内科学
内分泌学
IRS1
胰岛素
胰岛素受体
胰岛素样生长因子1受体
下丘脑
生物
葡萄糖稳态
生长激素
下调和上调
生长激素-释放激素
胰岛素样生长因子
IRS2
胰岛素抵抗
激素
受体
正中隆起
生长因子
医学
生物化学
基因
作者
Takanori Hayashi,Tetsuya Kubota,Mariko Inoue,Iseki Takamoto,Masakazu Aihara,Yoshitaka Sakurai,Nobuhiro Wada,Takashi Miki,Toshimasa Yamauchi,Naoto Kubota,Takashi Kadowaki
出处
期刊:Diabetes
[American Diabetes Association]
日期:2021-05-12
卷期号:70 (8): 1640-1653
被引量:17
摘要
Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone–releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.
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