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Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow\u2009+\u2009drinking water, chow\u2009+\u2009fructose, 15% or chow\u2009+\u2009fructose, 15%\u2009+\u2009hydroalcoholic extract of leaves of <jats:italic>Aegle marmelos<\/jats:italic> (AM-HM, 500\u2009mg\/kg\/d, po) and assessed for feed intake, fructose intake, body weight, fasting blood sugar, oral glucose tolerance test, HOMA-IR, insulin tolerance test and lipid profile. Activities of enzymes (glucose-6-phosphatase, hexokinase, phosphofructokinase, aldehyde dehydrogenase), hormones (leptin, ghrelin, insulin), insulin signaling molecules (Akt-PI3k, AMPK, JNK) hallmarks of inflammation (TNF-\u03b1), angiogenesis (VEGF), hypoxia (HIF-1), lipogenesis (mTOR) and regulatory nuclear transcription factors of <jats:italic>de novo<\/jats:italic> lipogenesis and hepatic insulin resistance gene (SREBP-1, FoxO1) that together govern the hepatic fructose metabolism, were also studied. The effect of fructose-rich environment on metabolic milieu of hepatocytes was confirmed using (human hepatocellular carcinoma) HepG2 cells. Using <jats:italic>in vitro<\/jats:italic> model, fructose uptake and glucose output from isolated murine hepatocytes were measured to establish the HepIR under fructose environment and delineate the effect of AM-HM. The leaves from the plant <jats:italic>Aegle marmelos<\/jats:italic> (L) Correa were extracted, fractionated and validated for rutin content using LC-MS\/MS. The rutin content of extract was quantified and correlated with oral pharmacokinetic parameters in rat. The outcomes of the study suggest that the molecular and metabolic markers of fructose induced HepIR in developing and adult rats are distinct. Further, AM-HM exerts a multi-pronged attack by raising insulin secretion, augmenting insulin action, improving downstream signaling of insulin, reducing overall requirement of insulin and modulating hepatic expression of glucose transporter (Glut2). The butanol fraction of AM-HM holds promise for future development.<\/jats:p>","DOI":"10.1038\/s41598-018-33503-x","type":"journal-article","created":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T11:29:08Z","timestamp":1540294148000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator"],"prefix":"10.1038","volume":"8","author":[{"given":"Jayachandran","family":"Nair","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thirumurthy","family":"Velpandian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ujjalkumar Subhash","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prateek","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tapas","family":"Nag","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep R.","family":"Mathur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajani","family":"Mathur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,10,29]]},"reference":[{"issue":"4","key":"33503_CR1","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s40618-016-0576-8","volume":"40","author":"P Di Bonito","year":"2017","unstructured":"Di Bonito, P. et al. \u201cCARdiometabolic risk factors in overweight and obese children in ITALY\u201d(CARITALY) Study Group. 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