The subfornical organ: a central nervous system site for actions of circulating leptin.

Adipose tissue plays a critical role in energy homeostasis, secreting adipokines that control feeding, thermogenesis, and neuroendocrine function. Leptin is the prototypic adipokine that acts centrally to signal long-term energy balance. While hypothalamic and brain stem nuclei are well-established sites of action of leptin, we tested the hypothesis that leptin signaling occurs in the subfornical organ (SFO). The SFO is a circumventricular organ (CVO) that lacks the normal blood-brain barrier, is an important site in central autonomic regulation, and has been suggested to have a role in modulating peripheral signals indicating energy status. We report here the presence of mRNA for the signaling form of the leptin receptor in SFO and leptin receptor localization by immunohistochemistry within this CVO. Central administration of leptin resulted in phosphorylation of STAT3 in neurons of SFO. Whole cell current-clamp recordings from dissociated SFO neurons demonstrated that leptin (10 nM) influenced the excitability of 64% (46/72) of SFO neurons. Leptin was found to depolarize the majority of responsive neurons with a mean change in membrane potential of 7.3 +/- 0.6 mV (39% of all SFO neurons), while the remaining cells that responded to leptin hyperpolarized (-6.9 +/- 0.7 mV, 25% of all SFO neurons). Similar depolarizing and hyperpolarizing effects of leptin were observed in recordings from acutely prepared SFO slice preparations. Leptin was found to influence the same population of SFO neurons influenced by amylin as three of four cells tested for the effects of bath application of both amylin and leptin depolarized to both peptides. These observations identify the SFO as a possible central nervous system location, with direct access to the peripheral circulation, at which leptin may act to influence hypothalamic control of energy homeostasis.