Fenretinide prevents obesity in aged female mice in association with increased retinoid and estrogen-signaling

Objective
The synthetic retinoid Fenretinide (FEN) inhibits adiposity in male mice fed a high-fat-diet (HFD) in association with alterations in retinoic acid (RA)-signaling. Young female mice are protected from obesity via estrogen-signaling. We therefore investigated whether FEN also influences adiposity in aged female mice differing in parity, and whether such effects are mediated by retinoid and estrogen-signaling.
Design and Methods
Aged nulliparous and parous female mice were maintained on HFD±FEN and adiposity was assessed. Quantitative-PCR was performed on white adipose tissue (WAT), liver and 3T3-L1 adipocytes treated with RA or FEN±estrogen.
Results
Parous females were more obese than nulliparous mice independent of age. FEN-HFD prevented the HFD-induced increase in adiposity and leptin levels independently of parity. FEN-HFD induced retinoid-responsive genes in WAT and liver. Parous females had reduced expression of hepatic estrogen-responsive genes but FEN-HFD up-regulated WAT Cyp19a1 and Esr2 in parous mice. Estrogen and RA acted synergistically to increase RA-receptor (RAR)-mediated gene expression in 3T3-L1 adipocytes. FEN increased Cyp19a1 and Esr2, similar to our findings in vivo.
Conclusions
The prevention of adiposity by FEN in response to HFD in female mice appears to involve increased retinoid-signaling in association with induction of local estrogen production and estrogen-signaling in WAT.