Sergi, DomenicoCampbell, Fiona M.Grant, ChristineMorris, Amanda C.Bachmair, Eva MaríaKoch, ChristianeMcLean, Fiona H.Muller, AifricHoggard, NigelRoos, Baukje dePorteiro Couto, BegoñaBoekschoten, Mark V.McGillicuddy, Fiona C.Kahn, DarcyNicol, PhyllisBenzler, JonasMayer, Claus-DieterDrew, Janice E.Roche, Helen M.Muller, MichaelNogueiras Pozo, RubénDiéguez González, CarlosTups, AlexanderWilliams, Lynda M.2020-05-082020-05-082018Sergi, D., Campbell, F.M., Grant, C. et al. SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes Nutr 13, 28 (2018)1555-8932http://hdl.handle.net/10347/22137Background Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1−/−) mice. Conclusions These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammationeng© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedhttps://creativecommons.org/licenses/by/4.0/SerpinA3NHypothalamusHigh-fat dietLeptinjournal article10.1186/s12263-018-0619-11865-3499open access