Kato H, Ohue M, Kato K, Nomura A, Toyosawa K, Furutani Y, Kimura S, Kadowaki T
Department of Pharmacology III, Dainippon Pharmacutical Co, Osaka, Japan.
Diabetes. 2001 Jan;50(1):113-22. doi: 10.2337/diabetes.50.1.113.
The mechanism by which the specific beta3-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-Ay/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-2 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-Ay/Ta diabetic obese mice.
通过研究特定的β3-肾上腺素能受体激动剂AJ-9677对KK-Ay/Ta糖尿病肥胖小鼠模型白色和棕色脂肪组织的影响，探讨其在体内缓解胰岛素抵抗的机制。AJ-9677通过减小脂肪细胞大小来降低白色脂肪组织的总重量，这一效应与肿瘤坏死因子-α（TNF-α）和瘦素表达水平的正常化相关。棕色脂肪组织中解偶联蛋白（UCP）-1 mRNA水平增加了三倍。AJ-9677使白色脂肪组织中UCP-1的表达显著增加（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进一步上调了棕色脂肪组织中UCP-2 mRNA水平，但降低了白色脂肪组织中的UCP-2 mRNA水平。AJ-9677对UCP-3 mRNA水平基本无影响。然而，AJ-9677显著上调了白色和棕色脂肪组织以及腓肠肌中葡萄糖转运蛋白4（GLUT4）的mRNA和蛋白水平（两至四倍）。除了对AJ-9677的反应性脂解增加外，UCP-1表达增加可能介导了小脂肪细胞的生成，这与TNF-α和游离脂肪酸生成减少有关，可能是KK-Ay/Ta糖尿病肥胖小鼠胰岛素抵抗改善的机制。
