Within cells, retinol is converted to retinoic acid (RA), the direct ligand for the nuclear RA-receptors (RARs) that bind to promoters of target genes to modulate transcription. Alterations in retinoid levels and RA-responsive genes have been observed in several models of obesity and type-2 diabetes. The synthetic retinoid Fenretinide (FEN), which can signal through RAR, inhibits adiposity and improves glucose homeostasis in mice fed a high-fat diet (HFD)1. However, the mechanisms behind these effects remain poorly understood. To identify target genes of FEN responsible for its beneficial effects, we performed global RNA-sequencing analysis in livers from male C57BL/6 mice fed 45% HFD (D12450B, Research Diets) +/- 0.04% FEN for both 7 days and 20 weeks (n=4, per group). Differential gene expression statistical analysis performed by DESeq22. Animal procedures were approved by University of Aberdeen Ethics Review Board and performed under project and personal licences approved by the UK Home Office. Chronic HFD feeding led to major alterations in gene expression with induction of genes regulating hepatic lipid metabolism e.g. very low density lipoprotein receptor, Vldlr (up 1.8-fold log2 scale, adjusted p<0.001) and repression of several members of the major urinary protein gene family such as Mup2, repressed (down 2.4-fold log2 scale, adjusted p<0.001). Chronic FEN treatment normalized the expression of many of these genes, including completely repressing levels of the metabolic regulator FGF213. Cyp2c70, an enzyme involved in bile acid metabolism, was identified as a novel induced hepatic FEN target, later confirmed by qPCR of livers from several FEN treated models. Data analysed by Pfaffl method, mean+/-SEM calculated and statistical analysis by one-way ANOVA. Particularly, genetically obese male C57BL/6 Lepdb/db mice had 80% repressed Cyp2c70 expression compared to lean counterparts (n=7-8, p<0.001) which was rescued by FEN treatment to 47% (n=7, p<0.001). Other bile acid metabolism genes Cyp39a1 and Cyp46a1 were also amongst genes significantly altered, suggesting that FEN has a major effect on this pathway. Obesity and metabolic dysregulation led to major alterations in many more genes with diverse physiology e.g. arginine vasopressin receptor 1A (Avpr1a) was repressed in multiple disease models e.g. ~90% (n=6-7, p<0.001) decreased in genetically obese BTBR female Lepob/ob mice, with and without FEN compared to lean controls (n=7). Our findings confirm the liver as a target tissue of FEN treatment in multiple disease models of obesity. Furthermore whole transcriptome analyses in gene expression associated with HFD feeding +/- FEN may have identified novel pathways of disease, giving scope for possible targets for the intervention of impaired lipid and glucose homeostasis.