Fenretinide mediated retinoic acid receptor signalling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function and nutrient stress signalling in adipocytes and adipose tissue

Abstract

Graphical abstractProposed mechanistic action of FEN in adipocytes. RA inhibits adipogenesis through early RAR activation, which PPARγ agonist ROSI cannot prevent. FEN inhibits adipogenesis with a delayed response in RAR signalling, however, inhibition is lost when combined with ROSI. The 4-OXO FEN catabolite cannot inhibit adipogenesis through RAR activation, but like FEN’s RAR-independent effects, displays increased phosphorylation of Akt, mild cellular stress/autophagy induction and decreased lipid accumulation. Moreover, FEN-mediated inhibition of DES-1 increases dihydroceramide levels in a RAR-independent manner, and is linked to a complete prevention of mitochondrial dysfunction and decreased adiposity in high-fat fed obese mice. Thus an alternative to the additive beneficial effects of FEN-mediated RAR-dependant and -independent signalling, 4-OXO FEN may be a novel therapeutic candidate to improve adipocyte hypertrophy via inhibition of ceramide biosynthesis and modulation of nutrient stress pathways.

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

“…We and others have already shown that FEN can inhibit the final step in ceramide synthesis through blockade of the enzyme dihydroceramide desaturase 1 in adipose tissue2022. Here, we have now shown that ceramide synthesis is also blocked by FEN in liver in a genetic model of severe obesity and insulin resistance.…”

“…Previous work has shown that FEN treatment results in alterations in ceramide and dihydroceramide levels in HFD obese mice, in association with improvements in glucose homeostasis and insulin sensitivity2022. To determine whether FEN could have the same effect in genetically-obese mice, lipid analysis was performed in liver tissue from Lepr db mice.…”

“…Male C57BL/6 mice fed HFD ± 0.04% FEN were previously reported (Supplementary Table S1)1822. HFD used in respective mouse cohorts through-out this study contained 45% lard-based fat.…”

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

“…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. 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.…”

Cystic fibrosis: the conductance regulator, ceramides, and possible treatments

“…In an earlier study, Mcilroy et al showed that fenretinide-mediated retinoic acid receptor signaling and inhibition of ceramide biosynthesis regulates adipogenesis, lipid accumulation, mitochondrial function, and nutrient stress signaling in adipocytes and adipose tissue. Their findings suggested that fenretinide utilizes retinoid-acid-receptor (RAR)-dependent and independent pathways to regulate cell biology that could be relevant to the current results [8].…”