Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons
Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus induce feeding and decrease energy expenditure. With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroin...
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| description | Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus induce feeding and decrease energy expenditure. With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroinflammation and secretion of cytokines, such as TNFα, and in turn activation of the canonical IKKβ/NFκB cascade. We describe a model of palmitate- and TNFα-induced neuroinflammation in a functionally characterized, immortalized NPY/AgRP-expressing cell model, mHypoE-46, to study whether the anti-diabetic metformin alone or in combination with the anti-inflammatory agent salicylate can ameliorate these detrimental effects. Treatment with palmitate increased mRNA expression of feeding peptides Npy and Agrp, and inflammatory cytokines Tnfa and Il-6, whereas treatment with TNFα increased mRNA expression of Npy, Nfkb, Ikba, Tnfa, and Il-6. The effects of metformin and/or sodium salicylate on these genes were assessed. Metformin increased phosphorylation of AMPK and S6K, while sodium salicylate increased phospho-AMPK and decreased phospho-S6K, but neither had any effect on phospho-ERK, -JNK or -p38 in the mHypoE-46 NPY/AgRP neurons. Furthermore, we utilized a pre-treatment and/or co-treatment paradigm to model potential clinical regimens. We determined co-treatment with metformin or sodium salicylate alone was successful in alleviating changes observed in feeding peptide mRNA regulation, whereas a preventative pre-treatment with metformin and sodium salicylate together was able to alleviate palmitate- and TNFα-induced induction of NPY and/or AgRP mRNA levels. These results highlight important differences in reactive versus preventative treatments on palmitate- and TNFα-induced neuroinflammation in NPY/AgRP neurons. |
| doi_str_mv | 10.1371/journal.pone.0166973 |
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With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroinflammation and secretion of cytokines, such as TNFα, and in turn activation of the canonical IKKβ/NFκB cascade. We describe a model of palmitate- and TNFα-induced neuroinflammation in a functionally characterized, immortalized NPY/AgRP-expressing cell model, mHypoE-46, to study whether the anti-diabetic metformin alone or in combination with the anti-inflammatory agent salicylate can ameliorate these detrimental effects. Treatment with palmitate increased mRNA expression of feeding peptides Npy and Agrp, and inflammatory cytokines Tnfa and Il-6, whereas treatment with TNFα increased mRNA expression of Npy, Nfkb, Ikba, Tnfa, and Il-6. The effects of metformin and/or sodium salicylate on these genes were assessed. Metformin increased phosphorylation of AMPK and S6K, while sodium salicylate increased phospho-AMPK and decreased phospho-S6K, but neither had any effect on phospho-ERK, -JNK or -p38 in the mHypoE-46 NPY/AgRP neurons. Furthermore, we utilized a pre-treatment and/or co-treatment paradigm to model potential clinical regimens. We determined co-treatment with metformin or sodium salicylate alone was successful in alleviating changes observed in feeding peptide mRNA regulation, whereas a preventative pre-treatment with metformin and sodium salicylate together was able to alleviate palmitate- and TNFα-induced induction of NPY and/or AgRP mRNA levels. These results highlight important differences in reactive versus preventative treatments on palmitate- and TNFα-induced neuroinflammation in NPY/AgRP neurons.