of cells for vehicle, n = 5 for TNFα treatments, P = 0.04 for TNFα). (H & I) CML stimulates microglial reactivity in the mediobasal hypothalamic area, arrowheads point to the areas where the tip of the infusion probes located. (J) Iba1-ir cell number and cell coverage in H & I (n = 4 mice for vehicle, n = 5 for CML). (K) ALCAM is expressed on part of the vasculature (laminin-ir, indicated by white arrows, two pericytes are indicated by white arrowheads); higher magnifications of the areas framed by dashed lines are presented in L. (M) ALCAM is expressed on pericytes (PDGFRβ-ir, white arrowheads). Higher magnifications of the areas framed by dashed lines are presented in N. Scale bar: 30 μm in C, E, K and M, 7.5um in D, F, L and N. Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01. P values for unpaired comparisons were analyzed by two-tailed Student's t test.CC BY-NC-ND · PubMed Central
Figure 4 Deletions of RAGE or ALCAM genes improve metabolic symptoms induced by a HCHF diet and exert diverse impacts on microglia, pericytes, and vasculature in the arcuate nucleus. (A & B) Daily caloric intake (in wk10) and weekly BW gain of chow or HCHF diet-fed WT versus RAGE−/− mice (n = 5–8 per group); For weekly BW gain, in all time points, WT and RAGE−/− mice have less BW gain on chow diet than on HCHF diet (P < 0.0001); from wk14 to wk16, BW gain on HCHF of RAGE−/− mice is significantly less than WT mice. (C & D) Daily caloric intake (in wk10) and weekly BW gain of chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 5–8 per group). For weekly BW gain, from wk2 on, WT and ALCAM−/− mice have less BW gain in chow than in HCHF; from wk12, wk14 to wk16, BW-gain on HCHF of ALCAM−/− mice is significantly less than WT mice. (E & F) Quantification of the number of iba1-ir microglia and the PDGFRβ-ir pericytes in the ARC in chow or HCHF diet fed WT mice versus RAGE−/− mice (n = 5–9 per group). (G & H) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT mice versus RAGE−/− mice (n = 5–7 per group). (I & J) Quantification of the number of iba1-ir microglia and the PDGFRβ-ir pericytes in the ARC in chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 5–6 per group). (K & L) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 6 per group). Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Asterisks in B and D indicate significance between WT and RAGE−/− or ALCAM−/− mice on HCHF diet. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interaction between genotype and diet on each parameter.
Figure 4 Deletions of RAGE or ALCAM genes improve metabolic symptoms induced by a HCHF diet and exert diverse impacts on microglia, pericytes, and vasculature in the arcuate nucleus. (A & B) Daily caloric intake (in wk10) and weekly BW gain of chow or HCHF diet-fed WT versus RAGE−/− mice (n = 5–8 per group); For weekly BW gain, in all time points, WT and RAGE−/− mice have less BW gain on chow diet than on HCHF diet (P < 0.0001); from wk14 to wk16, BW gain on HCHF of RAGE−/− mice is significantly less than WT mice. (C & D) Daily caloric intake (in wk10) and weekly BW gain of chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 5–8 per group). For weekly BW gain, from wk2 on, WT and ALCAM−/− mice have less BW gain in chow than in HCHF; from wk12, wk14 to wk16, BW-gain on HCHF of ALCAM−/− mice is significantly less than WT mice. (E & F) Quantification of the number of iba1-ir microglia and the PDGFRβ-ir pericytes in the ARC in chow or HCHF diet fed WT mice versus RAGE−/− mice (n = 5–9 per group). (G & H) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT mice versus RAGE−/− mice (n = 5–7 per group). (I & J) Quantification of the number of iba1-ir microglia and the PDGFRβ-ir pericytes in the ARC in chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 5–6 per group). (K & L) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT mice versus ALCAM−/− mice (n = 6 per group). Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Asterisks in B and D indicate significance between WT and RAGE−/− or ALCAM−/− mice on HCHF diet. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interaction between genotype and diet on each parameter.CC BY-NC-ND · PubMed Central
Figure 5 Deletion of RAGE and ALCAM genes improves metabolic symptoms induced by a HCHF diet. (A & B) Daily caloric intake (in wk10) and weekly body weight gain of chow or HCHF diet-fed WT versus RAGE-ALCAM−/− mice (n = 6–11 per group); for weekly BW gain, from wk5 on, WT and RAGE-ALCAM−/− mice have less BW gain in chow than in HCHF; From wk1 to wk4 and from wk9 to wk16, there are significant effect of genotype on BW gain on HCHF. (C) Body composition of WT versus RAGE-ALCAM−/− mice fed HCHF diet (n = 4–8 per group). (D) Glucose tolerance of WT versus RAGE-ALCAM−/− mice fed chow or HCHF diet (n = 5–7 per group). (E) Glucose tolerance of RAGE-ALCAM−/− mice fed chow or HCHF diet (n = 5–7 per group). Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Asterisks indicate significance between WT and RAGE-ALCAM−/− mice. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interactions between genotype and diet on daily caloric intake, BW gain and body mass. Two-tailed Student's t test was performed between each time point in D and E, to detect the effect of genotype on glucose tolerance on chow or HCHF diet.
