The PI3K signaling pathway mediates the biological effects of leptin

Abstract

SUMMARYThe activation of the leptin receptor recruits several intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway. While some of the leptin-induced signaling pathways, such as the JAK2/STAT3 pathway, induce cellular responses primarily through changes in gene expression, the PI3K pathway affects cellular properties more rapidly, through post-translational changes such as protein phosphorylation. Accordingly, several studies have shown that the PI3K pathway is required for the acute effects of leptin, such as a leptin-induced decrease in food intake. Leptin signaling through PI3K also affects the electrophysiological properties of neurons, including changes in their membrane potential and firing rates. In this review, we summarize the recent advances in our understanding of the role played by the PI3K signaling pathway in controlling food intake and energy balance. In particular, we focus on the importance of the PI3K signaling pathway as a mediator of the effects of leptin on hypothalamic neurons. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Keywords Phosphatidylinositol; phosphatidylinositol 3-kinases; energy balance; insulin; Akt; hypothalamus SUMÁRIO A ativação do receptor de leptina recruta diversas vias de sinalização intracelular, entre elas a via da fosfatidilinositol 3-quinase (PI3K). Enquanto algumas dessas vias, como a sinalização pelo JAK2/ STAT3, induzem respostas celulares por meio de mudanças na transcrição gênica, a via da PI3K altera propriedades celulares de forma rápida, via fosforilação de proteínas. Em concordância, estudos mostraram que a via da PI3K é necessária para que a leptina induza seus efeitos agudos, como redução da ingestão alimentar, após administração de leptina. A ativação da PI3K pela leptina também afeta as propriedades fisiológicas de neurônios, incluindo mudanças no potencial de membrana e no potencial de ação. Nesta revisão, resumimos os recentes avanços na compreensão do papel desempenhado pela via de sinalização da PI3K no controle da ingestão alimentar e do balanço energético. Discutimos, principalmente, como a via da PI3K é importante para mediar os efeitos da leptina sobre os neurônios hipotalâmicos. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Descritores Fosfatidilinositol; fosfatidilinositol 3-quinase; balanço energético; insulina; Akt; hipotálamo review

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

“…Leptin controls other two key signaling path ways, namely the extracellular signal regulated ki nase (ERK) 1/2 (Figure 2), and the activation of the phosphatidylinositol 3 kinase (PI3K) (Figure 3) (15). Janus activated kinase phosphorylation of Tyr 985 (or phosphorylated JAK2 itself, independent of phosphor ylated Tyr 985 ) leads to recruitment and phosphoryla tion of SHP 2 (src homology 2 containing tyrosine phosphatase).…”

“…This pathway originates with JAK2 autophos phorylation, which leads to the recruitment and phos phorylation of insulin receptor substrate (IRS) proteins. Then, phosphorylated IRS proteins recruit phosphati dylinositol 3' kinase (PI3K) and activate downstream signals (15). Leptin binds to the leptin receptor (Ob-Rb) and activates Janus-family tyrosine kinase 2 (JAK2) by auto-or cross-phosphorylation.…”

“…Members of the SOCS family (SOCS1 and SOCS3) suppress the action of leptin by binding to JAK 2 and tyrosine residues. The PI3K pathway is an acute phase contributor of inflammation, in contrast to JAK2/STAT3, which is a slower process as it functions by altering gene tran scription (15). Both JAK2 and the insulin receptor participate in the phosphorylation of IRS, which then stimulate the p85 subunit of PI3K, thereby activat ing it.…”

“…Akt is a key participant in regulating neuropeptide Y and nitric ox ide (NO) mTOR via p70S6K (19). The PI3K pathway has also been implicated in controlling the Rho family of GTPases, which regulate apoptosis and remodel the actin skeleton within cells (15,19).…”

Hypothyroidism reduces ObRb–STAT3 leptin signalling in the hypothalamus and pituitary of rats associated with resistance to leptin acute anorectic action

“…After leptin binds to ObRb, the receptor-associated Janus tyrosine kinases (JAK2) phosphorylate the leptin receptor, which results in the phosphorylation of STAT3 by JAK2 and the subsequent translocation of phosphorylated STAT3 (pSTAT3) to the nucleus to regulate gene transcription (Ahima & Flier 2000, Myers 2004, Hekerman et al 2005. pSTAT3 induces the transcription of several genes, including suppressor of cytokine signalling 3 (SOCS3), which inhibits JAK2-STAT3 signalling, leading to central leptin resistance (Bjørbaek et al 1999, Flier 2004, Howard et al 2004, Donato et al 2010. In vivo and in vitro evidence indicate that STAT3 mediates the effect of leptin in the regulation of TRH (Nillni et al 2000, Guo et al 2004, Huo et al 2004.…”