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Fenretinide Treatment Prevents Diet-Induced Obesity in Association with Major Alterations in Retinoid Homeostatic Gene Expression in Adipose, Liver and Hypothalamus

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Fenretinide Treatment Prevents Diet-Induced Obesity in Association with Major Alterations in Retinoid Homeostatic Gene Expression in Adipose, Liver and Hypothalamus ORIGINAL ARTICLE Fenretinide Treatment Prevents Diet-Induced Obesity in Association With Major Alterations in Retinoid Homeostatic Gene Expression in Adipose, Liver and Hypothalamus George D. Mcilroy, Mirela Delibegovic, Carl Owen, Patrick N. Stoney, Kirsty D. Shearer, Peter J. McCaffery, and Nimesh Mody The synthetic retinoid, Fenretinide (FEN), inhibits obesity and The synthetic retinoid, Fenretinide [N-(4-hydroxyphenyl) insulin resistance in mice and is in early clinical trials for treat- retinamide] (FEN) prevents obesity and insulin resistance ment of insulin resistance in obese humans. We aimed to deter- in mice fed a high-fat (HF) diet (2,3). In addition, FEN mine whether alterations in retinoic acid (RA)-responsive genes lowers serum retinol–binding protein (gene name RBP4) contribute to the beneficial effects of FEN. We examined levels in rodents and humans by disrupting the ternary the effect of FEN on 3T3-L1 adipocyte differentiation and alter- complex of retinol-RBP4-transthyretin and thereby by ations in gene expression in C57Bl/6 and retinaldehyde dehydro- promoting renal clearance of RBP4 (4,5). However, the genase (RALDH)1 knockout (KO) mice fed a high-fat (HF) diet. FEN completely inhibited adipocyte differentiation by antiobesity action of FEN appears to be independent of blocking CCAAT/enhancer-binding protein (C/EBP) a/peroxisome its ability to lower circulating levels of this protein because proliferator–activated receptor (PPAR) g2mediated induction of FEN reduces obesity development in mice lacking RBP4 downstream genes and upregulating RA-responsive genes like and does not appear to alter food intake or energy ex- cellular retinol-binding protein-1. In mice fed a HF diet, RA- penditure (3). Currently, FEN is undergoing a phase II trial responsive genes were markedly increased in adipose, liver, for treatment of insulin resistance in obese humans with and hypothalamus, with short-term and long-term FEN treatment. hepatic steatosis (6). Thus, the mechanisms by which FEN In adipose, FEN inhibited the downregulation of PPARg and im- can prevent obesity and insulin resistance are of great proved insulin sensitivity and the levels of adiponectin, resistin, and serum RBP (RBP4). FEN inhibited hyperleptinemia in vivo interest. FEN was originally developed as a chemothera- and leptin expression in adipocytes. Surprisingly, hypothalamic peutic agent (7), and then was found to attenuate cancer neuropeptide Y expression was completely suppressed, suggest- cell growth by mechanisms such as apoptosis and reactive ing a central effect of FEN to normalize hyperglycemia. More- oxygen species generation. However, these effects appear over, FEN induced RA-responsive genes in RALDH1 KO mice, to vary in different cells (8). FEN is now the most widely demonstrating that FEN can augment RA signaling when RA syn- studied retinoid in clinical trials of breast cancer chemo- fi thesis is impaired. We show that FEN-mediated bene cial effects prevention because of its selective accumulation in are through alterations in retinoid homeostasis genes, and these fi are strong candidates as therapeutic targets for the treatment of breast tissue and its favorable toxicological pro le (9,10). obesity and insulin resistance. One mild and reversible side effect is a reduction in cir- culating retinol levels and deficits in dark adaptation attributable to lowering of circulating RBP4 levels (4,5,11). ore than one-third of United States adults are Retinoid homeostasis is tightly regulated by a complex obese and at risk for development of type 2 system of enzymes and carriers that can promote the diabetes and a host of other metabolic dis- storage of retinol in the form of retinyl esters (RBP4, cel- Morders, including dyslipidemia and cardio- lular RBP1, CRBP1, and lecithin:retinol acyltransferase); vascular disease. Despite the development and clinical use metabolism to retinoic acid (RA) and signaling through its of many antidiabetes drugs, they are limited by adverse receptors (retinaldehyde dehydrogenase [RALDH1], cel- effects such as fluid retention, weight gain, congestive lular RA-binding protein, CRABP, and RA receptors heart failure, liver toxicity, and the potential for carcino- [RARs]); and degradation via cytochrome P450-type genesis (1). Therefore, alternative therapies for the treat- enzymes (CYP26A1) (12). It has long been known that RA ment of obesity and type 2 diabetes are needed. potently blocks adipogenesis when introduced at early stages of differentiation (13–15). More recently, the