Abstract
OBJECTIVE: Topiramate is a medication used off-label, or in combination with phentermine, for the management of obesity. However, its mechanism of action remains elusive. As many obesity medications target the brain, we aimed to determine if topiramate influences the activity of hypothalamic melanocortin neurons known to regulate energy balance. METHODS: Transgenic mice expressing a fluorescent protein in either "orexigenic" neuropeptide Y/agouti-related peptide (NPY/AgRP) or "anorexigenic" pro-opiomelanocortin (POMC) neurons were used to perform whole-cell patch clamp electrophysiology experiments in the arcuate nucleus (ARC) of the hypothalamus. RESULTS: Topiramate (1 μM) strongly inhibited NPY/AgRP neuron electrical excitability. Despite topiramate's well-known actions at GABA(A) receptors, we demonstrate that the topiramate-induced inhibition of NPY/AgRP neurons does not involve GABA(A) receptors. The effects of topiramate on NPY/AgRP neurons were suppressed by inhibitors of synaptic transmission and after blockade of GABA(B) receptors or potassium channels. In contrast, topiramate had negligible influence on the activity of POMC neurons. CONCLUSIONS: This study is the first demonstration that topiramate strongly inhibits the activity of ARC NPY/AgRP neurons and suggests that enhanced GABAergic tone to these neurons mediates this effect. The ability of topiramate to inhibit the orexigenic NPY/AgRP neurons may underlie some of its weight-lowering properties.