Separate and overlapping metabolic functions of LXRalpha and LXRbeta in C57Bl/6 female mice

The two liver X receptors (LXRs), LXRalpha and LXRbeta, 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 LXRalpha 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, LXRalpha(-/-), LXRbeta(-/-), and LXRalphabeta(-/-) 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 LXRbeta(-/-) and LXRalphabeta(-/-) mice are resistant to HFD-induced obesity independently of the presence of high cholesterol. Using tolerance tests, we found that, on an HFD, LXRbeta(-/-) mice enhanced their endogenous glucose production and became highly insulin resistant, whereas LXRalpha(-/-) and LXRalphabeta(-/-) mice remained glucose tolerant and insulin sensitive. Gene expression profiling confirmed that LXRbeta 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 LXRbeta(-/-) and LXRalphabeta(-/-) mice. LXRalpha is required for the control of cholesterol metabolism in the liver, while LXRbeta appears to be a major regulator of glucose homeostasis and energy utilization and of fat storage in muscle and WAT. We conclude that selective LXRbeta agonists would be novel pharmaceuticals in the treatment of T2D.