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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.*

Dietary sugars, not lipids, drive hypothalamic inflammation.

Mol. Metab. 6, 897-908 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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: Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Angiogenesis ; Microglia ; Obesity ; Pericytes ; Pomc; Glycation End-products; High-fat Diets; Low-carbohydrate; Proinflammatory Response; Metabolic Syndrome; Growth-factor; Obesity; Activation; Receptor; Protein
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 6, Issue: 8, Pages: 897-908 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
POF-Topic(s) 90000 - German Center for Diabetes Research
30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-501900-221
G-502200-001
PubMed ID 28752053
DOI 10.1016/j.molmet.2017.06.008
WOS ID WOS:000405803000011
Scopus ID 85021454934
Erfassungsdatum 2017-07-14
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