PI3K alpha inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

Author(s)

Garcia-Galiano, David ^[1] ; Borges, Beatriz C. ^{[1, 2]} ; Donato, Jr., Jose ^[3] ; Allen, Susan J. ^[1] ; Bellefontaine, Nicole ^[1] ; Wang, Mengjie ^[4] ; Zhao, Jean J. ^[5] ; Kozloff, Kenneth M. ^[6] ; Hill, Jennifer W. ^[4] ; Elias, Carol F. ^{[1, 7]}

Affiliation

^[1] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 - USA

^[2] Univ Sao Paulo, Dept Physiol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Physiol & Biophys, Sao Paulo - Brazil

^[4] Univ Toledo, Dept Physiol & Pharmacol, 2801 W Bancroft St, Toledo, OH 43606 - USA

^[5] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA - USA

^[6] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 - USA

^[7] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 - USA

• Document type: Journal article
• Source: JCI INSIGHT; v. 2, n. 23 DEC 7 2017.
• Web of Science Citations: 6

Abstract

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 p110 alpha and p110 beta subunits in leptin receptor cells (LR Delta alpha+beta) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LR Delta alpha+beta mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110 alpha in LR Delta alpha) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LR Delta alpha 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. LR Delta InsR 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. (AU)

• FAPESP's process: 13/03915-0 - Role of PI3K signaling pathway in endotoxin-induced leptin resistance
• Grantee: Beatriz de Carvalho Borges Del Grande
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor