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Development Leptin signaling via PI3K-dependent pathway


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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 toregulate energy balance. It is hormone, composed of 167 amino acid residues and producedalmost exclusively in adipose tissue. More-recent studies have revealed additionalpleiotrophic functions of Leptin, including the ability to affect neuroendocrinefunctions, the adaptive response to fasting, reproductive function, brain size, bonedevelopment, immune function, blood cell development, regulation of blood pressure,glucose homeostasis, fatty acid metabolism, and regulation of sensory nerve input andautonomic outflow [1].

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

Leptin signaling occurs typically through the JAK/STAT and MAPK pathways, butLeptin can also act through some of the components of the insulin-signalingcascade. However, the role of Leptin in insulin -induced gene expression iscontroversial. 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 ofPhosphatidylinositol 3-kinase ( PI3K ) that generates inositol-trisphosphate (PtdIns(3,4,5)P3 ). Increased PtdIns(3,4,5)P3 levels lead to the activationof 3-phosphoinositide dependent protein kinase-1 PDK1(PDPK1), which activatesv-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ). AKT(PKB) hasseveral targets including Glycogen synthase kinase-3 alpha/beta ( GSK3 alpha/beta) and Phosphodiesterase 3B, cGMP-inhibited ( PDE3B ). GSK3 alpha/betaphosphorylation inactivates of Glycogen synthase 2 ( GYS2 ) and activatesCCAAT/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 cyclicadenosine monophosphate ( cAMP ) and increased levels of 5'-Adenosinemonophosphate ( AMP). Protein kinase, AMP-activated ( AMPK ) is known toinhibits the activity of Acetyl-Coenzyme A carboxylase beta ( ACACB ) therebyreducing concentrations of malonyl-CoA. It was shown that Leptinselectively 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 andPDE3B activities resulting in a decrease in cAMP concentration anddecreased cAMP responsive element binding protein 1 ( CREB1 ) activity [6].

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

In C2C12 muscle cells, Leptin stimulates glucose transport by recruiting Solutecarrier family 2 (facilitated glucose transporter), member 4 ( GLUT4 ) to the cellsurface 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, subfamilyJ, 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 theLeptin receptor, including Nuclear factor of kappa light polypeptide geneenhancer in B-cells ( NF-kB ) and Hypoxia-inducible factor 1, alpha subunit (HIF1A ) pathways. Nuclear factor of kappa light polypeptide gene enhancer inB-cells 1 ( p50 ) and v-rel reticuloendotheliosis viral oncogene homolog A (p65 ) appear to be the major targets of the action of Leptin onNF-kB [12].