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Open AccessArticle

Interplay of Dietary Fatty Acids and Cholesterol Impacts Brain Mitochondria and Insulin Action

1
Junior Research Group Central Regulation of Metabolism, German Institute of Human Nutrition, D-14558 Nuthetal, Germany
2
German Center for Diabetes Research (DZD), D-85764 München-Neuherberg, Germany
3
Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany
4
Department of Molecular Epidemiology, German Institute of Human Nutrition, D-14558 Nuthetal, Germany
5
Department of Molecular and Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany
*
Author to whom correspondence should be addressed.
Equally contributed.
Equally contributed last authors.
Nutrients 2020, 12(5), 1518; https://doi.org/10.3390/nu12051518
Received: 24 April 2020 / Revised: 15 May 2020 / Accepted: 21 May 2020 / Published: 23 May 2020
(This article belongs to the Special Issue High-Fat High-Saturated Diet)
Overconsumption of high-fat and cholesterol-containing diets is detrimental for metabolism and mitochondrial function, causes inflammatory responses and impairs insulin action in peripheral tissues. Dietary fatty acids can enter the brain to mediate the nutritional status, but also to influence neuronal homeostasis. Yet, it is unclear whether cholesterol-containing high-fat diets (HFDs) with different combinations of fatty acids exert metabolic stress and impact mitochondrial function in the brain. To investigate whether cholesterol in combination with different fatty acids impacts neuronal metabolism and mitochondrial function, C57BL/6J mice received different cholesterol-containing diets with either high concentrations of long-chain saturated fatty acids or soybean oil-derived poly-unsaturated fatty acids. In addition, CLU183 neurons were stimulated with combinations of palmitate, linoleic acid and cholesterol to assess their effects on metabolic stress, mitochondrial function and insulin action. The dietary interventions resulted in a molecular signature of metabolic stress in the hypothalamus with decreased expression of occludin and subunits of mitochondrial electron chain complexes, elevated protein carbonylation, as well as c-Jun N-terminal kinase (JNK) activation. Palmitate caused mitochondrial dysfunction, oxidative stress, insulin and insulin-like growth factor-1 (IGF-1) resistance, while cholesterol and linoleic acid did not cause functional alterations. Finally, we defined insulin receptor as a novel negative regulator of metabolically stress-induced JNK activation. View Full-Text
Keywords: cholesterol; insulin signaling; mitochondria; brain; inflammation; fatty acids; JNK; insulin receptor cholesterol; insulin signaling; mitochondria; brain; inflammation; fatty acids; JNK; insulin receptor
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Schell, M.; Chudoba, C.; Leboucher, A.; Alfine, E.; Flore, T.; Ritter, K.; Weiper, K.; Wernitz, A.; Henkel, J.; Kleinridders, A. Interplay of Dietary Fatty Acids and Cholesterol Impacts Brain Mitochondria and Insulin Action. Nutrients 2020, 12, 1518.

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