Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2

In mammalian brown adipose tissue, thermogenesis is explained by uncoupling mitochondrial respiration from ATP synthesis. Uncoupling protein-1 (UCP1) is responsible for this uncoupled state, because it allows proton re-entry into the matrix and thus dissipates the proton gradient generated by the re spiratory chain. Proton transport by UCP1 is regulated negatively by nucleo tides and positively by fatty acids, Adrenergic stimulation of brown adipoc ytes stimulates lipolysis and therefore enhances uncoupling and thermogenes is. Adrenergic stimulation also boosts ucp1 gene transcription. Since retin oic acid also promotes ucp1 gene transcription and its structure makes it a possible activator of UCP1, we hypothesized that retinoic acid, like norad renaline, could have a dual action and trigger the activity of the protein UCP1 itself Here we show that retinoic acid strongly increases proton trans port by UCP1 in brown adipose tissue mitochondria and that it is much more potent than fatty acids. These data are corroborated with yeast mitochondri a where UCP1 was introduced by genetic manipulation. The yeast expression s ystem allows the comparison of the UCP1 with the newly described homologues UCP2 and UCP3. The search for regulators of UCP2 has demonstrated that it is positively regulated by retinoids in a pH-dependent manner.