fenretinide and Diabetes-Mellitus--Type-2

Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinide's use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinide's effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid.

Topics: Animals; Antineoplastic Agents; Autophagy; Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 2; Electron Transport; Fenretinide; Humans; Lipid Metabolism; Obesity; Reactive Oxygen Species; Retinoic Acid 4-Hydroxylase; Retinol-Binding Proteins, Plasma; Signal Transduction; Vitamin A

Fibroblast growth factor 21 (FGF21) has emerged as an important beneficial regulator of glucose and lipid homeostasis but its levels are also abnormally increased in insulin-resistant states in rodents and humans. The synthetic retinoid Fenretinide inhibits obesity and improves glucose homeostasis in mice and has pleotropic effects on cellular pathways. To identify Fenretinide target genes, we performed unbiased RNA-seq analysis in liver from mice fed high-fat diet ± Fenretinide. Strikingly, Fgf21 was the most downregulated hepatic gene. Fenretinide normalised elevated levels of FGF21 in both high-fat diet-induced obese mice and in genetically obese-diabetic Lepr

Topics: Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Fenretinide; Fibroblast Growth Factors; Gene Expression Regulation; Insulin Resistance; Liver; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Promoter Regions, Genetic