Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids
R. Alvarez et al., Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids, BIOCHEM J, 345, 2000, pp. 91-97
The intracellular pathways and receptors mediating the effects of retinoic
acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been anal
ysed. RA activates transcription of ucp-l and the RA receptor (RAR) is know
n to be involved in this effect. However, co-transfection of an expression
vector for retinoid-X receptor (RXR) increases the action of 9-cis RA but n
ot the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. E
ither RAR-specific {p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8,8-tetramethyl-2-nap
hthalenyl)-1-propenyl]benzoic acid} or RXR-specific [isopropyl-(E,E)-(R,S)-
11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic co
mpounds increase the expression of UCP-1 mRNA and the activity of chloramph
enicol acetyltransferase expression vectors driven by the ucp-1 promoter. T
he RXR-mediated action of 9-cis RA requires the upstream enhancer region at
- 2469/ - 2318 in ucp-1. During brown-adipocyte differentiation RXR alpha
and RXR gamma mRNA expression is induced in parallel with UCP-1 mRNA, where
as the mRNA for the three RAR subtypes, alpha, beta and gamma, decreases. C
o-transfection of murine expression vectors for the different RAR and RXR s
ubtypes indicates that RAR alpha and RAR beta as well as RXR alpha are the
major retinoid-receptor subtypes capable of mediating the responsiveness of
ucp-1 to retinoids. It is concluded that the effects of retinoids on ucp-1
transcription involve both RAR- and RXR-dependent signalling pathways. The
responsiveness of brown adipose tissue to retinoids in vivo relies on a co
mplex combination of the capacity of RAR and RXR subtypes to mediate ucp-1
induction and their distinct expression in the differentiated brown adipocy
te.