Abstract
BackgroundIn experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown.Methodology/Principal FindingsHere we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both ω3 and ω9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, ω3 and ω9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of ω3 and ω9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor.Conclusions/SignificanceUnsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting diet-induced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and genetic approaches, nutrients can also be attractive candidates for controlling hypothalamic inflammation in obesity.
Highlights
Defective hypothalamic activity plays an important role in the development of obesity [1,2,3]
Highly consumed in western diets, induce hypothalamic inflammation by activating signal transduction though TLR4, which leads to endoplasmic reticulum stress, in situ expression of inflammatory cytokines and eventually, apoptosis of neurons, all contributing to the development of adipostatic hormone resistance and anomalous expression of the neurotransmitters involved in the regulation of energy homeostasis [5,6]
Saturated fatty acids, acting directly in the hypothalamus or as a component of the diet, induce inflammation by activating TLR4 signaling and ER stress, which leads to increased inflammatory gene transcription, hypothalamic dysfunction and eventually neuronal apoptosis [5,6]
Summary
Defective hypothalamic activity plays an important role in the development of obesity [1,2,3]. Highly consumed in western diets, induce hypothalamic inflammation by activating signal transduction though TLR4, which leads to endoplasmic reticulum stress, in situ expression of inflammatory cytokines and eventually, apoptosis of neurons, all contributing to the development of adipostatic hormone resistance and anomalous expression of the neurotransmitters involved in the regulation of energy homeostasis [5,6]. Both genetic and pharmacological approaches, aimed at restraining hypothalamic inflammation, have proven useful for reducing hypothalamic dysfunction, correcting resistance to leptin and insulin and reducing body mass. The role of nutrients in the modulation of hypothalamic inflammation is unknown
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