Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator

Abstract The time course of pathogenesis of fructose mediated hepatic insulin resistance (HepIR) is not well-delineated and we chronicle it here from post-weaning to adulthood stages. Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow + drinking water, chow ...

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Autores principales:	Jayachandran Nair, Thirumurthy Velpandian, Ujjalkumar Subhash Das, Prateek Sharma, Tapas Nag, Sandeep R. Mathur, Rajani Mathur
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Marmelos Hepatic Insulin Resistance (HepIR) Fructose Intake Vascular Endothelial Growth Factor (VEGF) Ghrelin Medicine R Science Q
Acceso en línea:	https://doaj.org/article/306adb3df451467baa9f965956943161
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spelling	oai:doaj.org-article:306adb3df451467baa9f9659569431612021-12-02T15:08:50ZMolecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator10.1038/s41598-018-33503-x2045-2322https://doaj.org/article/306adb3df451467baa9f9659569431612018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33503-xhttps://doaj.org/toc/2045-2322Abstract The time course of pathogenesis of fructose mediated hepatic insulin resistance (HepIR) is not well-delineated and we chronicle it here from post-weaning to adulthood stages. Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow + drinking water, chow + fructose, 15% or chow + fructose, 15% + hydroalcoholic extract of leaves of Aegle marmelos (AM-HM, 500 mg/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-α), angiogenesis (VEGF), hypoxia (HIF-1), lipogenesis (mTOR) and regulatory nuclear transcription factors of de novo 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 in vitro 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 Aegle marmelos (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.Jayachandran NairThirumurthy VelpandianUjjalkumar Subhash DasPrateek SharmaTapas NagSandeep R. MathurRajani MathurNature PortfolioarticleMarmelosHepatic Insulin Resistance (HepIR)Fructose IntakeVascular Endothelial Growth Factor (VEGF)GhrelinMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Marmelos Hepatic Insulin Resistance (HepIR) Fructose Intake Vascular Endothelial Growth Factor (VEGF) Ghrelin Medicine R Science Q
spellingShingle	Marmelos Hepatic Insulin Resistance (HepIR) Fructose Intake Vascular Endothelial Growth Factor (VEGF) Ghrelin Medicine R Science Q Jayachandran Nair Thirumurthy Velpandian Ujjalkumar Subhash Das Prateek Sharma Tapas Nag Sandeep R. Mathur Rajani Mathur Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator
description	Abstract The time course of pathogenesis of fructose mediated hepatic insulin resistance (HepIR) is not well-delineated and we chronicle it here from post-weaning to adulthood stages. Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow + drinking water, chow + fructose, 15% or chow + fructose, 15% + hydroalcoholic extract of leaves of Aegle marmelos (AM-HM, 500 mg/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-α), angiogenesis (VEGF), hypoxia (HIF-1), lipogenesis (mTOR) and regulatory nuclear transcription factors of de novo 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 in vitro 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 Aegle marmelos (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.
format	article
author	Jayachandran Nair Thirumurthy Velpandian Ujjalkumar Subhash Das Prateek Sharma Tapas Nag Sandeep R. Mathur Rajani Mathur
author_facet	Jayachandran Nair Thirumurthy Velpandian Ujjalkumar Subhash Das Prateek Sharma Tapas Nag Sandeep R. Mathur Rajani Mathur
author_sort	Jayachandran Nair
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
title_short	Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator
title_full	Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator
title_fullStr	Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator
title_full_unstemmed	Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator
title_sort	molecular and metabolic markers of fructose induced hepatic insulin resistance in developing and adult rats are distinct and aegle marmelos is an effective modulator
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/306adb3df451467baa9f965956943161
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Molecular and Metabolic Markers of Fructose Induced Hepatic Insulin Resistance in Developing and Adult Rats are Distinct and Aegle marmelos is an Effective Modulator

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