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. Methods: Aged nulliparous and parous female mice were maintained on HFD 6 FEN, and adiposity was assessed. Quantitative polymerase chain reaction was performed on white adipose tissue (WAT), liver, and 3T3-L1 adipocytes treated with RA or FEN 6 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 estrogenresponsive genes, but FEN-HFD up-regulated WAT Cyp19a1 and Esr2 in parous mice. Estrogen and RA acted synergistically to increase RA receptor-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 seems to involve increased retinoid signaling in association with induction of local estrogen production and estrogen signaling in WAT.

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