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

Abstract

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.

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…This mainly occurs via the inhibition of adipogenesis through prevention of C/EBPβ transcription (Mcilroy et al, ). The treatment was not expected to alter the food intake (Shearer et al, ) and, indeed, food intake was unchanged in EKO and negligibly increased in WT mice.…”

“…The possible effects of fenretinide treatment on body weight, fat mass accumulation, glucose metabolism and plasma lipid levels, which has yet to be tested in the EKO model, were investigated in the present study. The reduction of body weight gain following fenretinide treatment has been thoroughly documented in wild‐type and in genetically obese mice (Koh et al, ; Mcilroy et al, ; Preitner et al, ; Shearer et al, ). Consistent with these findings, in the present study fenretinide treatment was found to reduce body weight gain and fat mass in both EKO and wild‐type mice.…”

Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice

“…We and others have recently identified FEN as a potential safe treatment for diet-induced obesity and type-2 diabetes in mice17181922. FEN can directly inhibit leptin gene transcription but does not have measureable effects on food intake or energy expenditure1718.…”

“…We have previously shown that FEN prevents obesity and improves insulin sensitivity in both high fat diet (HFD)-fed male and female mice171819. FEN acts via several different mechanisms including induction of retinoid signalling, increased hepatic lipid oxidation and inhibition of the final step of ceramide biosynthesis in multiple tissues to exert its metabolic effects202122.…”

The synergistic effect of fenretinide and metformin to achieve a decrease in insulin resistance and inflammatory mediators: an in vivo study

“…Fenretinide is a synthetic retinoid that is being tested in clinical trials for the treatment of breast cancer and insulin resistance, but its mechanism of action has been elusive. Data indicated that fenretinide inhibits dihydroceramide desaturase, an enzyme involved in the biosynthesis of lipotoxicceramides that antagonize insulin action (Shearer et al 2015). Because of this finding, we assessed whether fenretinide could improve insulin sensitivity and glucose homeostasis in vitro and in vivo by controlling ceramide.…”