title: The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis.
abstract: The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons.
  
  
  
  Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.
authors.affiliation: Molecular and Cellular Neuroscience Department and wfranc@scripps.edu bconti@scripps.edu.
authors.forename: Walter
authors.identifier: 0000-0002-8806-9023
authors.initials: W
authors.lastname: Francesconi
authors.affiliation: Molecular and Cellular Neuroscience Department and Department of Chemical Physiology, and.
authors.forename: Manuel
authors.identifier: 0000-0002-8164-8452
authors.initials: M
authors.lastname: Sánchez-Alavez
authors.affiliation: Department of Chemical Physiology, and Department of Biology, University of Pisa, Italy.
authors.forename: Fulvia
authors.identifier: 0000-0002-9046-0056
authors.initials: F
authors.lastname: Berton
authors.affiliation: Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy, and.
authors.forename: Silvia
authors.identifier: 0000-0002-2332-3166
authors.initials: S
authors.lastname: Alboni
authors.affiliation: Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy, and.
authors.forename: Cristina
authors.identifier: 0000-0003-0236-9525
authors.initials: C
authors.lastname: Benatti
authors.affiliation: Department of Chemical Physiology, and.
authors.forename: Simone
authors.identifier: 0000-0002-0793-7045
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Chemical Physiology, and.
authors.forename: William
authors.identifier: 0000-0003-1092-4859
authors.initials: W
authors.lastname: Nguyen
authors.affiliation: CNAD, The Scripps Research Institute, La Jolla, California.
authors.forename: Eric
authors.identifier: 0000-0003-2288-7899
authors.initials: E
authors.lastname: Zorrilla
authors.affiliation: Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Gianluca
authors.identifier: 0000-0002-0380-0105
authors.initials: G
authors.lastname: Moroncini
authors.affiliation: Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy, and.
authors.forename: Fabio
authors.identifier: 0000-0002-0958-7333
authors.initials: F
authors.lastname: Tascedda
authors.affiliation: Molecular and Cellular Neuroscience Department and Department of Chemical Physiology, and wfranc@scripps.edu bconti@scripps.edu.
authors.forename: Bruno
authors.identifier: 0000-0002-9185-5201
authors.initials: B
authors.lastname: Conti
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000502:physiology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D012686:Septal Nuclei / Q000502:physiology*; D013569:Synapses / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid
keywords: bed nucleus of the stria terminalis; cytokine; feeding; inflammatory; interleukin 18; sickness