Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, with Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus
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.
Funding
This work was supported by a grant for TSBMI from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Scientific Research (B) (18H02860), and (B) (15H04847) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N.K.), a Grant-in-Aid for Young Scientists (B) (15K19505) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.H.).