Pathway Map Details

Development_Leptin signaling via PI3K-dependent pathway



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GSK3 alpha/beta, Kir6.2, PDE3B, IRS-1, PKA-reg (cAMP-dependent), AMP, ATP1A1, 2.3.1.21, PKA-cat (cAMP-dependent), IKK-alpha, CPT-1B, CPT-1A, PTP-1B, 2.7.1.153, Acetyl-CoA cytosol, cAMP, LKB1, GYS2, GLUT4, NF-kB p50/p65, PtdIns(4,5)P2, PtdIns(3,4,5)P3, ACACB, AMPK alpha subunit, SUR1, C/EBPalpha, 3.1.4.17, Malonyl-CoA, PI3K cat class IA, Leptin, (L)-Carnitine mitochondrial matrix, Leptin receptor, Acyl-(L)-carnitine mitochondrial matrix, PI3K reg class IA, I-kB, IKK (cat), CREB1, Acyl-CoA, AKT(PKB), PDK (PDPK1), AMPK beta subunit, AMPK gamma subunit, AKT2, 6.4.1.2, ACACA, IRS-2, JAK2

Description:

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 L eptin 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:

  1. Hegyi K, Fulop K, Kovacs K, Toth S, Falus A
    Leptin-induced signal transduction pathways. Cell biology international 2004;28(3):159-69
  2. Bjorbaek C, Uotani S, da Silva B, Flier JS
    Divergent signaling capacities of the long and short isoforms of the leptin receptor. The Journal of biological chemistry 1997 Dec 19;272(51):32686-95
  3. Fruhbeck G
    Intracellular signalling pathways activated by leptin. The Biochemical journal 2006 Jan 1;393(Pt 1):7-20
  4. Cohen SM, Werrmann JG, Tota MR
    13C NMR study of the effects of leptin treatment on kinetics of hepatic intermediary metabolism. Proceedings of the National Academy of Sciences of the United States of America 1998 Jun 23;95(13):7385-90
  5. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB
    Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002 Jan 17;415(6869):339-43
  6. Zhao AZ, Huan JN, Gupta S, Pal R, Sahu A
    A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nature neuroscience 2002 Aug;5(8):727-8
  7. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ
    AMP-activated protein kinase plays a role in the control of food intake. The Journal of biological chemistry 2004 Mar 26;279(13):12005-8
  8. Berti L, Gammeltoft S
    Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2. Molecular and cellular endocrinology 1999 Nov 25;157(1-2):121-30
  9. Harvey J, McKay NG, Walker KS, Van der Kaay J, Downes CP, Ashford ML
    Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. The Journal of biological chemistry 2000 Feb 18;275(7):4660-9
  10. Sweeney G, Niu W, Kanani R, Klip A
    Regulation of the Na,K-pump by leptin in 3T3-L1 fibroblasts. Endocrinology 2000 Mar;141(3):1277-80
  11. Harvey J, Hardy SC, Irving AJ, Ashford ML
    Leptin activation of ATP-sensitive K+ (KATP) channels in rat CRI-G1 insulinoma cells involves disruption of the actin cytoskeleton. The Journal of physiology 2000 Aug 15;527 Pt 1:95-107
  12. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F
    Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology (Baltimore, Md.) 2005 Dec;42(6):1339-48