| First Author | Garcia-Galiano D | Year | 2017 |
| Journal | JCI Insight | Volume | 2 |
| Issue | 23 | PubMed ID | 29212950 |
| Mgi Jnum | J:288051 | Mgi Id | MGI:6407551 |
| Doi | 10.1172/jci.insight.96728 | Citation | Garcia-Galiano D, et al. (2017) PI3Kalpha inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction. JCI Insight 2(23) |
| abstractText | 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 p110alpha and p110beta subunits in leptin receptor cells (LRDeltaalpha+beta) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRDeltaalpha+beta mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110alpha in LRDeltaalpha) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRDeltaalpha 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. LRDeltaInsR 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. |
