Abstract

BackgroundThe 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.MethodsSwiss 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.ResultsThe 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.ConclusionsThe 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.

Highlights

  • 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

  • We first hypothesized that the median eminence (ME)-spinal fluid interface (SFI) is sensitive to dietary fats, leading to an early exposure of the neurons of the mediobasal hypothalamus to potentially damaging circulating factors; to explore this hypothesis, we microdissected the main periventricular BBB regions, i.e., ME, vascular organ of lamina terminalis (OVLT), subfornical organ (SFO), and subcomissural organ (SCO), and evaluated the impact of the consumption of large amounts of dietary fats on the expression of structural and inflammatory markers; we evaluated the expression of brain-derived neurotrophic factor (BDNF), which has an important trophic action in the blood-brain barrier (BBB) [16]

  • The earliest changes induced by the consumption of a high-fat diet (HFD) occurred after 1 week were as follows: GLAST was increased in OVLT, SFO, and ME and caveolin-1 was increased only in ME (Fig. 1f ); IL1β and TNFα (Fig. 1g) as well as BDNF (Fig. 1h) were increased only in ME

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Summary

Introduction

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. We first hypothesized that the ME-SFI is sensitive to dietary fats, leading to an early exposure of the neurons of the mediobasal hypothalamus to potentially damaging circulating factors; to explore this hypothesis, we microdissected the main periventricular BBB regions, i.e., ME, vascular organ of lamina terminalis (OVLT), subfornical organ (SFO), and subcomissural organ (SCO), and evaluated the impact of the consumption of large amounts of dietary fats on the expression of structural and inflammatory markers; we evaluated the expression of brain-derived neurotrophic factor (BDNF), which has an important trophic action in the blood-brain barrier (BBB) [16]. We show that reducing BDNF increases dietinduced body mass gain and enhances the functional and structural disarrangements in the ME-SFI zone

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