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Dissection of the Insulin-Sensitizing Effect of Liver X Receptor Ligands

The Genomics Institute of the Novartis Research Foundation (L.V., N.M., P.A.M., P.K., E.S.), San Diego, California 92121; Novartis Institutes for BioMedical Research (S.R.C., S.E.D., E.C.R., X.L., T.L.M.), Cambridge, Massachusetts 02139; and Department of Cell Biology (N.M., E.S.), The Scripps Research Institute, La Jolla, California 92037

Address all correspondence and requests for reprints to: Enrique Saez, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. E-mail: esaez{at}scripps.edu.

The liver X receptors (LXR and β) are nuclear receptors that coordinate carbohydrate and lipid metabolism. Treatment of insulin-resistant mice with synthetic LXR ligands enhances glucose tolerance, inducing changes in gene expression expected to decrease hepatic gluconeogenesis (via indirect suppression of gluconeogenic enzymes) and increase peripheral glucose disposal (via direct up-regulation of glut4 in fat). To evaluate the relative contribution of each of these effects on whole-body insulin sensitivity, we performed hyperinsulinemic-euglycemic clamps in high-fat-fed insulin-resistant rats treated with an LXR agonist or a peroxisome proliferator-activated receptor ligand. Both groups showed significant improvement in insulin action. Interestingly, rats treated with LXR ligand had lower body weight and smaller fat cells than controls. Insulin-stimulated suppression of the rate of glucose appearance (Ra) was pronounced in LXR-treated rats, but treatment failed to enhance peripheral glucose uptake (R'g), despite increased expression of glut4 in epididymal fat. To ascertain whether LXR ligands suppress hepatic gluconeogenesis directly, mice lacking LXR (the primary isotype in liver) were treated with LXR ligand, and gluconeogenic gene expression was assessed. LXR activation decreased expression of gluconeogenic genes in wild-type and LXRβ null mice, but failed to do so in animals lacking LXR. Our observations indicate that despite inducing suggestive gene expression changes in adipose tissue in this model of diet-induced insulin resistance, the antidiabetic effect of LXR ligands is primarily due to effects in the liver that appear to require LXR. These findings have important implications for clinical development of LXR agonists as insulin sensitizers.

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Nuclear Receptors:   LXRβ  |  LXRα

Coregulators:   PGC-1