The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110α and p110β subunits in leptin receptor cells (LRΔα+β) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRΔα+β mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110α in LRΔα) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRΔα mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin’s effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LRΔInsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.
David Garcia-Galiano, Beatriz C. Borges, Jose Donato Jr., Susan J. Allen, Nicole Bellefontaine, Mengjie Wang, Jean J. Zhao, Kenneth M. Kozloff, Jennifer W. Hill, Carol F. Elias
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