Figure 5 Deletion of RAGE and ALCAM genes improves metabolic symptoms induced by a HCHF diet. (A & B) Daily caloric intake (in wk10) and weekly body weight gain of chow or HCHF diet-fed WT versus RAGE-ALCAM−/− mice (n = 6–11 per group); for weekly BW gain, from wk5 on, WT and RAGE-ALCAM−/− mice have less BW gain in chow than in HCHF; From wk1 to wk4 and from wk9 to wk16, there are significant effect of genotype on BW gain on HCHF. (C) Body composition of WT versus RAGE-ALCAM−/− mice fed HCHF diet (n = 4–8 per group). (D) Glucose tolerance of WT versus RAGE-ALCAM−/− mice fed chow or HCHF diet (n = 5–7 per group). (E) Glucose tolerance of RAGE-ALCAM−/− mice fed chow or HCHF diet (n = 5–7 per group). Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Asterisks indicate significance between WT and RAGE-ALCAM−/− mice. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interactions between genotype and diet on daily caloric intake, BW gain and body mass. Two-tailed Student's t test was performed between each time point in D and E, to detect the effect of genotype on glucose tolerance on chow or HCHF diet.CC BY-NC-ND · PubMed Central
Figure 6 Deletion of RAGE and ALCAM genes reduces microglial reactivity and neovasculature formation in the arcuate nucleus (A, B & C) Quantification of iba1-ir microglial number, coverage and the PDGFRβ-ir pericytes number in the ARC from chow or HCHF diet fed WT (n = 5–8 per group) versus RAGE-ALCAM−/− mice (n = 7–10 per group). (D & E) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT (n = 5–7 per group) versus RAGE-ALCAM−/− mice (n = 5–7 per group). (F–H) Illustrations of the iba1-ir microglia, PDGFRβ-ir pericytes and FITC-albumin labeled vessels in WT versus RAGE-ALCAM−/− mice fed chow or HCHF diet, with a frame of 0.2 mm × 0.2 mm for quantifications in the ARC. (I) Illustration of the skeletonization of vessel in H for vascular density analysis. III: third cerebral ventricle. Scale bar: 50um in F and G, 100um in F. Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interaction between genotype and diet on each parameter.
Figure 6 Deletion of RAGE and ALCAM genes reduces microglial reactivity and neovasculature formation in the arcuate nucleus (A, B & C) Quantification of iba1-ir microglial number, coverage and the PDGFRβ-ir pericytes number in the ARC from chow or HCHF diet fed WT (n = 5–8 per group) versus RAGE-ALCAM−/− mice (n = 7–10 per group). (D & E) Quantification of vessel length and vascular density in the ARC from chow or HCHF diet fed WT (n = 5–7 per group) versus RAGE-ALCAM−/− mice (n = 5–7 per group). (F–H) Illustrations of the iba1-ir microglia, PDGFRβ-ir pericytes and FITC-albumin labeled vessels in WT versus RAGE-ALCAM−/− mice fed chow or HCHF diet, with a frame of 0.2 mm × 0.2 mm for quantifications in the ARC. (I) Illustration of the skeletonization of vessel in H for vascular density analysis. III: third cerebral ventricle. Scale bar: 50um in F and G, 100um in F. Data are presented as means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way ANOVA followed by Bonferroni multiple comparisons for post-hoc analysis was performed to detect significant interaction between genotype and diet on each parameter.CC BY-NC-ND · PubMed Central

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Authors
Gao, Y., Bielohuby, M., Fleming, T., Grabner, G. F., Foppen, E., Bernhard, W., Guzmán-Ruiz, M., Layritz, C., Legutko, B., Zinser, E., García-Cáceres, C., Buijs, R. M., Woods, S. C., Kalsbeek, A., Seeley, R. J., Nawroth, P. P., Bidlingmaier, M., Tschöp, M. H., & Yi, C.-X.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • LMU Klinikum (DE)
  • University Hospital Heidelberg (DE)
  • University of Graz (AT)
  • Helmholtz Munich (DE)
  • FH JOANNEUM University of Applied Sciences (AT)
  • Universidad Nacional Autónoma de México (MX)
  • University of Cincinnati (US)
  • Netherlands Institute for Neuroscience (NL)
  • University of Michigan (US)
Corresponding author
  • Bidlingmaier, Martin
  • Tschöp, Matthias H.
  • Yi, Chun-Xia
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2017-08
Volume
6
Issue
8
Pages
897-908
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2017.06.008
PMC
PMC5518723
OpenAlex
W2652575518
Cited by
131
References
41
Citations by year
2026: 6 · 2025: 10 · 2024: 12 · 2023: 15 · 2022: 18 · 2021: 23 · 2020: 13 · 2019: 22 · 2018: 9 · 2017: 2
FWCI
6.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • FH JOANNEUM ePUB (submittedVersion, cc-by-nc-nd)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc-nd)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • Site cant be reached (submittedVersion, cc-by-nc-nd)
Funders
  • Daiichi-Sankyo
  • Alexander von Humboldt-Stiftung
  • Deutsche Forschungsgemeinschaft (SFB1123, ANR- 15-CE14-0030, SFB1118)
  • U.S. Department of Homeland Security
  • Novartis
  • Novo Nordisk
  • Academisch Medisch Centrum
  • Helmholtz Association
  • European Research Council (695054)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
hypothalamic inflammation, dietary sugar, high-fat high-carbohydrate diet, advanced glycation end products, carboxymethyllysine, microglial activation, RAGE, ALCAM, arcuate nucleus, POMC neurons, NPY neurons, neovasculature, energy homeostasis, obesity, hypercaloric diet, endothelial cells, pericytes
MeSH terms
Receptor for Advanced Glycation End Products, Dietary Sugars, Animals, Dietary Fats, Gliosis, Hypothalamus, Inflammation, Male, Mice, Inbred C57BL, Glycation End Products, Advanced, Activated-Leukocyte Cell Adhesion Molecule, Mice, Rats

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