The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity
The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity
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DOI：
10.1152/ajpregu.00178.2008
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发表时间：
2008-06-01
影响因子：
2.8
通讯作者：
Beneze, Alan N.
中科院分区：
文献类型：
--
作者：
Henriksen, Erik J.;Teachey, Mary K.;Beneze, Alan N.
高脂喂养(HFF)是一种公认的营养性胰岛素抵抗模型。本研究的目的是评估雌性瘦Zucker大鼠喂饲普通饲料(4%脂肪)和高脂肪饲料(50%脂肪)15wk后的代谢反应。HFF大鼠自发调整食物摄入量，以使每日卡路里摄入量与食物喂养(CF)对照组相匹配。HFF动物从脂肪中摄入更多(P<；0.05)卡路里(31.9+/-1.2比2.4+/-0.2千卡/天)，并显著增加最终体重(280+/-10比250+/-5克)和总内脏脂肪(24+/-3比10+/-1克)。HFF大鼠的空腹血浆胰岛素水平升高了2.3倍。HFF动物的葡萄糖耐量(58%)和全身胰岛素敏感性(75%)明显受损。在HFF足底肌肉中，体内胰岛素受体β亚基(IR-β)和胰岛素受体底物-1(IRS-1)酪氨酸磷酸化以及Akt Ser473和糖原合成酶-3β(GSK-3β)Ser9的磷酸化，相对于循环胰岛素水平下降了40-59%。在体外，胰岛素刺激的比目鱼肌葡萄糖转运减少了54%，IRS-1酪氨酸磷酸化(26%)以及Akt Ser473和GSK-3βSer9的磷酸化(38%)和GSK-3βSer9(25%)也减少了，后者表明GSK-3过度活性。CT98014抑制GSK-3可增加胰岛素刺激的葡萄糖转运(28%)、IRS-1酪氨酸磷酸化(28%)以及Akt Ser473(38%)和GSK-3βSer9(48%)的磷酸化。综上所述，喂食高脂肪饲料的雌性Zucker大鼠代表了一种等卡路里模型，即营养诱导的胰岛素抵抗与中等内脏脂肪增加、高胰岛素血症和骨骼肌胰岛素信号功能损害相关，包括GSK-3β过度活性。
High-fat feeding (HFF) is a well-accepted model for nutritionally-induced insulin resistance. The purpose of this investigation was to assess the metabolic responses of female lean Zucker rats provided regular chow (4% fat) or a high-fat chow (50% fat) for 15 wk. HFF rats spontaneously adjusted food intake so that daily caloric intake matched that of chow-fed (CF) controls. HFF animals consumed more (P < 0.05) calories from fat (31.9 +/- 1.2 vs. 2.4 +/- 0.2 kcal/day) and had significantly greater final body weights (280 +/- 10 vs. 250 +/- 5 g) and total visceral fat (24 +/- 3 vs. 10 +/- 1 g). Fasting plasma insulin was 2.3-fold elevated in HFF rats. Glucose tolerance (58%) and whole body insulin sensitivity (75%) were markedly impaired in HFF animals. In HFF plantaris muscle, in vivo insulin receptor beta-subunit (IR-beta) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3 beta (GSK-3 beta) Ser9, relative to circulating insulin levels, were decreased by 40-59%. In vitro insulin-stimulated glucose transport in HFF soleus was decreased by 54%, as were IRS-1 tyrosine phosphorylation (26%) and phosphorylation of Akt Ser473 (38%) and GSK-3 beta Ser9 (25%), the latter indicative of GSK-3 overactivity. GSK-3 inhibition in HFF soleus using CT98014 increased insulin-stimulated glucose transport (28%), IRS-1 tyrosine phosphorylation (28%) and phosphorylation of Akt Ser473 (38%) and GSK-3 beta Ser9 (48%). In summary, the female lean Zucker rat fed a high-fat diet represents an isocaloric model of nutritionally-induced insulin resistance associated with moderate visceral fat gain, hyperinsulinemia, and impairments of skeletal muscle insulin-signaling functionality, including GSK-3 beta overactivity.