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 Muller,
Ruben Nogueiras,
Carlos Dieguez,
Alexander Tups and
Lynda M. WilliamsEmail author View ORCID ID profile

Genes & Nutrition201813:28

https://doi.org/10.1186/s12263-018-0619-1

Received: 24 May 2018
Accepted: 6 November 2018
Published: 29 November 2018

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 serpinA3Nexpression 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. SerpinA3Nexpression 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.