Partial deletion of Pten in the hypothalamus leads to growth defects that cannot be rescued by exogenous growth hormone

The GH/IGF-I axis plays a critical role in mammalian body growth. GH is secreted by the anterior pituitary, and its actions are primarily mediated by IGF-I that is secreted by the liver and other tissues. Local and circulating IGF-I action is largely mediated by the phosphoinositide 3-kinase signaling pathway, and phosphatase with tensin homology (PTEN) is a potent negative regulator of this pathway. Here we show that RIPcre(+)Pten(fl/fl) mice, which exhibit PTEN deletion in insulin-transcribing neurons of the hypothalamus in addition to pancreatic beta-cells, result in a small-body phenotype that is associated with an unexpected increase in serum IGF-I levels. We tested whether exogenous GH can override the growth defect in RIPcre(+)Pten(fl/fl) mice. Our results showed no significant difference in their growth between the RIPcre(+)Pten(fl/fl) mice injected with GH or vehicle. Together, PTEN in the hypothalamic insulin-transcribing neurons plays an essential role in body size determination, and systemic GH cannot overcome the growth defect in these mice.