Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis
Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis
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DOI：
10.1152/ajpendo.00362.2009
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发表时间：
2009-12-01
影响因子：
5.1
通讯作者：
Kahn, Barbara B.
中科院分区：
文献类型：
--
作者：
Preitner, Frederic;Mody, Nimesh;Kahn, Barbara B.
Preitner F，Mody N，Graham TE，Peroni OD，Kahn BB.芬维A胺长期治疗可预防高脂饮食诱导的肥胖、胰岛素抵抗和肝脂肪变性。Am J Physiol Endocrinol Metab 297：E1420-E1429，2009.首次发表于2009年10月13日; doi：10.1152/ajpendo.00362.2009.-合成类维生素A芬维A胺（FEN）增加肥胖啮齿动物的胰岛素敏感性，并在早期临床试验中用于治疗患有肝脂肪变性的肥胖人群的胰岛素抵抗（46）。我们的目的是确定FEN的胰岛素增敏作用的生理机制。从4-5周龄至36-37周龄（预防性研究）或在HF饮食诱导的肥胖22周后（12周干预性研究），给野生型小鼠喂食含或不含FEN的高脂饮食（HFD）。在预防性研究中，还向视黄醇结合蛋白-4（RBP 4）敲除小鼠喂食含或不含FEN的HFD。在两项研究中，FEN对HFD诱导的体重增加影响极小，但显著降低HFD诱导的肥胖和高瘦素血症。与没有FEN的HFD小鼠相比，FEN-HFD小鼠获得了附睾脂肪，但没有皮下或内脏脂肪量。FEN对能量消耗、食物摄入、体力活动或粪便脂质含量没有可测量的影响。与对照组相比，HFD小鼠在高胰岛素-正常葡萄糖钳夹期间的葡萄糖输注速率降低了86%，与HFD小鼠相比，FEN-HFD小鼠的葡萄糖输注速率提高了3.6倍。FEN改善胰岛素对葡萄糖摄取和肌肉中糖原水平的作用，胰岛素刺激的肝葡萄糖产生抑制，以及HFD小鼠血清FFA水平的抑制。值得注意的是，FEN也减少了肝脂肪变性。在RBP 4基因敲除小鼠中，FEN减少了HFD诱导的肥胖和高瘦素血症的增加。总之，FEN长期治疗可部分预防或逆转HFD小鼠的肥胖、胰岛素抵抗和肝脂肪变性。抗肥胖作用不依赖于RBP 4降低作用。
Preitner F, Mody N, Graham TE, Peroni OD, Kahn BB. Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am J Physiol Endocrinol Metab 297: E1420-E1429, 2009. First published October 13, 2009; doi:10.1152/ajpendo.00362.2009.-The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6- fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.