Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus.
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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作者：
Mcilroy GD;Delibegovic M;Owen C;Stoney PN;Shearer KD;McCaffery PJ;Mody N
合成类维生素A，芬维A胺（FEN），抑制小鼠肥胖和胰岛素抵抗，并在早期临床试验中治疗肥胖人类的胰岛素抵抗。我们的目的是确定是否在维甲酸（RA）响应基因的改变有助于FEN的有益效果。我们研究了FEN对3 T3-L1脂肪细胞分化的影响以及C57 Bl/6和视黄醇脱氢酶（RALDH）1敲除（KO）小鼠高脂（HF）饮食中基因表达的改变。FEN通过阻断CCAAT/增强子结合蛋白（C/EBP）α/过氧化物酶体增殖物激活受体（PPAR）γ介导的下游基因诱导和上调RA应答基因（如细胞视黄醇结合蛋白-1），完全抑制脂肪细胞分化。在喂食HF饮食的小鼠中，在短期和长期FEN治疗下，脂肪、肝脏和下丘脑中的RA反应基因显著增加。在脂肪组织中，FEN抑制了PPARγ的下调，改善了胰岛素敏感性和脂联素、脂联素和血清RBP（RBP 4）水平。FEN抑制体内高瘦素血症和脂肪细胞中瘦素的表达。令人惊讶的是，下丘脑神经肽Y的表达被完全抑制，这表明FEN的中枢作用，使高血糖症正常化。此外，FEN诱导RALDH 1 KO小鼠中的RA应答基因，表明当RA合成受损时，FEN可以增强RA信号传导。我们表明，FEN介导的有益作用是通过类维生素A稳态基因的改变，这些是治疗肥胖和胰岛素抵抗的治疗靶点的强有力的候选者。
The synthetic retinoid, Fenretinide (FEN), inhibits obesity and insulin resistance in mice and is in early clinical trials for treatment of insulin resistance in obese humans. We aimed to determine whether alterations in retinoic acid (RA)-responsive genes contribute to the beneficial effects of FEN. We examined the effect of FEN on 3T3-L1 adipocyte differentiation and alterations in gene expression in C57Bl/6 and retinaldehyde dehydrogenase (RALDH) 1 knockout (KO) mice fed a high-fat (HF) diet. FEN completely inhibited adipocyte differentiation by blocking CCAAT/enhancer-binding protein (C/EBP) α/peroxisome proliferator–activated receptor (PPAR) γ−mediated induction of downstream genes and upregulating RA-responsive genes like cellular retinol-binding protein-1. In mice fed an HF diet, RA-responsive genes were markedly increased in adipose, liver, and hypothalamus, with short-term and long-term FEN treatment. In adipose, FEN inhibited the downregulation of PPARγ and improved insulin sensitivity and the levels of adiponectin, resistin, and serum RBP (RBP4). FEN inhibited hyperleptinemia in vivo and leptin expression in adipocytes. Surprisingly, hypothalamic neuropeptide Y expression was completely suppressed, suggesting a central effect of FEN to normalize hyperglycemia. Moreover, FEN induced RA-responsive genes in RALDH1 KO mice, demonstrating that FEN can augment RA signaling when RA synthesis is impaired. We show that FEN-mediated beneficial effects are through alterations in retinoid homeostasis genes, and these are strong candidates as therapeutic targets for the treatment of obesity and insulin resistance.
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DOI：
10.1152/ajpendo.00362.2009
发表时间：
2009-12-01
影响因子：
5.1
作者：
Preitner, Frederic;Mody, Nimesh;Kahn, Barbara B.
通讯作者：
Kahn, Barbara B.
影响因子：
3.7
作者：
Owen C;Czopek A;Agouni A;Grant L;Judson R;Lees EK;Mcilroy GD;Göransson O;Welch A;Bence KK;Kahn BB;Neel BG;Mody N;Delibegović M
通讯作者：
Delibegović M
DOI：
10.1002/jss.400140214
发表时间：
1980-01-01
期刊：
JOURNAL OF SUPRAMOLECULAR STRUCTURE
影响因子：
--
作者：
MURRAY, T;RUSSELL, TR
通讯作者：
RUSSELL, TR
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
影响因子：
4.8
作者：
ALVAREZ, R;DEANDRES, J;VILLARROYA, F
通讯作者：
VILLARROYA, F