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. 2013 Sep 23:14:41.
doi: 10.1186/1471-2121-14-41.

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes

Maria Murholm  1 , Marie S Isidor, Astrid L Basse, Sally Winther, Cathrine Sørensen, Jonas Skovgaard-Petersen, Maja M Nielsen, Aina S Hansen, Bjørn Quistorff, Jacob B Hansen
Affiliations

Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes

Maria Murholm et al. BMC Cell Biol. .

Abstract

Background: Increased adipose thermogenesis is being considered as a strategy aimed at preventing or reversing obesity. Thus, regulation of the uncoupling protein 1 (UCP1) gene in human adipocytes is of significant interest. Retinoic acid (RA), the carboxylic acid form of vitamin A, displays agonist activity toward several nuclear hormone receptors, including RA receptors (RARs) and peroxisome proliferator-activated receptor δ (PPARδ). Moreover, RA is a potent positive regulator of UCP1 expression in mouse adipocytes.

Results: The effects of all-trans RA (ATRA) on UCP1 gene expression in models of mouse and human adipocyte differentiation were investigated. ATRA induced UCP1 expression in all mouse white and brown adipocytes, but inhibited or had no effect on UCP1 expression in human adipocyte cell lines and primary human white adipocytes. Experiments with various RAR agonists and a RAR antagonist in mouse cells demonstrated that the stimulatory effect of ATRA on UCP1 gene expression was indeed mediated by RARs. Consistently, a PPARδ agonist was without effect. Moreover, the ATRA-mediated induction of UCP1 expression in mouse adipocytes was independent of PPARγ coactivator-1α.

Conclusions: UCP1 expression is differently affected by ATRA in mouse and human adipocytes. ATRA induces UCP1 expression in mouse adipocytes through activation of RARs, whereas expression of UCP1 in human adipocytes is not increased by exposure to ATRA.

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Figures

Figure 1
Figure 1
Chronic treatment with ATRA induces UCP1 expression in differentiating mouse adipocytes. 3T3-L1 cells, WT MEFs, C3H10T½ cells and Rb−/− MEFs were treated with ATRA from day −2 to day 8 in the concentrations indicated. Total RNA and protein were harvested at day 8 and analyzed by RT-qPCR and immunoblotting, respectively. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to expression levels of TATA-binding protein (TBP). (A) 3T3-L1 cells. (B) WT MEFs. (C) C3H10T½. (D) Rb−/− MEFs. (E) Protein levels of UCP1 with GAPDH used as a loading control. (A-D) Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
Figure 2
Figure 2
Acute exposure of mature mouse adipocytes to ATRA induces UCP1 expression. ATRA (1 μM) was supplemented at day 8. Total RNA and protein were harvested after 24 h and analyzed by RT-qPCR and immunoblotting, respectively. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to levels of TBP. (A) 3T3-L1. (B) WT MEFs. (C) C3H10T½. (D) Rb−/− MEFs. (E) Protein levels of UCP1 with GAPDH used as a loading control. (A-D) Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells at day 9.
Figure 3
Figure 3
TTNPB mimics and BMS493 inhibits the effects of ATRA in WT MEFs. Total RNA was harvested at the indicated days (day 8 in panels A and C) and analyzed by RT-qPCR. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to TBP. (A) TTNPB was supplemented to differentiating cells from day −2 to day 8 at the concentrations indicated. (B) TTNPB (1 nM) was acutely supplemented to mature adipocytes (day 8) and harvested after 24 h. (C) Treatment with BMS493 (1 μM) and/or ATRA (1 μM) from day −2 to day 8. (D) Acute supplementation of BMS493 (1 μM) and/or ATRA (1 μM) to mature adipocytes from day 8 and harvested after 24 h. Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells. ▲, p < 0.05 versus ATRA-treated cells.
Figure 4
Figure 4
RAR subtype-selective ligands induce UCP1 expression in WT MEFs. Total RNA was harvested at day 8 (panel A) or at the indicated days (panel B) and analyzed by RT-qPCR. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to TBP. (A) RAR subtype-selective ligands AM580, tazarotene and CD1530 were supplemented from day −2 to day 8 at the concentrations indicated. (B) RAR subtype-selective ligands AM580 (1 μM), tazarotene (1 μM) and CD1530 (1 μM) were acutely supplemented to mature adipocytes from day 8 and harvested after 24 h. Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
Figure 5
Figure 5
Activation of PPARδ in WT MEFs does not increase UCP1 expression. Total RNA was harvested at day 8 (panel A) or at the indicated days (panel B) and analyzed by RT-qPCR. Relative mRNA expression levels of FABP4, UCP1 and ADRP were determined by normalization to TBP. (A) Treatment with the PPARδ agonist GW501516 (1 μM) from day −2 to day 8. (B) GW501516 (1 μM) was acutely supplemented to mature adipocytes from day 8 and harvested after 24 h. Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
Figure 6
Figure 6
ATRA enhances UCP1 expression independent of PGC-1α. Total RNA was harvested at day 8 (panel A) or at the indicated days (panel B) and analyzed by RT-qPCR. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to TBP. (A) ATRA was supplemented to differentiating PGC-1α+/+ and PGC-1α−/− brown preadipocytes from day −2 to day 8 at the concentrations indicated. (B) ATRA (1 μM) was acutely supplemented to mature PGC-1α+/+ and PGC-1α−/− adipocytes from day 8 and harvested after 24 h. Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
Figure 7
Figure 7
Chronic treatment with ATRA does not increase UCP1 expression in differentiating SGBS, hMADS and primary human adipocytes. Total RNA was harvested at the indicated days (day 12 in panel A and B) and analyzed by RT-qPCR. Relative mRNA expression levels of FABP4, UCP1 and RARβ were determined by normalization to TBP. ATRA was supplemented to differentiating SGBS cells (A), hMADS cells (B) and primary human white preadipocytes (HPrAD) (C) from day −2 to day 12 at the concentrations indicated. (D) Protein levels of UCP1 with GAPDH used as a loading control in SGBS and hMADS adipocytes. (A-C) Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
Figure 8
Figure 8
Acute exposure of mature human adipocytes to ATRA does not induce UCP1 expression. ATRA (1 μM) was supplemented to mature SGBS adipocytes (A), hMADS adipocytes (B) and primary human white preadipocytes (HPrAD) (C) from day 12 and harvested after 24 h. (D) Protein levels of UCP1 with GAPDH used as a loading control in SGBS and hMADS adipocytes. (A-C) Data represents mean + SEM (n = 3). *, p < 0.05 versus vehicle-treated cells.
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