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 Muller & 4 others Ruben Nogueiras, Carlos Diéguez, Alexander Tups, Lynda M. Williams

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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

Fingerprint

High Fat Diet
Leptin
Hypothalamus
Up-Regulation
Genes
Neurons
alpha 1-Antichymotrypsin
Interleukin-1 Receptors
Palmitic Acid
Palmitates
Oleic Acid
Knockout Mice
In Situ Hybridization
Interleukin-6
Homeostasis
Anti-Inflammatory Agents
Down-Regulation
Obesity
Immunohistochemistry
Fats

Keywords

  • SerpinA3N
  • Hypothalamus
  • High-fat diet
  • Leptin

Cite this

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. / Sergi, Domenico; Campbell, Fiona M.; Grant, Christine; Morris, Amanda C.; Bachmair, Eva-Maria; Koch, Christiane E.; McLean, Fiona H.; Muller, Aifric; Hoggard, Nigel; de Roos, Baukje; Porteiro, Begona ; Boekschoten, Mark V.; McGillicuddy, Fiona C.; Kahn, Darcy; Nicol, Phyllis; Benzler, Jonas; Mayer, Claus-Dieter; Drew, Janice E.; Roche, Helen M.; Muller, Michael; Nogueiras, Ruben; Diéguez, Carlos; Tups, Alexander; Williams, Lynda M. (Corresponding Author).

In: Genes & Nutrition, Vol. 13, 28, 29.11.2018, p. 1-14.

Research output: Contribution to journalArticle

Sergi, D, Campbell, FM, Grant, C, Morris, AC, Bachmair, E-M, Koch, CE, McLean, FH, Muller, A, Hoggard, N, de Roos, B, Porteiro, B, Boekschoten, MV, McGillicuddy, FC, Kahn, D, Nicol, P, Benzler, J, Mayer, C-D, Drew, JE, Roche, HM, Muller, M, Nogueiras, R, Diéguez, C, Tups, A & Williams, LM 2018, 'SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice', Genes & Nutrition, vol. 13, 28, pp. 1-14. https://doi.org/10.1186/s12263-018-0619-1
Sergi, Domenico ; Campbell, Fiona M. ; Grant, Christine ; Morris, Amanda C. ; Bachmair, Eva-Maria ; Koch, Christiane E. ; McLean, Fiona H. ; Muller, Aifric ; Hoggard, Nigel ; de Roos, Baukje ; Porteiro, Begona ; Boekschoten, Mark V. ; McGillicuddy, Fiona C. ; Kahn, Darcy ; Nicol, Phyllis ; Benzler, Jonas ; Mayer, Claus-Dieter ; Drew, Janice E. ; Roche, Helen M. ; Muller, Michael ; Nogueiras, Ruben ; Diéguez, Carlos ; Tups, Alexander ; Williams, Lynda M. / SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. In: Genes & Nutrition. 2018 ; Vol. 13. pp. 1-14.
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title = "SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice",
abstract = "BackgroundEnergy 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.ResultsMouse 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.ConclusionsThese data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.",
keywords = "SerpinA3N, Hypothalamus, High-fat diet, Leptin",
author = "Domenico Sergi and Campbell, {Fiona M.} and Christine Grant and Morris, {Amanda C.} and Eva-Maria Bachmair and Koch, {Christiane E.} and McLean, {Fiona H.} and Aifric Muller and Nigel Hoggard and {de Roos}, Baukje and Begona Porteiro and Boekschoten, {Mark V.} and McGillicuddy, {Fiona C.} and Darcy Kahn and Phyllis Nicol and Jonas Benzler and Claus-Dieter Mayer and Drew, {Janice E.} and Roche, {Helen M.} and Michael Muller and Ruben Nogueiras and Carlos Di{\'e}guez and Alexander Tups and Williams, {Lynda M.}",
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 Investigaci{\'o}n Biom{\'e}dica en Red (CIBER) de Fisiopatolog{\'i}a de la Obesidad y Nutrici{\'o}n (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).",
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TY - JOUR

T1 - SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

AU - Sergi, Domenico

AU - Campbell, Fiona M.

AU - Grant, Christine

AU - Morris, Amanda C.

AU - Bachmair, Eva-Maria

AU - Koch, Christiane E.

AU - McLean, Fiona H.

AU - Muller, Aifric

AU - Hoggard, Nigel

AU - de Roos, Baukje

AU - Porteiro, Begona

AU - Boekschoten, Mark V.

AU - McGillicuddy, Fiona C.

AU - Kahn, Darcy

AU - Nicol, Phyllis

AU - Benzler, Jonas

AU - Mayer, Claus-Dieter

AU - Drew, Janice E.

AU - Roche, Helen M.

AU - Muller, Michael

AU - Nogueiras, Ruben

AU - Diéguez, Carlos

AU - Tups, Alexander

AU - Williams, Lynda M.

N1 - 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).

PY - 2018/11/29

Y1 - 2018/11/29

N2 - BackgroundEnergy 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.ResultsMouse 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.ConclusionsThese data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.

AB - BackgroundEnergy 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.ResultsMouse 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.ConclusionsThese data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.

KW - SerpinA3N

KW - Hypothalamus

KW - High-fat diet

KW - Leptin

U2 - 10.1186/s12263-018-0619-1

DO - 10.1186/s12263-018-0619-1

M3 - Article

VL - 13

SP - 1

EP - 14

JO - Genes & Nutrition

JF - Genes & Nutrition

SN - 1555-8932

M1 - 28

ER -