title: Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice.
abstract: 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 Leprdbmice. Moreover, Fenretinide-mediated suppression of FGF21 was independent of body weight loss or improved hepatic insulin sensitivity and importantly does not induce unhealthy metabolic complications. In mice which have substantially decreased endogenous retinoic acid biosynthesis, Fgf21 expression was increased, whereas acute pharmacological retinoid treatment decreased FGF21 levels. The repression of FGF21 levels by Fenretinide occurs by reduced binding of RARα and Pol-II at the Fgf21 promoter. We therefore establish Fgf21 as a novel gene target of Fenretinide signalling via a retinoid-dependent mechanism. These results may be of nutritional and therapeutic importance for the treatment of obesity and type-2 diabetes.
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.|Centre for Genome Enabled Biology and Medicine, University of Aberdeen, 23 St Machar Drive, Old Aberdeen, Aberdeen, Scotland AB24 3UU, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Morrice
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.
authors.forename: George D
authors.initials: GD
authors.lastname: Mcilroy
authors.affiliation: Lipidomics Research Facility, Department of Diabetes and Cardiovascular Science, University of Highlands and Islands, Old Perth Road, Inverness, Scotland IV2 3JH, UK.
authors.forename: Seshu R
authors.initials: SR
authors.lastname: Tammireddy
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reekie
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.
authors.forename: Kirsty D
authors.initials: KD
authors.lastname: Shearer
authors.affiliation: Lipidomics Research Facility, Department of Diabetes and Cardiovascular Science, University of Highlands and Islands, Old Perth Road, Inverness, Scotland IV2 3JH, UK.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Doherty
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.
authors.forename: Mirela
authors.initials: M
authors.lastname: Delibegović
authors.affiliation: Lipidomics Research Facility, Department of Diabetes and Cardiovascular Science, University of Highlands and Islands, Old Perth Road, Inverness, Scotland IV2 3JH, UK.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Whitfield
authors.affiliation: Institute of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Health Campus, Aberdeen, Scotland AB25 2ZD, UK.
authors.forename: Nimesh
authors.initials: N
authors.lastname: Mody
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D017313:Fenretinide / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: C414620:fibroblast growth factor 21; D017313:Fenretinide; D005346:Fibroblast Growth Factors