Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21
Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21
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DOI：
10.1210/en.2014-2003
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发表时间：
2015-06-01
期刊：
影响因子：
4.8
通讯作者：
Huff, Murray W.
中科院分区：
文献类型：
--
作者：
Assini, Julia M.;Mulvihill, Erin E.;Huff, Murray W.
在C57 BL 6/J野生型小鼠和成纤维细胞生长因子21（FGF 21）缺失（Fgf 21（-/-））小鼠中研究了柑橘类黄酮、柚皮素降低血脂异常和改善葡萄糖耐量的分子机制和代谢途径。FGF 21调节能量稳态和对禁食的代谢适应。这种调节的一种途径是通过诱导过氧化物酶体增殖物激活受体-γ共激活因子-1 α（Pgc 1a），一种肝脂肪酸氧化和生酮的调节剂。由于柚皮素是肝脏FA氧化的有效激活剂，我们假设诱导FGF 21可能是柚皮素作用机制的组成部分。此外，我们预测FGF 21缺乏会增强高脂饮食（HFD）诱导的代谢失调，并损害柚皮素的代谢保护作用。FGF 21的缺乏加剧了对HFD的反应。有趣的是，在两种基因型中，向HFD中补充柚皮素都有力地预防了肥胖。基因表达分析表明，柚皮素不是主要针对脂肪酸代谢的白色脂肪组织。在野生型和Fgf 21（-/-）小鼠中，柚皮素校正了肝脏甘油三酯浓度，并使Pgc 1a、Cpt 1a和Srebf 1c的肝脏表达正常化。与野生型小鼠相比，HFD喂养的Fgf 21（-/-）小鼠显示出更大的肌肉甘油三酯沉积、高胰岛素血症和葡萄糖耐量受损，证实了FGF 21在胰岛素敏感性中的作用;然而，在两种基因型中，柚皮素补充改善了这些代谢参数。我们的结论是，FGF 21缺乏加剧HFD诱导的肥胖，肝脂肪变性和胰岛素抵抗。此外，FGF 21不是柚皮素保护小鼠免受HFD诱导的代谢失调所必需的。总之，这些研究支持这样的概念，即柚皮素具有有效的降脂作用，并可能在体内充当胰岛素增敏剂。
The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wildtype mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.