Leptin signaling via PI3K-dependent
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 .
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 .
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 .
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 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) . Consequently
Leptin up-regulates glycogen synthesis in liver .
Leptin stimulates the oxidation of fatty acids in muscle
via PDE3B .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 .
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
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 .
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 .
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 , , .
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
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