fenretinide and Obesity

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

Topics: Adult; Age Factors; Aged; Anticarcinogenic Agents; Breast Diseases; Breast Neoplasms; Contraceptives, Oral, Hormonal; Dietary Fats; Estrogen Antagonists; Estrogen Replacement Therapy; Female; Fenretinide; Humans; Life Style; Mass Screening; Maternal Age; Middle Aged; Obesity; Parity; Pedigree; Risk Factors; Tamoxifen

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

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.. Aged nulliparous and parous female mice were maintained on HFD ± 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 ± estrogen.. 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 estrogen-responsive 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.. 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.

Topics: Adiposity; Animals; Diet, High-Fat; Estrogens; Female; Fenretinide; Leptin; Mice; Mice, Inbred C57BL; Obesity; Retinoids; Signal Transduction

The synthetic retinoid, Fenretinide (FEN), inhibits obesity and insulin resistance in mice and is in early clinical trials for treatment of insulin resistance in obese humans. We aimed to determine whether alterations in retinoic acid (RA)-responsive genes contribute to the beneficial effects of FEN. We examined the effect of FEN on 3T3-L1 adipocyte differentiation and alterations in gene expression in C57Bl/6 and retinaldehyde dehydrogenase (RALDH) 1 knockout (KO) mice fed a high-fat (HF) diet. FEN completely inhibited adipocyte differentiation by blocking CCAAT/enhancer-binding protein (C/EBP) α/peroxisome proliferator-activated receptor (PPAR) γ-mediated induction of downstream genes and upregulating RA-responsive genes like cellular retinol-binding protein-1. In mice fed an HF diet, RA-responsive genes were markedly increased in adipose, liver, and hypothalamus, with short-term and long-term FEN treatment. In adipose, FEN inhibited the downregulation of PPARγ and improved insulin sensitivity and the levels of adiponectin, resistin, and serum RBP (RBP4). FEN inhibited hyperleptinemia in vivo and leptin expression in adipocytes. Surprisingly, hypothalamic neuropeptide Y expression was completely suppressed, suggesting a central effect of FEN to normalize hyperglycemia. Moreover, FEN induced RA-responsive genes in RALDH1 KO mice, demonstrating that FEN can augment RA signaling when RA synthesis is impaired. We show that FEN-mediated beneficial effects are through alterations in retinoid homeostasis genes, and these are strong candidates as therapeutic targets for the treatment of obesity and insulin resistance.

Topics: 3T3-L1 Cells; Adipogenesis; Adipose Tissue; Aldehyde Dehydrogenase 1 Family; Animals; Anti-Obesity Agents; Diet, High-Fat; Fenretinide; Gene Expression Regulation; Hypothalamus; Isoenzymes; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; PPAR gamma; Random Allocation; Response Elements; Retinal Dehydrogenase; Retinoids; Retinol-Binding Proteins, Plasma; RNA, Messenger

Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n=13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n=13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.

Topics: Adiponectin; Adipose Tissue, White; Alanine Transaminase; Animals; Aspartate Aminotransferases; Diet, High-Fat; Fatty Liver; Fenretinide; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Prealbumin; Retinol-Binding Proteins, Plasma; Weight Gain

The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.

Topics: Animals; Body Composition; Body Weight; Calorimetry, Indirect; Cohort Studies; Drug Administration Schedule; Eating; Fatty Liver; Fenretinide; Glucose Clamp Technique; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Retinoids; Retinol-Binding Proteins