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Τρίτη 8 Ιανουαρίου 2019

PI3K signaling in leptin receptor cells: role in growth and reproduction

Abstract

Nutrition and growth are important signals for pubertal development, but how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit the phosphatidylinositol 3‐kinase (PI3K) signaling in hypothalamic sites, but whether they converge into the same neuronal population(s) is also not known. In this review, we will 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 p110α and p110β catalytic subunits in leptin receptor cells (LRΔα+β) have a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. The LRΔα+β mice also show deficient growth and delayed puberty. Deletion of a single subunit (i.e., p110α) in LR cells (LRΔα) cause a similar phenotype of increased energy expenditure, deficient growth, and delayed pubertal development indicating that these functions are preferably controlled by p110α. The LRΔα mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to leptin's effects on growth and puberty. The PI3K is also recruited by insulin, and a subpopulation of LR neurons are responsive to intracerebroventricular insulin administration. Deletion of insulin receptor (InsR) in LR cells causes no changes in body weight or linear growth, and induces only 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 potential neural pathways underlying these effects.

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