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

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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 (α 1AC), 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.

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          MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.

          Andre Kleinridders, Dominik Schenten, A. Christine Könner … (2009)
          Obesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice are protected from high-fat diet (HFD)-induced weight gain, from the development of HFD-induced leptin resistance, and from the induction of leptin resistance by acute central application of palmitate. Moreover, CNS-restricted MyD88 deletion protects from HFD- and icv palmitate-induced impairment of peripheral glucose metabolism. Thus, we define neuronal MyD88-dependent signaling as a key regulator of diet-induced leptin and insulin resistance in vivo.
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            Hepatic acute phase proteins--regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling.

            Johannes Bode, Ute Albrecht, Dieter Häussinger … (2012)
            The function of the liver as an important constituent of the immune system involved in innate as well as adaptive immunity is warranted by different highly specialized cell populations. As the major source of acute phase proteins, including secreted pathogen recognition receptors (PRRs), short pentraxins, components of the complement system or regulators of iron metabolism, hepatocytes are essential constituents of innate immunity and largely contribute to the control of a systemic inflammatory response. The production of acute phase proteins in hepatocytes is controlled by a variety of different cytokines released during the inflammatory process with IL-1- and IL-6-type cytokines as the leading regulators operating both as a cascade and as a network having additive, inhibitory, or synergistic regulatory effects on acute phase protein expression. Hence, IL-1β substantially modifies IL-6-induced acute phase protein production as it almost completely abrogates production of acute phase proteins such as γ-fibrinogen, α(2)-macroglobulin or α(1)-antichymotrypsin, whereas production of for example hepcidin, C-reactive protein and serum amyloid A is strongly up-regulated. This switch-like regulation of IL-6-induced acute phase protein production by IL-1β is due to a complex processing of the intracellular signaling events activated in response to IL-6 and/or IL-1β, with the crosstalk between STAT3- and NF-κB-mediated signal transduction being of particular importance. Recent data suggest that in this context complex formation between STAT3 and the p65 subunit of NF-κB might be of key importance. The present review summarizes the regulation of acute phase protein production focusing on the role of the crosstalk of STAT3- and NF-κB-driven pathways for transcriptional control of acute phase gene expression. Copyright © 2011 Elsevier GmbH. All rights reserved.
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              Minireview: Inflammation and obesity pathogenesis: the hypothalamus heats up.

              Michael W. Schwartz, Joshua Thaler (2010)
              Obesity induced by high-fat (HF) feeding is associated with low-grade inflammation in peripheral tissues that predisposes to insulin resistance. Recent evidence suggests the occurrence of a similar process in the hypothalamus, which favors weight gain through impairment of leptin and insulin signaling. In addition to its implications for obesity pathogenesis, this hypothesis suggests that centrally targeted antiinflammatory therapies may prove effective in prevention and treatment of this disorder. This article highlights molecular and cellular mechanisms by which hypothalamic inflammation predisposes to diet-induced obesity.
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                Author and article information

                Contributors
                Lynda M. Williams:
                ORCID: http://orcid.org/0000-0002-8921-4173
                +44-(0)1224-438682 , l.williams@abdn.ac.uk
                Journal
                Journal ID (nlm-ta): Genes Nutr
                Journal ID (iso-abbrev): Genes Nutr
                Title: Genes & Nutrition
                Publisher: BioMed Central (London )
                ISSN (Print): 1555-8932
                ISSN (Electronic): 1865-3499
                Publication date (Electronic): 29 November 2018
                Publication date PMC-release: 29 November 2018
                Publication date Collection: 2018
                Volume: 13
                Electronic Location Identifier: 28
                Affiliations
                [1 ]ISNI 0000 0004 1936 7291, GRID grid.7107.1, Rowett Institute, University of Aberdeen, ; Aberdeen, AB25 2ZD UK
                [2 ]ISNI 0000 0004 1936 9756, GRID grid.10253.35, Department of Animal Physiology, Faculty of Biology, , Philipps University Marburg, ; Karl-von-Frisch Str. 8, 35043 Marburg, Germany
                [3 ]ISNI 0000 0004 1936 7830, GRID grid.29980.3a, Centre for Neuroendocrinology and Brain Health Research Centre, Department of Physiology, School of Medical Sciences, , University of Otago, ; Dunedin, 9054 New Zealand
                [4 ]ISNI 0000000109410645, GRID grid.11794.3a, Department of Physiology, , University of Santiago de Compostela, ; 15705 Santiago de Compostela, Spain
                [5 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), ; Madrid, Spain
                [6 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, , Wageningen University, ; Wageningen, The Netherlands
                [7 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, Nutrigenomics Research Group, , UCD Conway Institute, University College Dublin, ; Dublin, Ireland
                [8 ]ISNI 0000 0004 1936 7291, GRID grid.7107.1, Biomathematics & Statistics Scotland (BioSS), , Rowett Institute, University of Aberdeen, ; Aberdeen, AB25 2ZD UK
                [9 ]ISNI 0000 0001 1092 7967, GRID grid.8273.e, Nutrigenomics and Systems Nutrition Group, Norwich Medical School, , University of East Anglia, ; Norwich, NR4 7UQ UK
                Author information
                http://orcid.org/0000-0002-8921-4173
                Article
                Publisher ID: 619
                DOI: 10.1186/s12263-018-0619-1
                PMC ID: 6263559
                PubMed ID: 30519364
                SO-VID: f52f3db1-758f-4422-b62f-72ea4bff3b6c
                Copyright © © The Author(s) 2018
                License:

                Open AccessThis 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 stated.

                History
                Date received : 24 May 2018
                Date accepted : 6 November 2018
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: serpina3n,hypothalamus,high-fat diet,leptin
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: serpina3n, hypothalamus, high-fat diet, leptin

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