SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

Domenico Sergi, Fiona M. Campbell, Christine Grant, Amanda C. Morris, Eva-Maria Bachmair, Christiane E. Koch, Fiona H. McLean, Aifric Muller, Nigel Hoggard, Baukje de Roos, Begona Porteiro, Mark V. Boekschoten, Fiona C. McGillicuddy, Darcy Kahn, Phyllis Nicol, Jonas Benzler, Claus-Dieter Mayer, Janice E. Drew, Helen M. Roche, Michael MullerRuben Nogueiras, Carlos Diéguez, Alexander Tups, Lynda M. Williams

Research output: Contribution to journalArticle

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Abstract

Background
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 inflammation.
Original languageEnglish
Article number28
Pages (from-to)1-14
Number of pages14
JournalGenes & Nutrition
Volume13
DOIs
Publication statusPublished - 29 Nov 2018

Keywords

  • SerpinA3N
  • Hypothalamus
  • High-fat diet
  • Leptin

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    Sergi, D., Campbell, F. M., Grant, C., Morris, A. C., Bachmair, E-M., Koch, C. E., McLean, F. H., Muller, A., Hoggard, N., de Roos, B., Porteiro, B., Boekschoten, M. V., McGillicuddy, F. C., Kahn, D., Nicol, P., Benzler, J., Mayer, C-D., Drew, J. E., Roche, H. M., ... Williams, L. M. (2018). SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. Genes & Nutrition, 13, 1-14. [28]. https://doi.org/10.1186/s12263-018-0619-1