Unsaturated Fatty Acids Revert Diet-Induced Hypothalamic Inflammation in Obesity
Unsaturated Fatty Acids Revert Diet-Induced Hypothalamic Inflammation in Obesity
Year: 2011
Authors: Cintra, D.E. Ropelle, E.R. Moraes, J.C. Pauli, J. R. Morari, J. de Souza, C.T. Grimaldi, R. et.al.
Publication Name: PLoS ONE
Publication Details: Volume 7; Number 1; Pages e30571 – e30584.
Abstract:
In 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. Here 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 w3 and w9 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, w3 and w9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of w3 and w9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor. Unsaturated 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. (Authors abstract)
A number of recent studies have shown that in both diet-induced and genetically-determined animal models of obesity, inflammation of the hypothalamus is an important mechanism leading to the anomalous control of caloric intake and energy expenditure. 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. In this context, several proteins involved in the inflammatory response in the hypothamus have been targeted with generally positive outcomes. Unsaturated fatty acids have well known anti-inflammatory effects. In this study, the effects of two unsaturated fatty acids on hypothalamic inflammation in obesity were studied. Acting either as nutrients or directly in the hypothalamus, alpha linolenic (ALA) and oleic (C18:1n9) unsaturated fatty acids have outstanding anti-inflammatory effects, correcting hypothalamic dysfunction and reducing body mass. In the first part of the study, diet-induced obese mice were fed diets composed of a stepwise substitution of the saturated by unsaturated fatty acids. The substitutions of the fatty acid components in the diet resulted in increased relative amounts of unsaturated fatty acids, predominating oleic acid in the olive oil substituted diets and linolenic acid in the flax seed oil substituted diets. The FS substitution resulted in increased relative amount of n3 in the blood and hypothalamus. As a consequence of fatty acid substitution there was a reduction in food intake to levels similar to control, an effect that was independent of fatty acid type and quantity. Fatty acid substitution on whole body insulin action and glucose homeostasis was tested. Similarly to the effect of the substituted diets on food intake, a complete restoration of insulin action and glucose homeostasis to levels similar to those of lean controls was obtained, independently of diet composition and fatty acid type. Both fatty acids induced a large reduction in spontaneous food intake, which was completely restored after discontinuation. These fatty acids exerted a potent anti-inflammatory effect, reducing the hypothalamic expression of cytokines and inflammatory signaling proteins. Significant improvement of leptin and insulin signal transduction in the hypothalamus was achieved. Both fatty acids reduced hypothalamic expression of NPY and MCH while increasing the expressions of POMC and CART. The unsaturated fatty acid receptor, GPR120 is expressed in the hypothalamus and is activated in response to n3 and n9 fatty acids. GPR120 was recently identified as an important mediator of the anti-inflammatory and insulin sensitizing effects of unsaturated fatty acids in monocytes. In conclusion, unsaturated fatty acids can reproduce a number of the anti-inflammatory effects of TLR4 or TNF-a inhibition and, therefore, constitute an attractive nutritional approach to treat obesity. At least part of this effect may be mediated by the GPR120 receptor. (editors Comments)
A number of recent studies have shown that in both diet-induced and genetically-determined animal models of obesity, inflammation of the hypothalamus is an important mechanism leading to the anomalous control of caloric intake and energy expenditure. 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. In this context, several proteins involved in the inflammatory response in the hypothamus have been targeted with generally positive outcomes. Unsaturated fatty acids have well known anti-inflammatory effects. In this study, the effects of two unsaturated fatty acids on hypothalamic inflammation in obesity were studied. Acting either as nutrients or directly in the hypothalamus, alpha linolenic (ALA) and oleic (C18:1n9) unsaturated fatty acids have outstanding anti-inflammatory effects, correcting hypothalamic dysfunction and reducing body mass. In the first part of the study, diet-induced obese mice were fed diets composed of a stepwise substitution of the saturated by unsaturated fatty acids. The substitutions of the fatty acid components in the diet resulted in increased relative amounts of unsaturated fatty acids, predominating oleic acid in the olive oil substituted diets and linolenic acid in the flax seed oil substituted diets. The FS substitution resulted in increased relative amount of n3 in the blood and hypothalamus. As a consequence of fatty acid substitution there was a reduction in food intake to levels similar to control, an effect that was independent of fatty acid type and quantity. Fatty acid substitution on whole body insulin action and glucose homeostasis was tested. Similarly to the effect of the substituted diets on food intake, a complete restoration of insulin action and glucose homeostasis to levels similar to those of lean controls was obtained, independently of diet composition and fatty acid type. Both fatty acids induced a large reduction in spontaneous food intake, which was completely restored after discontinuation. These fatty acids exerted a potent anti-inflammatory effect, reducing the hypothalamic expression of cytokines and inflammatory signaling proteins. Significant improvement of leptin and insulin signal transduction in the hypothalamus was achieved. Both fatty acids reduced hypothalamic expression of NPY and MCH while increasing the expressions of POMC and CART. The unsaturated fatty acid receptor, GPR120 is expressed in the hypothalamus and is activated in response to n3 and n9 fatty acids. GPR120 was recently identified as an important mediator of the anti-inflammatory and insulin sensitizing effects of unsaturated fatty acids in monocytes. In conclusion, unsaturated fatty acids can reproduce a number of the anti-inflammatory effects of TLR4 or TNF-a inhibition and, therefore, constitute an attractive nutritional approach to treat obesity. At least part of this effect may be mediated by the GPR120 receptor. (editors Comments)
