Development - Leptin signaling via PI3K-dependent pathway

Leptin signaling via PI3K-dependent pathway

Leptin, the polypeptide product of the ob gene, acts on the brain to regulate energy balance. It is hormone, composed of 167 amino acid residues and produced almost exclusively in adipose tissue. More-recent studies have revealed additional pleiotrophic functions of Leptin, including the ability to affect neuroendocrine functions, the adaptive response to fasting, reproductive function, brain size, bone development, immune function, blood cell development, regulation of blood pressure, glucose homeostasis, fatty acid metabolism, and regulation of sensory nerve input and autonomic outflow [1].

Six splice variants of the Leptin receptor have been identified: four short isoforms (ObRa, ObRc, ObRd and ObRf) with shortened intra-cellular tails, the secreted isoform (ObRe) and the long isoform or ObRb. The long isoform consists of 1162 amino acids and is the only LR isoform with clearly demonstrated signaling capability [1].

Leptin signaling occurs typically through the JAK/STAT and MAPK pathways, but Leptin can also act through some of the components of the insulin-signaling cascade. However, the role of Leptin in insulin -induced gene expression is controversial. Leptin can enhance Insulin-receptor substrates 1 and 2 (IRS-1 or IRS-2) phosphorylation via Janus kinase 2 (JAK2) activation [2].

Phosphorylation of both IRS-1 and IRS-2 leads to the activation of Phosphatidylinositol 3-kinase (PI3K) that generates inositol-trisphosphate (PtdIns(3,4,5)P3). Increased PtdIns(3,4,5)P3 levels lead to the activation of 3-phosphoinositide dependent protein kinase-1 PDK1(PDPK1), which activates v-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)). AKT(PKB) has several targets including Glycogen synthase kinase-3 alpha/beta (GSK3 alpha/beta) and Phosphodiesterase 3B, cGMP-inhibited (PDE3B). GSK3 alpha/beta phosphorylation inactivates of Glycogen synthase 2 (GYS2) and activates CCAAT/enhancer binding protein (C/EBP), alpha (C/EBPalpha) [3]. Consequently Leptin up-regulates glycogen synthesis in liver [4].

Leptin stimulates the oxidation of fatty acids in muscle via PDE3B [5].The activation of PDE3B leads to reduced levels of cyclic adenosine monophosphate (cAMP) and increased levels of 5'-Adenosine monophosphate (AMP). Protein kinase, AMP-activated (AMPK) is known to inhibits the activity of Acetyl-Coenzyme A carboxylase beta (ACACB) thereby reducing concentrations of malonyl-CoA. It was shown that Leptin selectively stimulates phosphorylation and activation of the Protein kinase, AMP-activated, alpha catalytic subunits (AMPK alpha subunit) in skeletal muscle [5].

In the hypothalamus, Leptin increases hypothalamic PI3K and PDE3B activities resulting in a decrease in cAMP concentration and decreased cAMP responsive element binding protein 1 (CREB1) activity [6].

In the hypothalamus, Leptin has an opposite effect on malonyl-CoA level. The administration of Leptin leads to a reduction in food intake, a decrease in hypothalamic AMPK activity and a slight reduction in Serine/threonine kinase 11 (LKB1). Concomitant with their effects on AMPK, Leptin decreased ACC (acetyl coenzyme A carboxylase) phosphorylation and increase level of malonyl-CoA [7].

In C2C12 muscle cells, Leptin stimulates glucose transport by recruiting Solute carrier family 2 (facilitated glucose transporter), member 4 (GLUT4) to the cell surface in a wortmannin- sensitive manner, which can inhibit both PI3K and MAPK [8].

Leptin was found to inhibit ATPase, Na+/K+ transporting, alpha 1 polypeptide (ATP1A1) activity, and activates Potassium inwardly-rectifying channel, subfamily J, member 11/ ATP-binding cassette, sub-family C (CFTR/MRP), member 8 (Kir6.2/SUR1)) in a PI3K-dependent manner [9], [10], [11].

Leptin activates a variety of different signaling pathways downstream of the Leptin receptor, including Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB) and Hypoxia-inducible factor 1, alpha subunit (HIF1A) pathways. Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p50) and v-rel reticuloendotheliosis viral oncogene homolog A (p65) appear to be the major targets of the action of Leptin on NF-kB [12].

References:

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