Dataset Information

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 Lepr^dbmice. 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 RAR? 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.

SUBMITTER: Morrice N

PROVIDER: S-EPMC5335663 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice.

Morrice Nicola N Mcilroy George D GD Tammireddy Seshu R SR Reekie Jennifer J Shearer Kirsty D KD Doherty Mary K MK Delibegović Mirela M Whitfield Phillip D PD Mody Nimesh N

Scientific reports 20170303

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, Fgf ...[more]

PMID: 28256636

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Project description:UNLABELLED:In animals, high fibroblast growth factor 21 (FGF21) states improve insulin resistance but induce bone loss. Whether FGF21 relates to bone mineral density (BMD) is unknown in humans. Contrary to prediction from animal findings, we found higher FGF21 levels associating with greater BMD in women, independent of age and body composition. INTRODUCTION:Recent laboratory studies suggest that FGF21 is involved in reciprocal regulation of bone and energy homeostasis. Systemic administration of FGF21 protects animals from obesity and diabetes but causes severe bone loss, smothering the enthusiasm over FGF21 as a potential antiobesity therapeutic. To date, there is no information on whether FGF21 relates to BMD in humans. We thus studied the relationship between plasma FGF21 levels and BMD in healthy adults. METHODS:Fasting plasma FGF21 levels were measured by enzyme-linked immunosorbent assay and body composition by dual-energy X-ray absorptiometry. RESULTS:Among 40 healthy volunteers (age 32?±?10 year, 16 women), men had significantly higher lean body mass (p?<?0.01) and total BMD (p?<?0.05), and lower percent body fat than women (p?<?0.01). Median plasma FGF21 levels were not different between the sexes. While there was no association between FGF21 concentrations and body composition in men, FGF21 levels correlated positively with fat mass (p?<?0.01) in women. In men, no significant correlation between FGF21 with BMD was observed. However, in women, FGF21 correlated positively with total BMD (R (2)?=?0.69, p?=?0.003) and spine BMD (R (2)?=?0.76, p?=?0.001); the correlation remained significant after adjusting for age, ethnicity, and body composition. CONCLUSIONS:This study reveals for the first time a strong positive association between plasma FGF21 levels and BMD in healthy women, suggesting the association between bone loss and high FGF21 states in animals may not be directly translated to humans in physiologic states. We hypothesize that FGF21 may increase bone mass particularly in women through paracrine mechanisms in the bone-adipose interface.

Project description:In several species the retinal pigment epithelium (RPE) has the potential to transdifferentiate into retinal cells to regenerate functional retinal tissue after injury. However, this capacity for regeneration is lost in mammals. The synthetic retinoic acid derivative, fenretinide [N(4-hydroxyphenyl) retinamide], induces a neuronal-like phenotype in the human adult retinal pigment epithelial cell line (ARPE-19). These changes are characterized by the appearance of neural-like processes and the expression of neuronal markers not normally associated with RPE cells. Here we assess whether fenretinide can induce a neuroretinal cell phenotype in ARPE-19 cells, by examining retinal cell marker expression.ARPE-19 cells were treated daily with culture medium containing either 3 ?M fenretinide or dimethyl sulfoxide as a control for 7 days. Cells were processed for immunocytochemistry, western blotting, and for analysis by PCR to examine the expression of a panel of RPE, neural, and retinal-associated cellular markers, including classical and non-canonical opsins.Treatment with fenretinide for 7 days induced the formation of neuronal-like processes in ARPE-19 cells. Fenretinide induced the expression of the cone long wavelength sensitive opsin (OPN1lw) but not rhodopsin (RHO), while decreasing the expression of RPE cell markers. Many of the neuronal and retinal specific markers examined were expressed in both control and fenretinide treated cells, including those involved in photoreceptor cell development and the multipotency of neural retinal progenitor cells. Interestingly, ARPE-19 cells also expressed both photoreceptor specific and non-specific canonical opsins.The expression of retinal-associated markers and loss of RPE cell markers in control ARPE-19 cells suggests that these cells might have dedifferentiated from an RPE cell phenotype under standard culture conditions. The expression of molecules, such as the transcription factors paired box 6 gene (PAX6), sex determining region Y-box 2 (SOX2), cone-rod homeobox (CRX), and neural retina leucine zipper (NRL), further implies that in culture these cells are predisposed toward a retinal progenitor-like state. The fenretinide-induced increase in photoreceptor cell markers, accompanied by a decrease in RPE cell markers, suggests that retinoids may play a role in the transdifferentiation of RPE cells. Importantly, our data show for the first time the expression of a vertebrate ciliary opsin (OPN1lw) and rhabdomeric-like opsin, opsin 4 (OPN4 also known as melanopsin) in a clonal cell line. Together these data suggest that ARPE-19 cells are primed for and possess the capacity to differentiate toward a retinal cell-like lineage.

Dataset Information

Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice.

Publications

Elevated Fibroblast growth factor 21 (FGF21) in obese, insulin resistant states is normalised by the synthetic retinoid Fenretinide in mice.

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