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0166973</identifier><identifier>PMID: 27893782</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine ; Agouti-Related Protein - genetics ; Agouti-Related Protein - metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Antidiabetics ; Apoptosis ; Biology and Life Sciences ; Biomarkers - metabolism ; Cells, Cultured ; Cytokines ; Diabetes ; Diabetes mellitus ; Drug dosages ; Embryo, Mammalian - cytology ; Embryo, Mammalian - drug effects ; Embryo, Mammalian - metabolism ; Endocrinology ; Endoplasmic reticulum ; Energy expenditure ; Fatty acids ; Feeding ; Female ; Gene expression ; Gene Expression Regulation - drug effects ; Gene regulation ; High fat diet ; Homeostasis ; Hypoglycemic Agents - pharmacology ; Hypothalamus ; Hypothalamus - drug effects ; Hypothalamus - metabolism ; Hypothalamus - pathology ; Inflammation ; Inflammation - chemically induced ; Inflammation - metabolism ; Insulin resistance ; Interleukin 6 ; JNK protein ; Kinases ; Male ; Medicine ; Medicine and Health Sciences ; Metabolism ; Metformin ; Metformin - pharmacology ; Mice ; Mice, Inbred BALB C ; Neurons ; Neurons - drug effects ; Neurons - metabolism ; Neurons - pathology ; Neuropeptide Y ; Neuropeptide Y - genetics ; Neuropeptide Y - metabolism ; Neuropeptides ; NF-κB protein ; Obesity ; Palmitates - pharmacology ; Palmitic acid ; Peptides ; Phosphorylation ; Phosphorylation - drug effects ; Physical Sciences ; Physiology ; Proteins ; Rodents ; Salicylates - pharmacology ; Salicylic acid ; Signal transduction ; Sodium ; Sodium salicylate ; Tumor Necrosis Factor-alpha - pharmacology ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2016-11, Vol.11 (11), p.e0166973-e0166973</ispartof><rights>2016 Ye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Ye et al 2016 Ye et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c559t-3938699e9d14ae4899b67d389011929aaa66c70566d49092e5ec7b67aeb94fc13</citedby><cites>FETCH-LOGICAL-c559t-3938699e9d14ae4899b67d389011929aaa66c70566d49092e5ec7b67aeb94fc13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125651/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125651/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27893782$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ye, Wenqing</creatorcontrib><creatorcontrib>Ramos, Ernesto H</creatorcontrib><creatorcontrib>Wong, Brian C</creatorcontrib><creatorcontrib>Belsham, Denise D</creatorcontrib><title>Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus induce feeding and decrease energy expenditure. With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroinflammation and secretion of cytokines, such as TNFα, and in turn activation of the canonical IKKβ/NFκB cascade. We describe a model of palmitate- and TNFα-induced neuroinflammation in a functionally characterized, immortalized NPY/AgRP-expressing cell model, mHypoE-46, to study whether the anti-diabetic metformin alone or in combination with the anti-inflammatory agent salicylate can ameliorate these detrimental effects. Treatment with palmitate increased mRNA expression of feeding peptides Npy and Agrp, and inflammatory cytokines Tnfa and Il-6, whereas treatment with TNFα increased mRNA expression of Npy, Nfkb, Ikba, Tnfa, and Il-6. The effects of metformin and/or sodium salicylate on these genes were assessed. Metformin increased phosphorylation of AMPK and S6K, while sodium salicylate increased phospho-AMPK and decreased phospho-S6K, but neither had any effect on phospho-ERK, -JNK or -p38 in the mHypoE-46 NPY/AgRP neurons. Furthermore, we utilized a pre-treatment and/or co-treatment paradigm to model potential clinical regimens. We determined co-treatment with metformin or sodium salicylate alone was successful in alleviating changes observed in feeding peptide mRNA regulation, whereas a preventative pre-treatment with metformin and sodium salicylate together was able to alleviate palmitate- and TNFα-induced induction of NPY and/or AgRP mRNA levels. These results highlight important differences in reactive versus preventative treatments on palmitate- and TNFα-induced neuroinflammation in NPY/AgRP neurons.</description><subject>Adenosine</subject><subject>Agouti-Related Protein - genetics</subject><subject>Agouti-Related Protein - metabolism</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers - metabolism</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Drug dosages</subject><subject>Embryo, Mammalian - cytology</subject><subject>Embryo, Mammalian - drug effects</subject><subject>Embryo, Mammalian - metabolism</subject><subject>Endocrinology</subject><subject>Endoplasmic reticulum</subject><subject>Energy expenditure</subject><subject>Fatty acids</subject><subject>Feeding</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene regulation</subject><subject>High fat diet</subject><subject>Homeostasis</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Hypothalamus</subject><subject>Hypothalamus - drug effects</subject><subject>Hypothalamus - metabolism</subject><subject>Hypothalamus - pathology</subject><subject>Inflammation</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - metabolism</subject><subject>Insulin resistance</subject><subject>Interleukin 6</subject><subject>JNK protein</subject><subject>Kinases</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metformin</subject><subject>Metformin - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neuropeptide Y</subject><subject>Neuropeptide Y - genetics</subject><subject>Neuropeptide Y - metabolism</subject><subject>Neuropeptides</subject><subject>NF-κB protein</subject><subject>Obesity</subject><subject>Palmitates - pharmacology</subject><subject>Palmitic acid</subject><subject>Peptides</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physical Sciences</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Salicylates - pharmacology</subject><subject>Salicylic acid</subject><subject>Signal transduction</subject><subject>Sodium</subject><subject>Sodium salicylate</subject><subject>Tumor Necrosis Factor-alpha - pharmacology</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor necrosis factor-α</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNUstu1DAUjRCIlsIfILDEhs3M-JHY8QapVG0ZqS2jUhasLMe5GTw49tRJkIZfYsWP8E04nWnVIhas_LjnnnPu1cmylwRPCRNktgpD9NpN18HDFBPOpWCPsn0iGZ1witnje_e97FnXrTAuWMn502yPilIyUdL97Od78NBYY7VDx00Dpu9QaNA59E2IrfVI-3oWIvqknTUbp3tAwaOFdq3t02OCUu3q4uT3r8nc14OBGl3AEIP1jdNtq_sQN-hcx28QR6ZtcQ3r3taATpM0uoTlkGhtYk1q87YNsU9aP0amxZfZ4fJyse3y3fPsSaNdBy9250H2-eT46ujD5Ozj6fzo8GxiikL2EybTlFKCrEmuIS-lrLioWSkxIZJKrTXnRuCC8zqXWFIowIgE0VDJvDGEHWSvt7xrFzq123OnSJnnjDFajIj5FlEHvVLraFsdNypoq24-QlwqHXtrHCjBK6HrsqK0qHIthNSSYp7UCaaY4DJxvdupDVULtQHfR-0ekD6sePtVLcN3VRBa8Bszb3cEMVwP0PWqtZ0B57SHMIy-CyxESUrxH9A851gUfLT15i_ovxeRb1Emhq6L0Nz5JliNMb3tUmNM1S6mqe3V_Znvmm5zyf4A2OjnMw</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Ye, Wenqing</creator><creator>Ramos, Ernesto H</creator><creator>Wong, Brian C</creator><creator>Belsham, Denise D</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20161101</creationdate><title>Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons</title><author>Ye, Wenqing ; Ramos, Ernesto H ; Wong, Brian C ; Belsham, Denise D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c559t-3938699e9d14ae4899b67d389011929aaa66c70566d49092e5ec7b67aeb94fc13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenosine</topic><topic>Agouti-Related Protein - genetics</topic><topic>Agouti-Related Protein - metabolism</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Antidiabetics</topic><topic>Apoptosis</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers - metabolism</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Drug dosages</topic><topic>Embryo, Mammalian - cytology</topic><topic>Embryo, Mammalian - drug effects</topic><topic>Embryo, Mammalian - metabolism</topic><topic>Endocrinology</topic><topic>Endoplasmic reticulum</topic><topic>Energy expenditure</topic><topic>Fatty acids</topic><topic>Feeding</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene regulation</topic><topic>High fat diet</topic><topic>Homeostasis</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Hypothalamus</topic><topic>Hypothalamus - drug effects</topic><topic>Hypothalamus - metabolism</topic><topic>Hypothalamus - pathology</topic><topic>Inflammation</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - metabolism</topic><topic>Insulin resistance</topic><topic>Interleukin 6</topic><topic>JNK protein</topic><topic>Kinases</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Metformin</topic><topic>Metformin - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neurons</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neuropeptide Y</topic><topic>Neuropeptide Y - genetics</topic><topic>Neuropeptide Y - metabolism</topic><topic>Neuropeptides</topic><topic>NF-κB protein</topic><topic>Obesity</topic><topic>Palmitates - pharmacology</topic><topic>Palmitic acid</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Physical Sciences</topic><topic>Physiology</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Salicylates - pharmacology</topic><topic>Salicylic acid</topic><topic>Signal