Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice

1 Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen; 2 TNO Prevention and Health and Departments of General Internal Medicine and Cardiology and of 3 Endocrinology and Diabetes, Leiden University Medical Center, Leiden, The Netherlands and the 4 Atherosclerosis Department, GlaxoSmithKline Pharmaceuticals, Stevenage, United Kingdom Submitted 14 April 2005 ; accepted in final form 27 May 2005 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. hepatic glucose production; hepatic steatosis; hyperinsulinemic euglycemic clamp; stable isotopes; triglycerides Address for reprint requests and other correspondence: A. Grefhorst, Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, Rm. Y2117, CMC IV, Univ. Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands (e-mail: A.Grefhorst{at}med.umcg.nl )