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.

Proposed 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.