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 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* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)
9 Downloads (Pure)

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
Number of pages14
JournalGenes & Nutrition
Volume13
DOIs
Publication statusPublished - 29 Nov 2018

Bibliographical note

LMW, CG, ACM, EB, AM, BdR, MVB, MM and C-DM were supported by a project grant from NuGO; LMW, AM and FHM were supported by a project support grant from the British Society for Neuroendocrinology; DS was supported by a SULSA studentship; FHM was supported by a EASTBIO DTP BBSRC studentship; LMW, CG, ACM, EB, BdR, C-DM, FMC, PN, JED and NH were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS).

AT and KC were funded by the German Ministry of Research and Education (Ref. No: 0315087).

HMR was supported by the Irish Department of Agriculture, Food and Marine ImmunoMet Programme (14/F/828). FCM and HMR were supported by Science Foundation Ireland Principal Investigator Programme (11/PI/1119).

RN and CD were supported by grants from Ministerio de Economia y Competitividad (CD: BFU2011-29102; RN: BFU2012-35255), Xunta de Galicia (RN: EM 2012/039 and 2012-CP069). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. The research leading to these results has also received funding from the European Community’s Seventh Framework Programme under the following grants: no 245009: NeuroFAST to CD and ERC StG-2011-OBESITY53-281408 to RN.

Availability of data and materials
The transcriptomic data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus [58] and are accessible through GEO Series accession number GSE113943 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113943) (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi).

Keywords

  • SerpinA3N
  • Hypothalamus
  • High-fat diet
  • Leptin

Fingerprint

Dive into the research topics of 'SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice'. Together they form a unique fingerprint.

Cite this