Abstract
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.
Highlights
The growing obesity pandemic is nowadays a global health concern and affects all age classes.Obesity is a major determinant for the establishment of insulin resistance and can lead to metabolicNutrients 2020, 12, 1518; doi:10.3390/nu12051518 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 1518 disorders, such as non-alcoholic fatty liver disease, type 2 diabetes and metabolic syndrome [1]
Despite similar weight gain between mice fed a CHO + SOY, CHO + lard without additional cholesterol (LAR) or LAR diet, animals fed the LAR diet were significantly more insulin resistant than other groups, as evidenced by four-fold increased fasting serum insulin levels and higher blood glucose levels in response to glucose or insulin administration compared to standard chow diet (STD) control, confirming the detrimental effect of long-chain saturated fatty acids (LCSFA)-containing diets on insulin sensitivity (Figure 1B, Supplementary Figure S1A–C)
As the CHO + SOY compared to CHO + STD and CHO + LAR diet groups had an enormous effect on liver function and caused massive hepatic inflammation [5], we assessed their effects on brain homeostasis and mitochondrial dysfunction
Summary
Obesity is a major determinant for the establishment of insulin resistance and can lead to metabolic. Nutrients 2020, 12, 1518 disorders, such as non-alcoholic fatty liver disease, type 2 diabetes and metabolic syndrome [1]. Feeding mice high caloric diets containing either high-fructose or high-fat concentrations induces obesity and insulin resistance [2]. In line with this, increased portion sizes with concomitant increased caloric intake cause obesity in humans [3]. Though high-fat diets (HFDs) have been shown to be instrumental for the induction of obesity and insulin resistance, it is of importance to differentiate between the quality of consumed fatty acids and their potential interplay with other nutrients. Not every high-fat diet has to exert only negative effects on metabolism.
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