Masaki Takayuki, Chiba Seiichi, Noguchi Hitoshi, Yasuda Tohru, Tobe Kazuyuki, Suzuki Ryo, Kadowaki Takashi, Yoshimatsu Hironobu
Department of Internal medicine, School of Medicine, Oita Medical University, Hasama, Oita 879-5593, Japan.
Obes Res. 2004 May;12(5):878-85. doi: 10.1038/oby.2004.106.
Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate-2 (IRS-2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS-2 KO mice.
We measured the histological characterization of adipose tissues, mRNA levels of pro-opiomelanocortin, agouti-related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS-2 KO mice.
Female IRS-2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS-2 KO mice. Both male and female IRS-2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro-opiomelanocortin, was decreased in both male and female IRS-2 KO mice, whereas expression of agouti-related protein and neuropeptide Y were increased in female IRS-2 KO mice.
In IRS-2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.
胰岛素信号紊乱已被证明会在脑胰岛素受体或胰岛素受体底物-2（IRS-2）基因敲除（KO）小鼠中诱发肥胖和/或食欲亢进。本研究旨在探讨IRS-2基因敲除小鼠表型背后的中枢和外周机制。
我们测量了IRS-2基因敲除小鼠脂肪组织的组织学特征、下丘脑中阿片促黑素皮质素原、刺鼠相关蛋白和神经肽Y的mRNA水平以及外周组织中的解偶联蛋白（UCPs）。
雌性IRS-2基因敲除小鼠的每日食物摄入量增加。两性的体重和肥胖程度均增加，尽管这些差异在雌性IRS-2基因敲除小鼠中比在雄性中更为明显。雄性和雌性IRS-2基因敲除小鼠的棕色脂肪组织中UCP1 mRNA表达均降低，体温调节功能受损，雌性基因敲除小鼠白色脂肪组织中的UCP2 mRNA表达增加。此外，雄性和雌性IRS-2基因敲除小鼠中阿片促黑素皮质素原的弓状核mRNA表达均降低，而雌性IRS-2基因敲除小鼠中刺鼠相关蛋白和神经肽Y的表达增加。
在IRS-2基因敲除小鼠中，下丘脑神经肽水平和UCP mRNA表达的控制紊乱可能导致肥胖的发生。
