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.
Highlights
Fibroblast growth factor (FGF) 21 is a predominantly liver derived hormone and is being investigated as an anti-obesity/anti-diabetes therapy[1]
To test whether directly improving hepatic insulin sensitivity and glucose homeostasis in the background of high fat diet (HFD)-induced obesity could lead to a reduction in Fibroblast growth factor 21 (FGF21) levels, we examined mice with a hepatocyte-specific knock-out of PTP1B
FGF21 is an important regulator of lipid and glucose metabolism and is undergoing trials in humans to evaluate its efficacy as a treatment for obesity and type-2 diabetes[3]
Summary
Fibroblast growth factor (FGF) 21 is a predominantly liver derived hormone and is being investigated as an anti-obesity/anti-diabetes therapy[1]. FGF21 binds cognate receptors FGFR and β-klotho, which are expressed at high levels in adipose tissue, to mediate its metabolic effects including control of lipid metabolism, body weight and glucose homeostasis[1,2]. Circulating FGF21 levels are elevated in states of metabolic stress in both rodents and humans and are positively correlated with body mass index and insulin resistance[6]. This has to led the hypothesis that a rise in serum FGF21 levels may be a predictor for metabolic syndrome and type-2 diabetes and that these may be states of relative “FGF21-resistance”[7]. We further tested the potential role of FEN in regulating hepatic Fgf[21] in mouse models of diet and genetically-induced obesity and in wild-type animals
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