PI3K signalling in leptin receptor cells: Role in growth and reproduction

Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3-kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte-derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110 alpha and p110 beta catalytic subunits in leptin receptor cells (LR Delta alpha+beta) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LR Delta alpha+beta mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110 alpha) in LR cells (LR Delta alpha) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110 alpha. The LR Delta alpha mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.