Winder W W, Holmes B F
Brigham Young University, Provo, Utah 84602, USA.
J Appl Physiol (1985). 2000 Dec;89(6):2430-7. doi: 10.1152/jappl.2000.89.6.2430.
Fatty acid oxidation in muscle has been reported to be diminished when insulin and glucose levels are elevated. This study was designed to determine whether activation of AMP-activated protein kinase (AMPK) will prevent inhibitory effects of insulin and glucose on the rate of fatty acid oxidation. Rat hindlimbs were perfused with medium containing 0, 0.3, or 60 nM insulin with or without 2 mM 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Glucose uptake was stimulated four- to fivefold by inclusion of insulin in the medium. Insulin attenuated the increase in AMPK caused by AICAR both in perfused hindlimbs and in isolated epitrochlearis muscles. The activation constant for citrate activation of acetyl-CoA carboxylase (ACC) was significantly increased in response to AICAR, and the increase was slightly attenuated if insulin was present in the perfusion medium. Insulin stimulated an increase in malonyl-CoA content of the muscles in the absence of AICAR. Malonyl-CoA was decreased to approximately the same value in AICAR-perfused muscle, regardless of insulin concentration. Muscle glucose 6-phosphate and citrate were significantly increased in response to AICAR and insulin. The rate of palmitate oxidation tended to decrease in response to insulin and in the absence of AICAR. AICAR increased palmitate oxidation to approximately the same level regardless of the insulin concentration or the rate of glucose uptake into the muscle. The rate of palmitate oxidation showed a curvilinear relationship as a function of muscle malonyl-CoA content, with half-maximal inhibition at approximately 0.6 nmol/g. We conclude that AMPK activation can prevent high rates of glucose uptake and glycolytic flux from inhibiting palmitate oxidation in predominantly fast-twitch muscle under these conditions.
据报道，当胰岛素和葡萄糖水平升高时，肌肉中的脂肪酸氧化会减少。本研究旨在确定AMP激活的蛋白激酶（AMPK）的激活是否能预防胰岛素和葡萄糖对脂肪酸氧化速率的抑制作用。用含有0、0.3或60 nM胰岛素且有或无2 mM 5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）的培养基灌注大鼠后肢。培养基中加入胰岛素可使葡萄糖摄取增加4至5倍。胰岛素在灌注的后肢和分离的肱三头肌中均减弱了AICAR引起的AMPK增加。响应AICAR，乙酰辅酶A羧化酶（ACC）的柠檬酸激活常数显著增加，且如果灌注培养基中存在胰岛素，这种增加会略有减弱。在没有AICAR的情况下，胰岛素刺激了肌肉中丙二酰辅酶A含量的增加。无论胰岛素浓度如何，在AICAR灌注的肌肉中丙二酰辅酶A均降至大致相同的值。响应AICAR和胰岛素，肌肉中的葡萄糖6-磷酸和柠檬酸显著增加。在没有AICAR的情况下，响应胰岛素，棕榈酸氧化速率趋于降低。无论胰岛素浓度或肌肉中葡萄糖摄取速率如何，AICAR均将棕榈酸氧化增加至大致相同的水平。棕榈酸氧化速率与肌肉丙二酰辅酶A含量呈曲线关系，在约0.6 nmol/g时出现半数最大抑制。我们得出结论，在这些条件下，AMPK激活可防止高葡萄糖摄取率和糖酵解通量抑制主要为快肌纤维的肌肉中的棕榈酸氧化。
