Mol Metab. 2017 Jun 20;6(8):897-908. doi: 10.1016/j.molmet.2017.06.008. eCollection 2017 Aug. Dietary sugars, not lipids, drive hypothalamic inflammation. Gao Y1,2, Bielohuby M3, Fleming T4, Grabner GF5, Foppen E2, Bernhard W6, Guzmán-Ruiz M7, Layritz C1, Legutko B1, Zinser E6, García-Cáceres C1, Buijs RM7, Woods SC8, Kalsbeek A2,9, Seeley RJ10, Nawroth PP4, Bidlingmaier M3, Tschöp MH1,11, Yi CX2. Author information 1Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German Center for Diabetes Research (DZD), München-Neuherberg, Germany.2Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, The Netherlands.3Endocrine Research Unit, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany.4Department of Medicine and Clinical Chemistry, University Hospital of Heidelberg, Germany.5Institute of Molecular Biosciences, University of Graz, Austria.6FH JOANNEUM University for Applied Sciences, Graz, Austria.7Universidad Nacional Autónoma de México, Mexico.8Institute for Metabolic Diseases, University of Cincinnati, USA.9Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.10Department of Surgery, University of Michigan, USA.11Division of Metabolic Diseases, Technische Universität München, Munich, Germany. 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: 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. KEYWORDS: Angiogenesis; Microglia; Obesity; POMC; Pericytes See Full-Text Endothelial Function Scientific Update Sponsored by Endothelix Inc. Click here to view previous updates.
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