Mechanism of amelioration of insulin resistance by β3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model
Mechanism of amelioration of insulin resistance by β3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model
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DOI：
10.2337/diabetes.50.1.113
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发表时间：
2001-01-01
期刊：
影响因子：
7.7
通讯作者：
Kadowaki, T
中科院分区：
文献类型：
--
作者：
Kato, H;Ohue, M;Kadowaki, T
通过研究特异性 β (3)-肾上腺素受体激动剂 AJ-9677 在 KK-A(y)/Ta 糖尿病肥胖小鼠模型的白色和棕色脂肪组织中的作用，研究了其在体内缓解胰岛素抵抗的机制。 AJ-9677 通过减少脂肪细胞的大小来减少白色脂肪组织的总重量，这种作用与肿瘤坏死因子-α (TNF-α) 和瘦素表达水平的正常化有关。棕色脂肪组织中解偶联蛋白（UCP）-1 mRNA 的水平增加了三倍。 AJ-9677 导致白色脂肪组织中 UCP-1 的表达显着增加（20 至 80 倍）。糖尿病肥胖小鼠的白色和棕色脂肪组织中 UCP-2 mRNA 水平均升高，AJ-9677 进一步上调棕色脂肪组织中的 UCP-8 mRNA 水平，但降低白色脂肪组织中的 UCP-8 mRNA 水平。 AJ-9677 并未本质上改变 UCP-3 mRNA 水平。然而，AJ-9677 显着（两到四倍）上调白色和棕色脂肪组织以及腓肠肌中的 GLUT4 mRNA 和蛋白质水平。小脂肪细胞的产生可能是由 UCP-1 表达增加以及 AJ-9677 引起的脂肪分解增加介导的，与 TNF-α 和游离脂肪酸产生减少有关，可能是改善 KK-A(y)/Ta 糖尿病肥胖小鼠胰岛素抵抗的机制。
The mechanism by which the specific beta (3)-adrenoceptor agonist AJ-9677 relieves insulin resistance in vivo was investigated by studying its effects in the white and brown adipose tissues of the KK-A(y)/Ta diabetic obese mouse model. AJ-9677 reduced the total weight of white adipose tissues by reducing the size of the adipocytes, an effect associated with the normalization of tumor necrosis factor-alpha (TNF-alpha) and leptin expression levels. The levels of uncoupling protein (UCP)-1 mRNA in brown adipose tissue were increased threefold. AJ-9677 caused a marked increase (20- to 80-fold) in the expression of UCP-1 in white adipose tissues. The levels of UCP-2 mRNA were increased in both the white and brown adipose tissues of diabetic obese mice, and AJ-9677 further upregulated UCP-8 mRNA levels in brown adipose tissue, but reduced its levels in white adipose tissue. UCP-3 mRNA levels were not essentially changed by AJ-9677. However, AJ-9677 significantly (two- to four-fold) upregulated the GLUT4 mRNA and protein levels in white and brown adipose tissues and the gastrocnemius. The generation of small adipocytes, presumably mediated by increased expression of UCP-1 in addition to increased lipolysis in response to AJ-9677, was associated with decreased TNF-alpha and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-A(y)/Ta diabetic obese mice.