Separate and overlapping metabolic functions of LXRα and LXRβ in C57Bl/6 female mice

Separate and overlapping metabolic functions of LXR alpha and LXR beta in C57Bl/6 female mice. Am J Physiol Endocrinol Metab 298: E167-E178, 2010. First published August 18, 2009; doi:10.1152/ajpendo.00184.2009.-The two liver X receptors (LXRs), LXR alpha and LXR beta, are transcriptional regulators of cholesterol, lipid, and glucose metabolism and are both activated by oxysterols. Impaired metabolism is linked with obesity, insulin resistance, and type 2-diabetes (T2D). In the present study, we aimed to delineate the specific roles of LXR alpha and -beta in metabolic processes. C57Bl/6 female mice were fed a normal or a high-fat diet (HFD) and metabolic responses in wild-type, LXR alpha(-/-), LXR beta(-/-), and LXR alpha beta(-/-) mice were analyzed. Whole body fat and intramyocellular lipid contents were measured by nuclear magnetic resonance. Energy expenditure was measured in individual metabolic cages. Glucose, insulin, and pyruvate tolerance tests were performed and gene expression profiles analyzed by qPCR. We found that both LXR beta(-/-) and LXR alpha beta(-/-) mice are resistant to HFD-induced obesity independently of the presence of high cholesterol. Using tolerance tests, we found that, on an HFD, LXR beta(-/-) mice enhanced their endogenous glucose production and became highly insulin resistant, whereas LXR alpha(-/-) and LXR alpha beta(-/-) mice remained glucose tolerant and insulin sensitive. Gene expression profiling confirmed that LXR beta is the regulator of lipogenic genes in visceral white adipose tissue (WAT) and muscle tissue and, surprisingly, that Ucp1 and Dio2 are not responsible for the protection against diet-induced obesity observed in LXR beta(-/-) and LXR alpha beta(-/-) mice. LXR alpha is required for the control of cholesterol metabolism in the liver, while LXR beta appears to be a major regulator of glucose homeostasis and energy utilization and of fat storage in muscle and WAT. We conclude that selective LXR beta agonists would be novel pharmaceuticals in the treatment of T2D.