Print Email Facebook Twitter Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice Title Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice Author TNO Kwaliteit van Leven Grefhorst, A. van Dijk, T.H. Hammer, A. van der Sluijs, F.H. Havinga, R. Havekes, L.M. Romijn, J.A. Groot, P.H. Reijngoud, D.J. Kuipers, F. Publication year 2005 Abstract Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 ± 7.2 vs. 12.1 ± 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 ± 13 vs. 176 ± 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 ± 1.0 vs. 14.3 ± 1.4 ml·kg -1·min-1, P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fas in ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity. Copyright © 2005 the American Physiological Society. Chemicals/CAS: Acetyltransferases, EC 2.3.1.-; aminoglycoside N1-acetyltransferase, EC 2.3.1.-; Antigens, CD95; Benzoic Acids; Benzylamines; Blood Glucose; DNA-Binding Proteins; Fatty Acids; Glucose Transporter Type 4; Glucose, 50-99-7; GW 3965; Insulin, 11061-68-0; liver X receptor; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Slc2a4 protein, mouse; Triglycerides Subject Hepatic glucose productionHepatic steatosisHyperinsulinemic euglycemic clampStable isotopescell nucleus receptorliver X receptortriacylglycerolanimal experimentanimal modelcontrolled studydrug effectfatty liverglucose blood levelglucose metabolismglucose transporthyperinsulinemiainsulin sensitivitylean body weightliver parenchymametabolic clearance ratemousenonhumanprotein contentAcetyltransferasesAdipose TissueAnimalsAntigens, CD95Benzoic AcidsBenzylaminesBlood GlucoseDNA-Binding ProteinsFatty AcidsGene ExpressionGlucoseGlucose Clamp TechniqueGlucose Transporter Type 4InsulinLiverMaleMiceMice, Inbred C57BLMice, ObeseReceptors, Cytoplasmic and NuclearReverse Transcriptase Polymerase Chain ReactionRNA, MessengerTriglycerides To reference this document use: http://resolver.tudelft.nl/uuid:f7d14719-5722-4c69-9487-7dc535f111a6 DOI https://doi.org/10.1152/ajpendo.00165.2005 TNO identifier 280160 ISSN 0193-1849 Source American Journal of Physiology - Endocrinology and Metabolism, 289 (289), E829-E838 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.