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

Abstract

The intracellular pathways and receptors mediating the effects of retinoic acid (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA activates transcription of ucp-1 and the RA receptor (RAR) is known 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 not the effects of all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific ¿p-[(E)-2-(5,6,7,8,-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid¿ or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7, 11-trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown-adipocyte differentiation RXRalpha and RXRgamma mRNA expression is induced in parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, alpha, beta and gamma, decreases. Co-transfection of murine expression vectors for the different RAR and RXR subtypes indicates that RARalpha and RARbeta as well as RXRalpha 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 complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1 induction and their distinct expression in the differentiated brown adipocyte.

Vitamin A and the regulation of fat reserves

“…In fact, synthetic specific RXR ligands have been shown to promote adipogenesis, especially in conjunction with PPAR ligands, in keeping with the bifunctionality of the PPAR:RXR heterodimer [80]. It appears that the net effect of retinoids on adipogenesis is the result of a complex balance between RA metabolism and relative RAR and RXR availability in the preadipose cell [16], which in itself is greatly influenced by RA [26,28,30,31]. The studies reviewed in this section suggest that RA influences adipocyte differentiation and survival in cell culture systems.…”

“…RAR:RXR heterodimers can transactivate transcription of sensitive genes upon binding of all-trans RA or 9-cis RA to the RAR moiety, while PPAR:RXR heterodimers require binding of 9-cis RA to the RXR moiety, in addition to a PPAR ligand (likely certain fatty acids or fatty acid derivatives), for maximal transactivating effect on transcription [9]. The involvement of both RAR-and RXRdependent pathways is indicated by the ability of overexpressed receptors to enhance the responsiveness of the UCP1 gene to retinoids in transfection experiments [28,43] and by the ability of selective receptor antagonists to suppress RA-induced UCP1 appearance in cell culture systems [31].…”

“…Interestingly, RAR and RXR mRNAs experience characteristic changes in their relative abundances throughout the process of acquisition of the mature adipocyte phenotype [28,29]. Furthermore, RA automodulates the steady-state levels of its receptors (both RAR and RXR isoforms), and this seems to be an important component of the response of adipose tissues to RA (see below) [26,28,30,31].…”

“…Retinoid receptors belonging to both the RAR and RXR subfamilies are expressed in WAT and BAT [16, 25 -27]. The two adipose tissues show a differential pattern of expression of RAR and RXR subtypes: RARb and RXRg messenger RNAs (mRNAs), for instance, are expressed at low levels in WAT depots and differentiated 3T3-L1 white adipocytes [26] and are more abundant in BAT and brown adipocytes differentiated in culture [27,28]. Interestingly, RAR and RXR mRNAs experience characteristic changes in their relative abundances throughout the process of acquisition of the mature adipocyte phenotype [28,29].…”

“…The two adipose tissues show a differential pattern of expression of RAR and RXR subtypes: RARb and RXRg messenger RNAs (mRNAs), for instance, are expressed at low levels in WAT depots and differentiated 3T3-L1 white adipocytes [26] and are more abundant in BAT and brown adipocytes differentiated in culture [27,28]. Interestingly, RAR and RXR mRNAs experience characteristic changes in their relative abundances throughout the process of acquisition of the mature adipocyte phenotype [28,29]. Furthermore, RA automodulates the steady-state levels of its receptors (both RAR and RXR isoforms), and this seems to be an important component of the response of adipose tissues to RA (see below) [26,28,30,31].…”