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Background: The consumption of large amounts of dietary fats activates an inflammatory response in the hypothalamus, damaging key neurons involved in the regulation of caloric intake and energy expenditure. It is currently unknown why the mediobasal hypothalamus is the main target of diet-induced brain inflammation. We hypothesized that dietary fats can damage the median eminence blood/spinal fluid interface.Methods: Swiss mice were fed on a high-fat diet, and molecular and structural studies were performed employing real-time PCR, immunoblot, immunofluorescence, transmission electron microscopy, and metabolic measurements.Results: The consumption of a high fat diet was sufficient to increase the expression of inflammatory cytokines and brain-derived neurotrophic factor in the median eminence, preceding changes in other circumventricular regions. In addition, it led to an early loss of the structural organization of the median eminence β1-tanycytes. This was accompanied by an increase in the hypothalamic expression of brain-derived neurotrophic factor. The immunoneutralization of brain-derived neurotrophic factor worsened diet-induced functional damage of the median eminence blood/spinal fluid interface, increased diet-induced hypothalamic inflammation, and increased body mass gain.Conclusions: The median eminence/spinal fluid interface is affected at the functional and structural levels early after introduction of a high-fat diet. Brain-derived neurotrophic factor provides an early protection against damage, which is lost upon a persisting consumption of large amounts of dietary fats. [ABSTRACT FROM AUTHOR]

Background: The consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation.Methods: We used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet.Results: Using a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance.Conclusion: Hypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice. [ABSTRACT FROM AUTHOR]

Background: Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice.Methods: Male Swiss mice were fed either chow or a high-fat diet. RvD2 receptor and synthetic enzymes were evaluated by real-time PCR and immunofluorescence. RvD2 was determined by mass spectrometry. Dietary and pharmacological approaches were used to modulate the RvD2 system in the hypothalamus, and metabolic phenotype consequences were determined.Results: All enzymes involved in the synthesis of RvD2 were detected in the hypothalamus and were modulated in response to the consumption of dietary saturated fats, leading to a reduction of hypothalamic RvD2. GPR18, the receptor for RvD2, which was detected in POMC and NPY neurons, was also modulated by dietary fats. The substitution of saturated by polyunsaturated fats in the diet resulted in increased hypothalamic RvD2, which was accompanied by reduced body mass and improved glucose tolerance. The intracerebroventricular treatment with docosahexaenoic acid resulted in increased expression of the RvD2 synthetic enzymes, increased expression of anti-inflammatory cytokines and improved metabolic phenotype. Finally, intracerebroventricular treatment with RvD2 resulted in reduced adiposity, improved glucose tolerance and increased hypothalamic expression of anti-inflammatory cytokines.Conclusions: Thus, RvD2 is produced in the hypothalamus, and its receptor and synthetic enzymes are modulated by dietary fats. The improved metabolic outcomes of RvD2 make this substance an attractive approach to treat obesity. [ABSTRACT FROM AUTHOR]