The nuclear retinoid-related orphan receptor RORalpha controls circadian thermogenic programming in white fat depots (Équipe Fève)

Physiol Rep. 2018;6(8):e13678

The RORalpha-deficient staggerer (sg/sg) mouse is lean and resistant to diet-induced obesity. Its thermogenic activity was shown to be increased not only in brown adipose tissue (BAT), but also in subcutaneous white adipose tissue (WAT) where UCP1 content was enhanced, however, without Prdm16 coexpression. Our observation of partial multilocular lipid morphology of WAT in sg/sg mice both in the inguinal and perigonadal sites led us to focus on the phenotype of both fat depots. Because RORalpha is a nuclear factor acting in the clock machinery, we looked at the circadian expression profile of genes involved in thermogenesis and browning in WAT and BAT depots of sg/sg and WT mice, through real-time quantitative PCR and western blotting. This 24-h period approach revealed both a rhythmic expression of thermogenic genes in WAT and an increased browning of all the WAT depots tested in sg/sg mice that indeed involved the canonical browning process (through induction of Pgc-1alpha and Prdm16). This was associated with an enhanced isoproterenol-induced oxygen consumption rate of WAT explants from sg/sg mice, which was reproducible in WT explants by treatment with a RORalpha inverse agonist SR 3335, that induced a parallel increase in the UCP1 protein. Inhibitors of browning differentiation, such as TLE3 and RIP140, could be new targets of RORalpha that would be rather implicated in the whitening of adipocytes. Our study showed the pivotal role of RORalpha as an inhibitor of the thermogenic program in WAT, the role that could be counteracted in vivo with the RORalpha antagonists currently in development.