im- portance of retinoid homeostasis in whole-body energy balance and glucose homeostasis has been highlighted in From the University of Aberdeen, College of Life Sciences & Medicine, In- genetic knockout (KO) studies of RALDH1 (lean pheno- stitute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, Scotland, – United Kingdom. type), CRBP1, and CRABP1 (obese phenotype) (16 18). Corresponding author: Nimesh Mody, [email protected]. Because initial mouse studies indicated that FEN could be Received 13 April 2012 and accepted 6 September 2012. a promising therapeutic agent to treat or prevent obesity, DOI: 10.2337/db12-0458 This article contains Supplementary Data online at http://diabetes and because insulin resistance, glucose intolerance, and .diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0458/-/DC1. human cancer trials have demonstrated few side effects, Ó 2013 by the American Diabetes Association. Readers may use this article as we sought to further investigate the mechanisms by which long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by FEN inhibits adiposity and alters glucose and lipid ho- -nc-nd/3.0/ for details. meostasis. We aimed to determine whether FEN inhibits diabetes.diabetesjournals.org DIABETES 1 Diabetes Publish Ahead of Print, published online November 27, 2012 FENRETINIDE PREVENTS OBESITY adipocyte differentiation and alters adipose and hepatic RESULTS gene expression, and whether alterations in retinoid ho- Fenretinide inhibits 3T3-L1 differentiation. Because meostasis could contribute to the mechanism of FEN- RA has been shown to inhibit adipocyte differentiation, we induced leanness in the setting of diet-induced obesity. examined the effect of FEN on adipocyte differentiation in 3T3-L1 cells. The 1 mmol/L FEN potently inhibited 3T3-L1 differentiation (Fig. 1A). Similar inhibition was obtained RESEARCH DESIGN AND METHODS with RA, whereas the peroxisome proliferator–activated Cell culture. The 3T3-L1 preadipocytes (ZenBio) were cultured in Dulbecco modified Eagle medium with 10% bovine calf serum (16170; Gibco) and 1% receptor (PPAR) g activator ROSI, a potent inducer of the pyruvate (growth media). Differentiation was induced 2 days postconfluency adipogenic program, was used to stimulate the rate of with Dulbecco modified Eagle medium containing 10% fetal bovine serum differentiation. Up to five-fold higher FEN did not affect (A15–104; PAA), 1% pyruvate, 1% penicillin/streptomycin, 1 mmol/L dexa- cell viability (Supplementary Fig. 1). Terminal markers of methasone, 0.5 mmol/L 3-Isobutyl-1-methylxanthine, and 10 mg/mL insulin adipogenesis aP2, CD36, adiponectin, and lipoprotein li- (MDI media). MDI media was removed after 48 h and was replaced every 2 pase were almost completely inhibited by FEN or RA days with MDI media without 3-Isobutyl-1-methylxanthine and dexametha- sone. FEN, RA, and rosiglitazone (ROSI) were dissolved in DMSO and added (Fig. 1B). GLUT4 mRNA was highly expressed in differen- as indicated (see Figure legends). FEN was a generous gift from U. Thurneer tiated cells but was not detected in undifferentiated control (Cilag AG, Switzerland). Cells were tested for viability using Resazurin assays ([2VE CONT]), RA, or FEN cells (data not shown). Similar (R&D Systems). results were obtained with the upstream intermedi- Animals. Male C57BL/6 wild-type mice were from Charles River (Edinburgh, ate markers PPARg and C/EBPa (Fig. 1C). Expression of UK). Mice were group-housed (four per box) for gene expression studies or individually housed for food intake and calorimetry, were exposed to 12-h/12-h C/EBPb mRNA, which normally increases transiently light–dark, and had ad libitum access to food and water. Three-month-old mice during early phases of adipogenesis, was not affected by were randomized by body weight and were administered a 45% HF diet FEN or RA (Fig. 1C). (D12450B; Research Diets, New Brunswick, NJ), HF-containing 0.04% wt/wt Because FEN is a synthetic retinoid, we tested its effects FEN (Research Diets), or chow diet (801722 CRM(P); Special Diets Service) on retinoid-signaling genes (Fig. 1D and 1E). RARa was for the duration of the studies. FEN HF mice received FEN ;30 mg/kg per transiently upregulated with differentiation, and this was day. Six-week-old mice were used for the short-term diet study. RALDH1 KO mice were generously provided by G. Duester (19); RBP4 KO mice were prevented by RA only. RARg levels were downregulated provided by L. Quadro (20). Mice were killed at the end of each experiment by during differentiation, and this was prevented by RA or cardiac exsanguination under CO2-induced anesthesia or cervical dislocation. FEN and expression levels induced above those of 2VE Hypothalamus was precisely dissected from fresh brains on an ice-cold plat- CONT cells. RARb was not expressed in these cells. RA form following anatomical landmarks. All tissues were rapidly dissected, fro- signaling
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