Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, with Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus
| Autor: | Iseki Takamoto, Toshimasa Yamauchi, Yoshitaka Sakurai, Masakazu Aihara, Inoue Mariko, Nobuhiro Wada, Naoto Kubota, Tetsuya Kubota, Takashi Kadowaki, Takanori Hayashi, Takashi Miki |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
endocrine system Adipose Tissue White Endocrinology Diabetes and Metabolism medicine.medical_treatment Hypothalamus Growth Hormone-Releasing Hormone Mice Downregulation and upregulation Internal medicine Internal Medicine medicine Animals Homeostasis Glucose homeostasis Insulin-Like Growth Factor I Muscle Skeletal Growth Disorders Mice Knockout Neurons biology Chemistry Insulin Brain Growth hormone–releasing hormone IRS1 Insulin receptor Glucose Endocrinology Liver Growth Hormone Insulin Receptor Substrate Proteins biology.protein Insulin Resistance Hormone |
| DOI: | 10.2337/figshare.14555988 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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