PPAR gamma agonist rosiglitazone switches fuel preference to lipids in promoting adaptive thermogenesis under cold exposure

抄録

Background Brown and beige adipose tissues play key roles in adaptive thermogenesis, which is essential for homoiotherms to maintain core temperature under cold exposure. PPAR gamma is a transcriptional regulator critical for brown adipose tissue (BAT) recruitment and white adipose tissue (WAT) browning.

Methods To determine the impact of PPAR gamma activation on thermogenic activity under thermo-neutral and 4 degree celsius cold environment, and to reveal the regulating mechanism and metabolic basis. The impact of PPAR gamma agonist rosiglitazone on core-temperature and glucose uptake was evaluated in C57BL/6 mice, and its impact on serum and adipose tissues were comparatively studied with cold exposure by targeted transcriptomic and untargeted metabolomic analysis.

Results Rosiglitazone significantly increase the survival time of normal C57BL/6 mice at extreme low temperature in a time and dose dependent way. Furthermore, it slowed body temperature loss in 4 degrees celsius cold environment in C57BL/6 mice, suppressed cold-induced decreases in blood glucose, reversed cold-promoted 18F-FDG uptake, and increased lipid consumption in BAT. Serum/adipose tissue metabolomic and transcriptomic analyses revealed that cold exposure and rosiglitazone affect metabolism in different way, especially in terms of free fatty acid/lipid metabolism. While all tested treatments stimulated stored-substance mobilization in epididymal WAT, in heat-generating adipose tissues (BAT and subcutaneous WAT), Rosiglitazone -only treatment promoted the storage of substances such as lipids for subsequent thermogenic activation; conversely, cold exposure favoured glucose consumption and mobilization/transport of extracellular lipids. When combined with cold exposure, Rosiglitazone treatment preferentially triggered BAT lipid consumption, mobilized and transported lipids from epididymal to subcutaneous WAT, and reduced glucose usage.

Conclusions. Therefore, it can be speculated rosiglitazone promoted the thermogenesis under cold exposure and enhanced the ability of normal mice in defending against hypothermia through switching fuel preference from carbohydrate to lipids. These findings thus underline the remarkable actions of PPAR gamma in the control of energy metabolism in target tissues, especially the BAT, which is valuable for organism to improve cold endurance.