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Leptin‐mediated Sympatho‐excitation in Obese Rats: Role for Astrocyte‐Neuron Crosstalk in the Arcuate Nucleus

Accumulated evidence indicates that enhanced sympathetic activation is associated with obesity. Hypothalamic leptin‐mediated signaling may contribute to the exaggerated sympatho‐excitation in obesity. The present study was conducted to investigate “neuron‐astrocyte” interactions regulating leptin signaling within the arcuate nucleus (ARCN) of hypothalamus in obese rats. High‐fat diet (42% fat for 12 weeks) induced hyperlipidemia and hyperleptinemia in Sprague Dawley rats. In anaesthetized condition, microinjections of leptin (5ng~100ng) and N‐methyl‐D‐aspartate (NMDA 50–200pmol) into the ARCN induced increases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in both control and obese rats. Pre‐inhibition of astrocytes with astrocytic metabolic inhibitor fluorocitrate reduced leptin‐induced, but not NMDA‐induced RSNA and MAP within the ARCN. In the ARCN, leptin/leptin receptor is localized in both neurons and astrocytes. In obese rats, leptin and leptin receptor were increased in the ARCN, particularly increased more in the astrocytes than in the neurons. Furthermore, we found that the expressions of glutamate transporter GLT1 and excitatory amino acid transporter‐2 (EAAT‐2) which are major glutamate transporters expressed predominantly in astrocytes were decreased within the ARCN in obese rats. Consistent with these in‐vivo observations, in cultured astrocytic C6 cells, GLT1 and EAAT‐2 levels decreased with leptin (100 ng/ml) treatment for 24 hours. Taken together, these results suggest leptin signaling via neuron‐astrocytes interactions in the ARCN may contribute to the exaggerated sympatho‐excitation observed in obese rats. This effect maybe mediated by the action of leptin regulating glutamate transporters in the astrocytes within the ARCN of the hypothalamus.