{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T17:03:30Z","timestamp":1770915810345,"version":"3.50.1"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T00:00:00Z","timestamp":1480291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes for Health Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000064","name":"Banting and Best Diabetes Centre, University of Toronto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000064","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000064","name":"Banting and Best Diabetes Centre, University of Toronto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000064","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005709","name":"Endocrine Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005709","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0166973","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T14:59:24Z","timestamp":1480345164000},"page":"e0166973","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Beneficial Effects of Metformin and\/or Salicylate on Palmitate- or TNF\u03b1-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY\/AgRP Neurons"],"prefix":"10.1371","volume":"11","author":[{"given":"Wenqing","family":"Ye","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesto H.","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian C.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise D.","family":"Belsham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2016,11,28]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/nrn1245","article-title":"Monitoring of stored and available fuel by the CNS: implications for obesity","volume":"4","author":"RJ Seeley","year":"2003","journal-title":"Nat Rev Neurosci"},{"issue":"10","key":"ref2","doi-asserted-by":"crossref","first-page":"4192","DOI":"10.1210\/en.2004-1520","article-title":"Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus","volume":"146","author":"CT De Souza","year":"2005","journal-title":"Endocrinology"},{"issue":"1","key":"ref3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1172\/JCI59660","article-title":"Obesity is associated with hypothalamic injury in rodents and humans","volume":"122","author":"JP Thaler","year":"2012","journal-title":"The Journal of clinical investigation"},{"issue":"2","key":"ref4","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1523\/JNEUROSCI.2760-08.2009","article-title":"Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity","volume":"29","author":"M Milanski","year":"2009","journal-title":"J Neurosci"},{"key":"ref5","article-title":"Saturated fatty acids trigger TLR4-mediated inflammatory response","year":"2016","journal-title":"Saturated fatty acids trigger TLR4-mediated inflammatory response"},{"issue":"11","key":"ref6","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1172\/JCI28898","article-title":"TLR4 links innate immunity and fatty acid-induced insulin resistance","volume":"116","author":"H Shi","year":"2006","journal-title":"The Journal of clinical investigation"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"27384","DOI":"10.1074\/jbc.M109.044065","article-title":"Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner","volume":"284","author":"SW Wong","year":"2009","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"ref8","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1210\/en.2010-0659","article-title":"Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion","volume":"152","author":"AP Arruda","year":"2011","journal-title":"Endocrinology"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"12870","DOI":"10.1074\/jbc.M110.173021","article-title":"Inflammation of the hypothalamus leads to defective pancreatic islet function","volume":"286","author":"VC Calegari","year":"2011","journal-title":"The Journal of biological chemistry"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.peptides.2007.03.006","article-title":"TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient--effects on leptin and insulin signaling pathways","volume":"28","author":"T Romanatto","year":"2007","journal-title":"Peptides"},{"issue":"5","key":"ref11","doi-asserted-by":"crossref","first-page":"E1003","DOI":"10.1152\/ajpendo.90377.2008","article-title":"Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet","volume":"296","author":"KA Posey","year":"2009","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"847246","DOI":"10.1155\/2012\/847246","article-title":"Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high-fat diet","volume":"2012","author":"X Wang","year":"2012","journal-title":"Exp Diabetes Res"},{"issue":"6","key":"ref13","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.2337\/db11-0390","article-title":"Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver","volume":"61","author":"M Milanski","year":"2012","journal-title":"Diabetes"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1056\/NEJMoa012512","article-title":"Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin","volume":"346","author":"WC Knowler","year":"2002","journal-title":"The New England journal of medicine"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1758-5996-5-6","article-title":"Metformin: an old but still the best treatment for type 2 diabetes","volume":"5","author":"LB Rojas","year":"2013","journal-title":"Diabetol Metab Syndr"},{"issue":"Suppl 1","key":"ref16","first-page":"S87","article-title":"Aspirin therapy in diabetes","volume":"26","author":"JA Colwell","year":"2003","journal-title":"Diabetes Care"},{"key":"ref17","first-page":"2379","article-title":"Metformin inhibits food intake and neuropeptide Y gene expression in the hypothalamus","volume":"8","author":"Y Duan","year":"2013","journal-title":"Neural Regen Res"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/0361-9230(91)90117-3","article-title":"Immune