Calcitriol down-modulates the 3,5,3' triiodothyronine (T3) receptors and affects, in a biphasic manner, the T3-dependent adipose differentiation of Ob 17 preadipocytes.
In previous reports, we showed that T3 is required for terminal differentiation of the murine Ob 17 preadipocytes, and that it partially down-modulates the abundance of its own nuclear receptor sites (T3R). We also reported that a profound depletion of the T3R was produced by all-trans-retinoic acid at concentrations that inhibit adipose differentiation. Here, we report that calcitriol (VD), which activates a nuclear receptor (VDR) closely related to the T3R and retinoid receptors, also markedly affects nuclear T3 binding and T3-induced differentiation of Ob 17 cells. Within a nearly physiological concentration range (0.1-2.5 nM), calcitriol profoundly down-modulated T3R abundance without altering the affinity for T3. The T3R depletion was a fast event, sustained under VD and reversed within 48 h of VD withdrawal. The order of efficient concentration ranges of VD and analogs suggests an involvement of the VDR. The T3R-depleting effect of VD was observed at every stage of adipose differentiation and was additive to the depleting effect of T3. Within the 0.1-2.5 nM VD concentration range, the c-erbA alpha and -alpha 1 messenger RNA levels (only c-erbA alpha gene products were detected in these cells) were poorly decreased; VD also did not alter a protein band specifically detected with specific anti-c-erbA alpha 1 antibodies in Western blots of nuclear extracts. VD accelerated the T3R disappearance rate; the results suggest that this would probably involve sequestration, rather than degradation, events. Interestingly, calcitriol added to the culture medium of Ob 17 preadipocytes markedly influenced the adipose differentiation, exerting a clear-cut stimulation at levels of 0.25 nM or less and profound inhibition at concentrations above 0.25 nM. Both effects were observed provided that VD was added within an early critical period of the differentiation process, as we previously reported for T3. The stimulations caused by low concentrations of VD and 1.5 nM T3 were additive. Increasing the VD concentration produced a progressive attenuation, then a suppression, of the stimulating effect of T3. Comparative analyses of VD-related changes in adipose differentiation and T3R abundance suggest that a correlation may exist between optimal differentiation and a partial depletion of the T3R, whereas a profound depletion of the T3R occurred at inhibitory concentrations of VD. The present results sustain the concept that T3R play a role in the differentiation of Ob 17 preadipocytes. Moreover, the results suggest that there may be a T3 receptor site concentration optimal for efficient differentiation. A regulation of this concentration involves ligands of other closely related receptors and, thus, probably the interplays that exist between these receptors.
Lenoir
C
C
Dace
A
A
Martin
C
C
Bonne
J
J
Teboul
M
M
Planells
R
R
Torresani
J
J
D017667:Adipocytes / Q000166:cytology*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D051379:Mice; D014176:Protein Biosynthesis; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D014284:Triiodothyronine / Q000494:pharmacology / Q000502:physiology*
D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D002117:Calcitriol