Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin-Induced Diabetic Mice

Activation of liver X receptors (LXRs) can improve glucose tolerance in insulin-independent diabetes, however, whether similar effects can be achieved in insulin-dependent diabetes remains unclear. Here, we evaluated the anti-diabetic activity of T0901317, a potent agonist of LXRs, in diabetic mice induced by streptozotocin, and our data demonstrate that T0901317 is most effective when combined with cold treatment of animals. Treatment with T0901317 improved glucose tolerance of diabetic mice, which was associated with repressed expression of key genes involved in hepatic gluconeogenesis such as Pepck and G6p. Combined treatment by T0901317 and cold exposure reduced transcription of gluconeogenic genes to similar levels. Intriguingly, combined treatment greatly increased expression of Ucp1, Cidea, Dio2, and Elvol3 predominantly in the inguinal white adipose tissue, consequently leading to browning of this fat pad, and resulting in further improvement of glucose tolerance which was associated with increased protein levels of UCP1 and GLUT4. Collectively, these results suggest that browning of white adipose tissue via cold exposure in combination with activation of liver X receptors is an alternative and effective strategy to manage insulin-dependent diabetes.