cytokines and regulation of body temperature, food intake and cellular immunity","volume":"27","author":"T Hori","year":"1991","journal-title":"Brain Res Bull"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"R499","DOI":"10.1152\/ajpregu.00099.2013","article-title":"Central administration of metformin into the third ventricle of C57BL\/6 mice decreases meal size and number and activates hypothalamic S6 kinase","volume":"305","author":"HJ Kim","year":"2013","journal-title":"American journal of physiology Regulatory, integrative and comparative physiology"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainres.2012.01.028","article-title":"The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats","volume":"1444","author":"WS Lv","year":"2012","journal-title":"Brain Res"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0031-9384(02)01002-8","article-title":"Salicylate as a partial inhibitor of emotional fever and body weight set-point in rats: behavioral and neuroendocrine study","volume":"78","author":"C Michel","year":"2003","journal-title":"Physiol Behav"},{"issue":"1","key":"ref22","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1210\/en.2003-0946","article-title":"Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders","volume":"145","author":"DD Belsham","year":"2004","journal-title":"Endocrinology"},{"issue":"1","key":"ref23","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.mce.2012.03.012","article-title":"Gene array analysis of embryonic- versus adult-derived hypothalamic NPY-expressing cell lines","volume":"358","author":"SS Dhillon","year":"2012","journal-title":"Molecular and cellular endocrinology"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1128\/MCB.13.6.3301","article-title":"Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation","volume":"13","author":"AA Beg","year":"1993","journal-title":"Mol Cell Biol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/43466","article-title":"NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase","volume":"401","author":"ON Ozes","year":"1999","journal-title":"Nature"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1046\/j.1464-5491.1999.00067.x","article-title":"Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus","volume":"16","author":"P Bj\u00f6rntorp","year":"1999","journal-title":"Diabetic medicine: a journal of the British Diabetic Association"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.2337\/db07-0193","article-title":"Glucose ingestion fails to inhibit hypothalamic neuronal activity in patients with type 2 diabetes","volume":"56","author":"S Vidarsdottir","year":"2007","journal-title":"Diabetes"},{"issue":"3","key":"ref28","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.bbrc.2011.08.103","article-title":"Palmitate alters the rhythmic expression of molecular clock genes and orexigenic neuropeptide Y mRNA levels within immortalized, hypothalamic neurons","volume":"413","author":"LJ Fick","year":"2011","journal-title":"Biochemical and biophysical research communications"},{"issue":"1\u20132","key":"ref29","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.mce.2009.02.031","article-title":"Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK\/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons","volume":"307","author":"CM Mayer","year":"2009","journal-title":"Molecular and cellular endocrinology"},{"issue":"1","key":"ref30","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1210\/en.2009-0838","article-title":"Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation","volume":"151","author":"CM Mayer","year":"2010","journal-title":"Endocrinology"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1098\/rstb.2006.1855","article-title":"Neuropeptide Y in normal eating and in genetic and dietary-induced obesity","volume":"361","author":"B Beck","year":"2006","journal-title":"Philosophical transactions of the Royal Society of London Series B, Biological sciences"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1097\/00001756-199810260-00015","article-title":"Induction of neuropeptide Y expression in dorsomedial hypothalamus of diet-induced obese mice","volume":"9","author":"XM Guan","year":"1998","journal-title":"Neuroreport"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.bbalip.2009.09.016","article-title":"Hypothalamic lipotoxicity and the metabolic syndrome","volume":"1801","author":"PB de Morentin","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cell.2009.12.052","article-title":"Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression","volume":"140","author":"EJ Park","year":"2010","journal-title":"Cell"},{"issue":"1","key":"ref35","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cell.2008.07.043","article-title":"Hypothalamic IKKbeta\/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity","volume":"135","author":"X Zhang","year":"2008","journal-title":"Cell"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cmet.2008.12.004","article-title":"Endoplasmic reticulum stress plays a central role in development of leptin resistance","volume":"9","author":"L Ozcan","year":"2009","journal-title":"Cell metabolism"},{"issue":"1","key":"ref37","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1210\/er.2007-0015","article-title":"The role for endoplasmic reticulum stress in diabetes mellitus","volume":"29","author":"DL Eizirik","year":"2008","journal-title":"Endocrine reviews"},{"issue":"Suppl 7","key":"ref38","doi-asserted-by":"crossref","first-page":"S52","DOI":"10.1038\/ijo.2008.238","article-title":"Inflammation and endoplasmic reticulum stress in obesity and diabetes","volume":"32","author":"GS Hotamisligil","year":"2008","journal-title":"International journal of obesity (2005)"},{"issue":"5","key":"ref39","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1172\/JCI117936","article-title":"Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance","volume":"95","author":"GS Hotamisligil","year":"1995","journal-title":"The Journal of clinical investigation"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"E745","DOI":"10.1152\/ajpendo.2001.280.5.E745","article-title":"Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance","volume":"280","author":"PA Kern","year":"2001","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1126\/science.3140380","article-title":"I kappa B: a specific inhibitor of the NF-kappa B transcription factor","volume":"242","author":"PA Baeuerle","year":"1988","journal-title":"Science"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.8096091","article-title":"NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway","volume":"259","author":"SC Sun","year":"1993","journal-title":"Science"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1038\/sj.ijo.0801915","article-title":"The NPY\/AgRP neuron and energy homeostasis","volume":"25","author":"GJ Morton","year":"2001","journal-title":"Int J Obes Relat Metab Disord"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1677\/jme.1.01819","article-title":"Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event","volume":"35","author":"MJH Kas","year":"2005","journal-title":"Journal of Molecular Endocrinology"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.2337\/diab.46.9.1526","article-title":"Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice","volume":"46","author":"J Ventre","year":"1997","journal-title":"Diabetes"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1126\/science.1120781","article-title":"The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin","volume":"310","author":"RJ Shaw","year":"2005","journal-title":"Science"},{"issue":"8","key":"ref47","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"G Zhou","year":"2001","journal-title":"The Journal of clinical investigation"},{"issue":"3","key":"ref48","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2174\/1871530315666150316124019","article-title":"Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect","volume":"15","author":"Y Saisho","year":"2015","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"issue":"2","key":"ref49","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1210\/en.2009-1122","article-title":"Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5&apos; monophosphate-activated protein kinase activation","volume":"151","author":"CM Mayer","year":"2010","journal-title":"Endocrinology"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"750","DOI":"10.2337\/diab.27.7.750","article-title":"Restoration of the acute insulin response by sodium salicylate. A glucose dose-related phenomenon","volume":"27","author":"M Chen","year":"1978","journal-title":"Diabetes"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1136\/bmj.1.2100.760","article-title":"On the Treatment of Glycosuria and Diabetes Mellitus with Sodium Salicylate","volume":"1","author":"RT Williamson","year":"1901","journal-title":"Br Med J"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1126\/science.1061620","article-title":"Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta","volume":"293","author":"M Yuan","year":"2001","journal-title":"Science (New York, NY)"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1073\/pnas.94.7.2869","article-title":"Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase\/stress-activated protein kinase activation","volume":"94","author":"P Schwenger","year":"1997","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"6083","key":"ref54","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1126\/science.1215327","article-title":"The ancient drug salicylate directly activates AMP-activated protein kinase","volume":"336","author":"SA Hawley","year":"2012","journal-title":"Science"},{"issue":"10","key":"ref55","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.tem.2013.06.002","article-title":"AMPK: mediating the metabolic effects of salicylate-based drugs?","volume":"24","author":"GR Steinberg","year":"2013","journal-title":"Trends Endocrinol Metab"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1042\/BJ20150125","article-title":"Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity","volume":"468","author":"RJ Ford","year":"2015","journal-title":"The Biochemical journal"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1039\/C4AN01443J","article-title":"In vivo fluorescence sensing of the salicylate-induced change of zinc ion concentration in the auditory cortex of rat brain","volume":"140","author":"Q Jiang","year":"2015","journal-title":"Analyst"},{"issue":"5","key":"ref58","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S1734-1140(10)70357-1","article-title":"Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide","volume":"62","author":"K Labuzek","year":"2010","journal-title":"Pharmacol Rep"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"17675","DOI":"10.1074\/jbc.M113.475343","article-title":"Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing","volume":"288","author":"I \u00c7akir","year":"2013","journal-title":"Journal of Biological Chemistry"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0166973","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,15]],"date-time":"2019-09-15T21:26:45Z","timestamp":1568582805000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0166973"}},"subtitle":[],"editor":[{"given":"Miguel","family":"L\u00f3pez","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2016,11,28]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,11,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0166973","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,28]]}}}