Rapid inhibition of neural excitability in the nucleus tractus solitarii by leptin: implications for ingestive behaviour.
The fat-derived peptide leptin regulates cellular activity in areas of the CNS related to feeding, and application of leptin to the fourth ventricle or the nucleus tractus solitarii (NTS) inhibits food intake and weight gain. The hypothesis that leptin modulates cellular activity in the NTS was tested using whole-cell patch-clamp recordings in brainstem slices. Leptin caused a rapid membrane hyperpolarization in 58% of rat NTS neurones, including neurones receiving tractus solitarius input (i.e. viscerosensory) and those involved in regulating output to the stomach, identified after gastric inoculation with a transneuronal retrograde viral label. The hyperpolarization was accompanied by a decrease in input resistance and cellular responsiveness, reversed near the K(+) equilibrium potential, and was prevented by intracellular Cs(+). Perfusion of tolbutamide (200 microm) or wortmannin (100-200 nm) prevented the hyperpolarization, indicating activation of an ATP-sensitive K(+) channel via a PI3 kinase-dependent mechanism. Constant latency tractus solitarius-evoked EPSCs were decreased in amplitude by leptin, and the paired-pulse ratio was increased, suggesting effects on evoked EPSCs involved activation of receptors on vagal afferent terminals. Leptin reduced the frequency of spontaneous and miniature EPSCs, whereas IPSCs were largely unaffected. Leptin's effects were observed in neurones from lean, but not obese, Zucker rats. Neurones that expressed enhanced green fluorescent protein (EGFP) in a subpopulation of putative GABAergic neurones in transgenic mice did not respond to leptin, whereas unlabelled murine neurones responded similarly to rat neurones. Leptin therefore directly and rapidly suppresses activity of excitatory NTS neurones likely to be involved in viscerosensory integration and/or premotor control of the stomach.
Department of Cell and Molecular Biology, Tulane University, 6400 Freret Street, New Orleans, LA 70118, USA.
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Williams
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Smith
D000818:Animals; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D020738:Leptin / Q000494:pharmacology* / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017552:Solitary Nucleus / Q000187:drug effects / Q000502:physiology*
D020738:Leptin