背景:高蛋白饮食通常富含已知可增强蛋白质合成并提供许多生理益处的支链氨基酸(BCAAs),但是最近的研究揭示了它们与肥胖和糖尿病的关系。为了支持这一点,蛋白质或BCAA补充被证明破坏葡萄糖代谢,而限制改善它。然而,目前尚不清楚这些是否是主要的,BCAAs的直接作用或在饮食BCAAs的慢性操作期间继发于其他生理变化。
方法:三个月大的C57Bl/6小鼠用赋形剂/BCAA或BT2(一种降低BCAA的化合物)进行急性治疗,和详细的体内代谢表型,包括频繁取样和胰管钳,进行了。
结果:在小鼠中使用导管引导的频繁采样方法,本研究表明,单次输注BCAAs足以使血糖和血浆胰岛素急剧升高.虽然用BCAAs预处理不影响葡萄糖耐量,高胰岛素-正常血糖钳夹期间持续输注BCAA会损害全身胰岛素敏感性。同样,单次注射BT2足以防止禁食期间BCAA升高,并显着改善高脂喂养小鼠的葡萄糖耐量,提示肥胖患者血糖控制异常可能与高循环BCAAs有因果关系。我们进一步表明,下丘脑中AgRP神经元的化学遗传学过度激活,如目前的肥胖症,显著损害通过急性BCAA降低完全正常化的葡萄糖耐量。有趣的是,这些影响大多只在男性身上表现出来,但不是在雌性老鼠身上。
结论:这些发现表明,BCAA本身可以严重损害葡萄糖稳态和胰岛素敏感性,从而解释了它们如何在肥胖和糖尿病中长期破坏葡萄糖代谢。我们的发现还表明,AgRP神经元对血糖的调节是通过BCAAs介导的,进一步阐明了大脑控制葡萄糖稳态的新机制。
BACKGROUND: High-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs.
METHODS: Three-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted.
RESULTS: Using a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic-euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice.
CONCLUSIONS: These findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.