Leptin is a peptide hormone mainly synthesised and secreted from adipocytes (1). It is also
expressed in other tissues including placenta, stomach and skeletal muscle (1, 2). Leptin
mediates its effects by binding to its receptor, leptin receptor (LEPR) (3). LEPR belongs
to gp130 family of cytokine receptor (4). LEPR is expressed in many tissues such as brain,
adipose tissue, heart, placenta, lung and liver (1, 5, 6, 7). Alternative splicing of LEPR results
in six different isoforms, LEPRa, LEPRb, LEPRc, LEPRd, LEPRe and LEPRf (8). LEPRb
is the longest isoform and possess signaling capacity (9). The role of other isoforms in leptin
signaling is not clear (9). Leptin plays a major role in the regulation of energy homeostasis
and regulate food intake and energy expenditure (10, 11). Leptin is found to be transported
to various regions of the brain across blood brain barrier (12). Impairment in leptin signaling
across the blood brain barrier induces leptin resistance and thus obesity (13). Leptin is known
to regulate reproduction, bone homeostasis and immune signaling (14, 15). Leptin is also
implicated in various physiological processers such as angiogenesis and hematopoiesis (16,
LEPRb forms a homodimer and binds to leptin in 1:1 stoichiometry. This tetrameric receptor/
ligand complex appears to be essential for singaling (18, 19). Leptin receptor lacks intrinsic
kinase activity. It mediates multiple signaling pathways by binding to cytoplasmic kinases
such as Janus Kinase 2 (JAK2) (20). Activation of JAK2 by leptin promotes the tyrosine
phosphorylation of LEPRb at Tyr-986, Try-1078 and Tyr-1141, thus activating LEPRb (21).
Activation of leptin receptor with leptin activates signaling modules such as JAK/STAT,
RAS/RAF/MAPK, IRS1/PI-3K, PLC gamma and AMPK/ACC modules. Tyrosine
phosphorylation of LEPRb induces binding of STATs to LEPRb (21). Binding of STATs to
the phosphorylated residues of LEPR leads to the JAK2 mediated tyrosine phosphorylation
and activation of STATs (22). Activated STATs translocate to the nucleus and induces
expression of genes such as suppressor of cytokine signaling 3 (SOCS3) and TIMP
metallopeptidase inhibitor 1 (TIMP1) (23, 24). SOCS3 mediates feedback inhibition of leptin
pathway by binding to Tyr-986 residue of LEPR (25). Cytosolic PTP1B also negatively
regulates leptin pathway by dephosphorylating JAK2 and STAT3 (26). Binding of leptin to
its receptor results in the phosphorylation of PTPN1. Phosphorylated PTPN11 provides a
docking site for GRB2, resulting in the activation of ERK module through RAS-RAF-MEK
signaling (27). Leptin induces the activation of PI-3K by promoting the interaction and
formation of SH2B/JAK2/IRS complex (28). Activation PI-3K mediates the activation of
activation of protein kinases such as protein kinase B (AKT1) and downstream signaling
cascades such as mammalian target of rapamycin (MTOR) (29), nitric oxide synthase 3
(NOS3) and phosphodiesterase 3A, cGMP-inhibited (PDE3A) (30). Activated AKT also
regulates glycogen synthase kinase 3 alpha/beta (GSK3A/B) proteins (31). IkappaB kinases
(IKKs) are activated in response to AKT activation. Activated IKKs induce nuclear
translocation of NF-kappaB (28). Leptin also regulates 5'-AMP-activated protein kinase
(AMPK) signaling. AMPK function as energy sensor and is activated in response to rise in
AMP to ATP ratio (32). Activated AMPK regulate fatty acid biosymthesis by regulating the
activity the enzyme, fatty acid biosynthesis-acetyl-CoA carboxylase (ACC) (33, 34). PLC
gamma is activated in response to leptin signaling. Activated PLC gamma regulate
intracellular calcium levels and also protein kinase C activation by hydrolysing phospholipid
phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and
diacylglycerol (DAG) (35, 36).
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