transduction</topic><topic>Sodium</topic><topic>Sodium salicylate</topic><topic>Tumor Necrosis Factor-alpha - pharmacology</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ye, Wenqing</creatorcontrib><creatorcontrib>Ramos, Ernesto H</creatorcontrib><creatorcontrib>Wong, Brian C</creatorcontrib><creatorcontrib>Belsham, Denise D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ye, Wenqing</au><au>Ramos, Ernesto H</au><au>Wong, Brian C</au><au>Belsham, Denise D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>11</volume><issue>11</issue><spage>e0166973</spage><epage>e0166973</epage><pages>e0166973-e0166973</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Neuropeptide Y (NPY)/Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus induce feeding and decrease energy expenditure. With consumption of a diet high in fat, there is an increase in circulating saturated free fatty acids, including palmitate, leading to the development of neuroinflammation and secretion of cytokines, such as TNFα, and in turn activation of the canonical IKKβ/NFκB cascade. We describe a model of palmitate- and TNFα-induced neuroinflammation in a functionally characterized, immortalized NPY/AgRP-expressing cell model, mHypoE-46, to study whether the anti-diabetic metformin alone or in combination with the anti-inflammatory agent salicylate can ameliorate these detrimental effects. Treatment with palmitate increased mRNA expression of feeding peptides Npy and Agrp, and inflammatory cytokines Tnfa and Il-6, whereas treatment with TNFα increased mRNA expression of Npy, Nfkb, Ikba, Tnfa, and Il-6. The effects of metformin and/or sodium salicylate on these genes were assessed. Metformin increased phosphorylation of AMPK and S6K, while sodium salicylate increased phospho-AMPK and decreased phospho-S6K, but neither had any effect on phospho-ERK, -JNK or -p38 in the mHypoE-46 NPY/AgRP neurons. Furthermore, we utilized a pre-treatment and/or co-treatment paradigm to model potential clinical regimens. We determined co-treatment with metformin or sodium salicylate alone was successful in alleviating changes observed in feeding peptide mRNA regulation, whereas a preventative pre-treatment with metformin and sodium salicylate together was able to alleviate palmitate- and TNFα-induced induction of NPY and/or AgRP mRNA levels. These results highlight important differences in reactive versus preventative treatments on palmitate- and TNFα-induced neuroinflammation in NPY/AgRP neurons.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27893782</pmid><doi>10.1371/journal.pone.0166973</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-11, Vol.11 (11), p.e0166973-e0166973 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1844333251 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Agouti-Related Protein - genetics Agouti-Related Protein - metabolism Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Antidiabetics Apoptosis Biology and Life Sciences Biomarkers - metabolism Cells, Cultured Cytokines Diabetes Diabetes mellitus Drug dosages Embryo, Mammalian - cytology Embryo, Mammalian - drug effects Embryo, Mammalian - metabolism Endocrinology Endoplasmic reticulum Energy expenditure Fatty acids Feeding Female Gene expression Gene Expression Regulation - drug effects Gene regulation High fat diet Homeostasis Hypoglycemic Agents - pharmacology Hypothalamus Hypothalamus - drug effects Hypothalamus - metabolism Hypothalamus - pathology Inflammation Inflammation - chemically induced Inflammation - metabolism Insulin resistance Interleukin 6 JNK protein Kinases Male Medicine Medicine and Health Sciences Metabolism Metformin Metformin - pharmacology Mice Mice, Inbred BALB C Neurons Neurons - drug effects Neurons - metabolism Neurons - pathology Neuropeptide Y Neuropeptide Y - genetics Neuropeptide Y - metabolism Neuropeptides NF-κB protein Obesity Palmitates - pharmacology Palmitic acid Peptides Phosphorylation Phosphorylation - drug effects Physical Sciences Physiology Proteins Rodents Salicylates - pharmacology Salicylic acid Signal transduction Sodium Sodium salicylate Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-TNF Tumor necrosis factor-α |
| title | Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons |
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