Nat Med:激活小肠FXR,向肥胖说不!
生物谷 · 2015/02/23
美国科学家的一项最新研究成果显示,他们发现特异性激活肠道FXR会促进肠道FGF15表达改变胆汁酸组成成分,同时能够通过增加产热以及白色脂肪棕色化,改善肥胖小鼠的体重及代谢恶化表型。

近日,著名国际期刊Nature Medicine发表了美国科学家的一项最新研究成果,他们发现特异性激活肠道FXR会促进肠道FGF15表达改变胆汁酸组成成分,同时能够通过增加产热以及白色脂肪棕色化,改善肥胖小鼠的体重及代谢恶化表型。

研究人员指出,目前利用胆汁酸感应因子FXR的全身性表达靶向胆固醇代谢,甘油三酯合成,肝脏脂肪变性和胆汁淤积治疗相关疾病正成为新兴疗法。相比于全身性治疗方法,在进食情况下选择性释放胆汁酸能够激活肠道FXR。通过模拟这种组织特异性效应,利用特异性FXR激动剂fexaramine能够诱导肠道FGF15表达,从而导致BA成分变化,但是不会激活肝脏中FXR目标基因的表达。但是与全身性表达不同,研究人员发现Fex能够降低饮食诱导的体重增加,改善全身性炎症和肝脏葡萄糖产生,同时伴有产热增加以及白色脂肪棕色化的现象。

综上所述,该文章发现肠道特异性激活FXR能够改善小鼠肥胖及代谢恶化表型,促进机体产热以及白色脂肪棕色化,这些代谢改善表明组织特异性抑制FXR激活可作为治疗肥胖和代谢综合征的新疗法。

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  • Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

    The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

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