Leptin’s Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals

384 Moon et al Effects of Leptin on Glucose Metabolism Endocrine Reviews, June 2013, 34(3):377–412
tracerebroventricular (icv) administration of PI3K inhibitors
(116, 286). Interestingly, the insulin-PI3K pathway
hyperpolarizes POMC neurons, which makes them less
sensitive to leptin, and may be one common mechanism
for both leptin and insulin resistance in obesity (117, 118).
Chronic activation of the PI3K pathway in POMC neurons
may cause leptin resistance and hyperphagia in mice
with POMC neuron-specific deletion of phosphatase and
tensin homolog (PTEN) (105). Hence, activation of the
PI3K signaling pathway in neuronal cells may influence
energy homeostasis and neuroendocrine function,
whereas activation of this pathway in the peripheral tissues
may mediate leptin’s effect on insulin resistance.
D. Leptin and FoxO1 signaling
Forkhead box protein O1 (FoxO1) belongs to the forkhead
family of transcription factors that are characterized
by a distinct forkhead domain (119) (Table 2 and Figure
1).Thespecificfunctionofthistranscriptionfactorhasnot
yet been determined; however, it may contribute to myogenic
growth and differentiation (119). FoxO1 is a downstream
effector of insulin signaling with an important role
in the regulation of metabolism in various organs including
liver (120), pancreas (121), muscle (122), adipose tissue
(122), and hypothalamus (123). Also, FoxO1, as a
transcription factor, is one of the substrates for Akt phosphorylation
resulting in cytoplasmic shuttling from the
nucleus, thereby inactivating FoxO1 (124, 125). FoxO1,
which stimulates the expression of AgRP and NPY and
inhibits POMC expression, is an important downstream
mediator of the PI3K pathway (286). It has been demonstrated
that the activation of hypothalamic FoxO1 is inhibited
by leptin via the PI3K pathway (123). In contrast,
overexpression of constitutively active FoxO1 in the
mediobasal hypothalamus of rats by adenoviral microinjection
leads to a loss of the inhibitory effect of leptin
on feeding and results in body weight gain (126). Moreover,
hypothalamus-specific FoxO1 knock-in mice
have increased food intake and decreased energy expenditure
(127).
E. Leptin and SHP2/MAPK signaling
MAPKs are serine/threonine-specific protein kinases
that respond to extracellular stimuli (mitogens, osmotic
stress, heat-shock, and proinflammatory cytokines) and
regulate various cellular activities, such as gene expression,
mitosis, differentiation, proliferation, and cell survival/apoptosis
(19, 21, 128, 129). MAPKs encompass a
number of signaling molecules that include ERK1/2, p38
and c-Jun N-terminal kinase (JNK) (21). ERK1/2 represents
the major MAPK involved in leptin’s central effects
contributing to the regulation of food intake, energy expenditure,
and body weight (3).
Leptin stimulates ERK1/2 activation via SH2-containing
protein tyrosine phosphatase 2 (SHP2) (Table 2 and
Figure 1). SHP2 is a protein tyrosine phosphatase (PTP)
that contains 2 SH2 domains located in its NH 2 terminus
as well as a COOH-terminal PTP domain (130). This specific
structure suggests that SHP2 is involved in regulating
signals initiated by receptor tyrosine kinases (130). These
phosphotyrosines act as docking sites for recruitment of
SH2-containing proteins, including SHP2, to activate
downstream signaling cascades (131). SHP2 promotes
ERK1/2 activation in response to insulin and epidermal
growth factor binding to their receptors (132, 133).
Leptin induces phosphorylation of the Tyr 985 amino
acid residue of the ObRb after JAK2 activation, thereby
creating a binding site for the carboxyl-terminal SH2 domain
of SHP2 (134). SHP2 itself becomes phosphorylated,
recruits the adaptor protein growth factor receptor-bound
protein-2 and induces JAK2-dependent activation of
ERK1/2 (135). Leptin also activates the MAPK pathway
independently of SHP2, probably via receptor activation
leading to direct binding of growth factor receptor-bound
protein-2 to JAK2 (136). Recently, it has been shown that
young mice homozygous for a mutation at the site of the
leptin receptor phosphorylation were slightly leaner than
wild-type mice, although they still developed adult-onset
or DIO (137). These phenotypes probably do not reflect
the effect of this mutation on leptin-induced ERK activation
but are consistent with the role of the mutation site as
a binding site for the suppressor of cytokine signaling 3
(SOCS3), which is a negative regulator of leptin receptor
signaling (137). In vitro studies have also demonstrated
that ERK is required for the phosphorylation of S6 by the
S6 kinase, which enhances cap-dependent translation and
protein synthesis (138).
Other members of the MAPK family, p38 and JNK, are
also activated by leptin in several cell types and present
mainly peripheral actions (139–141), although the associated
pathways have not been well characterized. In rat
cardiomyocytes, leptin administration stimulates p38,
which results in an increase in fatty acid oxidation,
whereas inhibition of p38 activation prevents
leptin-induced fatty acid oxidation (134). Similar to p38,
JNK is not activated in response to leptin treatment in
neuronal cells (135, 136) but confers an oncogenic potential
to leptin’s action after its activation by promoting cancer
cell survival and invasion (137).
F. Leptin and JAK2-independent signaling
You et al (137) observed that leptin may stimulate the
MAPK and STAT3 pathways in cultured cells that are
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