Defective hypothalamic activity plays an important role in the development of obesity [1], [2], [3]. 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 [4], [5], [6], [7], [8], [9]. Saturated fatty acids, 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. In this context, several proteins involved in the inflammatory response in the hypothamus have been targeted with generally positive outcomes. …
… Due to the known anti-inflammatory actions of unsaturated fatty acids in other tissues or cell-types [12], [13], [14], we hypothesized that, by acting as nutrients and/or directly in the hypothalamus, these molecules could, at least partially, reduce inflammation and correct hypothalamic activity in the regulation of energy homeostasis. 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. … 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. However, this was accompanied by a dose-dependent-like effect on body mass, with maximum effect in the 30% substituted diets, irrespectively of fatty acid type. …
… We next evaluated the effect of fatty acid substitution on whole body insulin action and glucose homeostasis. Similarly to the effect of the substituted diets on food intake, here, 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. Since the effect of substitutions on body mass were dependent on the quantity of the unsaturated fatty acids, we believe the effect on insulin action and glucose homeostasis was simply due to the presence of the increased amounts of unsaturated fatty acids in the diets and not secondary to body mass reduction. In this regard, studies by L. Rossetti’s group have shown the direct effect of central administration of oleic acid on the control of peripheral glucose homeostasis, which depends, at least in part, on the neural control of hepatic gluconeogenesis [29], [30], [31].
Recent data have increased interest in the effects of hypothalamic inflammation on whole body energy homeostasis [28]. The activation of inflammatory signaling in this particular anatomical region is capable of modulating glucose homeostasis and thermogenesis, mostly by controlling neural inputs to specific organs [31], [32]. This mechanism, acts in concert with inflammation-induced hypothalamic resistance to the anorexigenic hormones, leptin and insulin, to produce the multiple components of the complex phenotype observed in obesity. The reduction of hypothalamic inflammation in obesity corrects simultaneously feeding, thermogenesis and metabolic disarrangements, placing this phenomenon in a central position in the pathogenesis of obesity [4], [5], [8]. Here, when mice were fed unsaturated fatty acid-rich diets, a reduction in the hypothalamic expression of a number of inflammatory markers was achieved, which is in accordance with the results obtained in animal models treated with anti-inflammatory drugs [4], [5], [11], or harboring genetic modifications that impair inflammatory signaling [5], [8]. In addition, the expression of pro-apoptotic proteins was decreased, while the signaling through the AMPK/ACC pathway was corrected, showing that the effect of the unsaturated fatty acid was broad, restoring, at least in part, all defects reported so far in animal models of obesity [4], [5], [6], [33]. …
… In conclusion, unsaturated fatty acids can reproduce a number of the anti-inflammatory effects of TLR4 or TNF-α inhibition and, therefore, constitute an attractive nutritional approach to treat obesity. At least part of this effect may be mediated by the GPR120 receptor.