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Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding.

ABSTRACT: Direct detection of circulating nutrients by the central nervous system has been implicated in the regulation of energy balance, and the mediobasal hypothalamus is considered as the primary sensing site mediating these effects. Neurons sensitive to energyrelated signals have also been identified outside the hypothalamus, particularly within the caudomedial nucleus of the solitary tract (cmNTS) in brainstem, but the consequences of direct cmNTS nutrient detection on energy balance remain poorly characterized. Here we determined the behavioral and metabolic consequences of direct L-leucine detection by the cmNTS and investigated the intracellular signaling and neurochemical pathways implicated in cmNTS L-leucine sensing in rats. Our results support the distributed nature of central nutrient detection, evidence a role for the cmNTS S6K1 pathway in the regulation of meal size and body weight, and suggest that the cmNTS integrates direct cmNTS nutrient detection with gut-derived, descending forebrain, and adiposity signals of energy availability to regulate food intake.

SUBMITTER: Blouet C

PROVIDER: S-EPMC3537851 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding.

Blouet Clemence C Schwartz Gary J GJ

Cell metabolism 20121101 5

Direct detection of circulating nutrients by the central nervous system has been implicated in the regulation of energy balance, and the mediobasal hypothalamus is considered as the primary sensing site mediating these effects. Neurons sensitive to energyrelated signals have also been identified outside the hypothalamus, particularly within the caudomedial nucleus of the solitary tract (cmNTS) in brainstem, but the consequences of direct cmNTS nutrient detection on energy balance remain poorly c ...[more]

PMID: 23123165

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Project description:Maintenance of cardiorespiratory homeostasis depends on autonomic reflexes controlled by neuronal circuits of the brainstem. The neurophysiology and neuroanatomy of these reflex pathways are well understood, however, the mechanisms and functional significance of autonomic circuit modulation by glial cells remain largely unknown. In the experiments conducted in male laboratory rats we show that astrocytes of the nucleus of the solitary tract (NTS), the brain area that receives and integrates sensory information from the heart and blood vessels, respond to incoming afferent inputs with [Ca2+]i elevations. Astroglial [Ca2+]i responses are triggered by transmitters released by vagal afferents, glutamate acting at AMPA receptors and 5-HT acting at 5-HT2A receptors. In conscious freely behaving animals blockade of Ca2+-dependent vesicular release mechanisms in NTS astrocytes by virally driven expression of a dominant-negative SNARE protein (dnSNARE) increased baroreflex sensitivity by 70% (p < 0.001). This effect of compromised astroglial function was specific to the NTS as expression of dnSNARE in astrocytes of the ventrolateral brainstem had no effect. ATP is considered the principle gliotransmitter and is released by vesicular mechanisms blocked by dnSNARE expression. Consistent with this hypothesis, in anesthetized rats, pharmacological activation of P2Y1 purinoceptors in the NTS decreased baroreflex gain by 40% (p = 0.031), whereas blockade of P2Y1 receptors increased baroreflex gain by 57% (p = 0.018). These results suggest that glutamate and 5-HT, released by NTS afferent terminals, trigger Ca2+-dependent astroglial release of ATP to modulate baroreflex sensitivity via P2Y1 receptors. These data add to the growing body of evidence supporting an active role of astrocytes in brain information processing.SIGNIFICANCE STATEMENT Cardiorespiratory reflexes maintain autonomic balance and ensure cardiovascular health. Impaired baroreflex may contribute to the development of cardiovascular disease and serves as a robust predictor of cardiovascular and all-cause mortality. The data obtained in this study suggest that astrocytes are integral components of the brainstem mechanisms that process afferent information and modulate baroreflex sensitivity via the release of ATP. Any condition associated with higher levels of "ambient" ATP in the NTS would be expected to decrease baroreflex gain by the mechanism described here. As ATP is the primary signaling molecule of glial cells (astrocytes, microglia), responding to metabolic stress and inflammatory stimuli, our study suggests a plausible mechanism of how the central component of the baroreflex is affected in pathological conditions.

Dataset Information

Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding.

Publications

Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding.

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