PPARγ agonist rosiglitazone switches fuel preference to lipids in promoting thermogenesis under cold exposure in C57BL/6 mice.

Unlabelled: Brown and beige adipose tissues play key roles in adaptive thermogenesis, which is essential for homoiotherms to maintain core temperature under cold exposure. PPARγ is a transcriptional regulator critical for brown adipose tissue (BAT) recruitment and white adipose tissue (WAT) browning. Here we evaluated the impact of PPARγ activation on thermogenic activity in C57BL/6 mice under thermo-neutral and 4 °C cold environment, and revealed the regulating mechanism and metabolic basis. Rosiglitazone slowed body temperature loss in cold environment in C57BL/6 mice, suppressed cold-induced decreases in blood glucose, reversed cold-promoted F-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. Thus, rosiglitazone might promote thermogenesis under cold exposure by switching fuel preference.

Significance: In current study, for the first time, PPARγ agonism by rosiglitazone was proved to promote thermogenesis under near-freezing conditions and enhance the heat generating response against cold-induced hypothermia in mice by switching the fuel preference from carbohydrates to lipids. The lipid substrates stored in BAT in response to PPARγ activation are spared for eventual thermogenic activation. These findings thus underline the remarkable actions of PPARγ in the control of energy metabolism in adipose tissues, especially the BAT.