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

Abstract

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 currentclamp 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 Ϯ 0.6 mV (39% of all SFO neurons), while the remaining cells that responded to leptin hyperpolarized (Ϫ6.9 Ϯ 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. circumventricular organ; hypothalamus ADIPOSE TISSUE PLAYS A CRITICAL role in energy homeostasis, secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. Leptin, a 16 kDa peptide, is the prototypic adipokine that has been shown to be an important afferent signal regulating body weight. A missense mutation in the ob gene (the gene that encodes leptin) in the ob/ob mouse, results in a markedly obese phenotype that is normalized by both systemic and central leptin administration (9,19,37). Leptin administration also has been shown to dose-dependently decrease body weight, preferentially reducing body fat while sparing lean tissue in both ob/ob and wild-type mice (18,19). Plasma leptin levels reflect both energy stores and acute energy balance. Circulating leptin decreases food intake and increases energy expenditure through activation of receptors in hypothalamic and brain stem neurons (16) .The leptin receptor, encoded by the Ob-R gene, was isolated from choroid plexus by expression cloning and is a member of the cytokine family (48). Although five leptin receptor isoforms have been identified (Ob-Ra to Ob-Re), only the long form of the rece...

Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ

“…Because receptors of several peptide hormones are known to be highly expressed in the SFO (Orskov, et al, 1996;Pulman et al, 2006;Smith, et al, 2009), neural modulations by these peptides are plausible mechanisms for the thirst regulation. Among the peptides that are known to modulate the excitability of the SFO neurons, cholecystokinin (CCK) has been reported to inhibit water intake when injected into the cerebroventricle (Willis et al, 1984).…”

Central angiotensin II has catabolic action at white and brown adipose tissue

“…Systemic Ang II is thought to influence the central nervous system by activating neurons within circumventricular organs such as the subfornical organ, which has been implicated in the regulation of energy balance (42,77,78). However, within the brain, Ang II is synthesized locally and acts as a neurotransmitter (49).…”

Hypothalamic melanin-concentrating hormone projections to the septo-hippocampal complex in the rat

“…Nevertheless, a parallel lateral column, represented by the LHA (considering here its cytoarchitecture, anatomy, connections, neurochemical, physiological, and pharmacological characteristics), should be considered as the ''integrator/arousal center'' for goal-oriented behaviors (Adamantidis and de Lecea, 2009;Berthoud and Munzberg, 2011;Bittencourt, 2011;Broberger et al, 1998;Kilduff and Peyron, 2000;Sawchenko, 1998;Swanson, 1987). In addition, the LHA receives information about the energy stores, via the long form of the leptin receptor, mainly from two hypothalamic sites: the Arc and the subfornical organ (SFO), as previously described (Elias et al, 1998a;Elmquist et al, 1999;Smith et al, 2009). Although the neurochemical profile of the responsive neurons in the SFO has yet to be characterized, the SFO transcriptome shows a quite unusual response after dehydration and food deprivation (Hindmarch et al, 2008).…”