β-Adrenergic-AMPK Pathway Phosphorylates Acetyl-CoA Carboxylase in a High-epinephrine Rat Model, SPORTS
β-Adrenergic-AMPK Pathway Phosphorylates Acetyl-CoA Carboxylase in a High-epinephrine Rat Model, SPORTS
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DOI：
10.1038/oby.2009.145
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发表时间：
2010-01-01
期刊：
影响因子：
6.9
通讯作者：
Nakaya, Yutaka
中科院分区：
文献类型：
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作者：
Hattori, Atsushi;Mawatari, Kazuaki;Nakaya, Yutaka
我们建立了一种名为 SPORTS（自发奔跑的德岛-四国）大鼠的新动物模型，该模型显示出高肾上腺素 (Epi) 水平。最近的报告表明 Epi 激活脂肪细胞中的单磷酸腺苷 (AMP) 激活的蛋白激酶 (AMPK)。乙酰辅酶A羧化酶(ACC)是脂肪酸合成的限速酶，当其Ser-79被AMPK磷酸化时，酶活性受到抑制。本研究的目的是研究 Epi 对 ACC 和腹部内脏脂肪积累的体内影响。我们将 6 周龄的雄性对照和运动大鼠分为两组，分别喂食正常饮食或高脂肪和蔗糖 (HFS) 饮食 16 周。在饮食治疗结束时，收集腹膜后脂肪用于蛋白质印迹和组织学分析。各组之间的食物摄入量没有差异，但两个饮食组中运动大鼠的体重增加均显着低于对照组大鼠。经过10周的饮食治疗后，葡萄糖耐量测试（GTT）显示SPORTS大鼠的胰岛素敏感性增加。此外，运动大鼠的腹部脂肪和血浆甘油三酯（TG）含量较低。在腹部脂肪中，在 SPORTS 大鼠中观察到 ACC Ser-79 磷酸化升高，并被 β-肾上腺素能受体 (AR) 拮抗剂普萘洛尔或 AMPK 抑制剂化合物 C 抑制。从这些结果来看，高水平的 Epi 诱导 SPORTS 大鼠腹部内脏脂肪中通过 β-AR 和 AMPK 信号通路介导的 ACC 磷酸化，这可能有助于减少 腹部内脏脂肪堆积，增加胰岛素敏感性。我们的结果表明，β-AR 调节的 ACC 活性将成为治疗肥胖等生活方式相关疾病的目标。
We established a new animal model called SPORTS (Spontaneously-Running Tokushima-Shikoku) rats, which show high-epinephrine (Epi) levels. Recent reports show that Epi activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) in adipocytes. Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis, and the enzymatic activity is suppressed when its Ser-79 is phosphorylated by AMPK. The aim of this study was to investigate the in vivo effect of Epi on ACC and abdominal visceral fat accumulation. We divided both 6-week male control and SPORTS rats into two groups, which were fed either normal diet or high fat and sucrose (HFS) diet for 16 weeks. At the end of diet treatment, retroperitoneal fat was collected for western blotting and histological analysis. Food intake was not different among the groups, but SPORTS rats showed significantly lower weight gain than control rats in both diet groups. After 10 weeks of diet treatment, glucose tolerance tests (GTTs) revealed that SPORTS rats had increased insulin sensitivity. Furthermore, SPORTS rats had lower quantities of both abdominal fat and plasma triglyceride (TG). In abdominal fat, elevated ACC Ser-79 phosphorylation was observed in SPORTS rats and suppressed by an antagonist of beta-adrenergic receptor (AR), propranolol, or an inhibitor of AMPK, Compound C. From these results, high level of Epi induced ACC phosphorylation mediated through beta-AR and AMPK signaling pathways in abdominal visceral fat of SPORTS rats, which may contribute to reduce abdominal visceral fat accumulation and increase insulin sensitivity. Our results suggest that beta-AR-regulated ACC activity would be a target for treating lifestyle-related diseases, such as obesity.