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Obesity increases the risk of insulin resistance and age\u2010related cognitive decline, accompanied by peripheral inflammation. (\u2014)\u2010Epigallocatechin\u20103\u2010gallate (EGCG), the major polyphenol in green tea, possesses antioxidant, anti\u2010inflammatory, and cardioprotective activities; however, few reports have focused on its potential effect on cognitive disorders. In this study, our goal was to investigate the protective effects of EGCG treatment on insulin resistance and memory impairment induced by a high\u2010fat and high\u2010fructose diet (HFFD). We randomly assigned 3\u2010mo\u2010old C57BL\/6J mice to 3 groups with different diets: control group, HFFD group, and HFFD plus EGCG group. Memory loss was assessed by using the Morris water maze test, during which EGCG was observed to prevent HFFD\u2010elicited memory impairment and neuronal loss. Consistent with these results, EGCG attenuated HFFD\u2010induced neuronal damage. Of note, EGCG significantly ameliorated insulin resistance and cognitive disorder by up\u2010regulating the insulin receptor substrate\u20101 (IRS\u20101)\/AKT and ERK\/cAMP response element binding protein (CREB)\/brain\u2010derived neurotrophic factor (BDNF) signaling pathways. Long\u2010term HFFD\u2010triggered neuroinflammation was restored by EGCG supplementation by inhibiting the MAPK and NF\u2010\u03baB pathways, as well as the expression of inflammatory mediators, such as TNF\u2010\u03b1. EGCG also reversed high glucose and glucosamine\u2010induced insulin resistance in SH\u2010SY5Y neuronal cells by improving the oxidized cellular status and mitochondrial function. To our knowledge, this study is the first to provide compelling evidence that the nutritional compound EGCG has the potential to ameliorate HFFD\u2010triggered learning and memory loss.\u2014Mi, Y., Qi, G., Fan, R., Qiao, Q., Sun, Y., Gao, Y., Liu, X. EGCG ameliorates high\u2010fat\u2013 and high\u2010fructose\u2010induced cognitive defects by regulating the IRS\/AKT and ERK\/CREB\/BDNF signaling pathways in the CNS. FASEB J. 31, 4998\u20135011 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700400rr","type":"journal-article","created":{"date-parts":[[2017,7,24]],"date-time":"2017-07-24T20:50:21Z","timestamp":1500929421000},"page":"4998-5011","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["EGCG ameliorates high\u2010fat\u2013 and high\u2010fructose\u2010induced cognitive defects by regulating the IRS\/AKT and ERK\/CREB\/BDNF signaling pathways in the CNS"],"prefix":"10.1096","volume":"31","author":[{"given":"Yashi","family":"Mi","sequence":"first","affiliation":[{"name":"Laboratory of Functional Chemistry and Nutrition of Food College of Food Science and Engineering Northwest A&amp;F University Yangling 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