The nuclear retinoid‐related orphan receptor ROR α controls circadian thermogenic programming in white fat depots

The ROR α ‐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 UCP 1 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 ROR α 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‐1α 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 ROR α inverse agonist SR 3335, that induced a parallel increase in the UCP 1 protein. Inhibitors of browning differentiation, such as TLE 3 and RIP 140, could be new targets of ROR α that would be rather implicated in the whitening of adipocytes. Our study showed the pivotal role of ROR α as an inhibitor of the thermogenic program in WAT , the role that could be counteracted in vivo with the ROR α antagonists currently in development.