Biomedical Engineering Reference
In-Depth Information
energy expenditure. Protein tyrosine phosphatase 1B (PTP1B)
and suppressor of cytokine signaling (SOCS)-3 are negative regu-
lators of leptin signaling. SOCS3 binds to tyrosine 985 of LRb
and JAK2 and inhibits LRb signaling via STAT3.
ER stress caused by increased circulating fatty acid and homo-
cysteine levels may interfere with leptin signaling at several levels.
Leptin is produced in adipose tissue. To exert its effects on hypo-
thalamic neurons, leptin crosses the blood brain barrier using a
saturable transport mechanism which may involve soluble splice
variants of the LR. Secretion of these soluble LR splice variants
may be inhibited by ER stress. Activation of NF-kB by ER stressed
hypothalamic neurons induces expression of SOCS3, inhibiting
LRb signaling (
51
). ER stress also activates PTP1B which inhibits
leptin signaling (
52
). Serine phosphorylation of IRS proteins by
JNK may inhibit their tyrosine phosphorylation by JAK2, again
attenuating LRb signaling.
3.2. Insulin Resistance
Insulin resistance is characterized by the inhibition of glucose
uptake by muscle cells for glycogen synthesis (
53
), hepatic glucose
secretion even when blood glucose levels are already high (
54
),
and inhibition of negative control of the hormone-sensitive lipase
by insulin in adipocytes (
55
). At the molecular level, insulin resis-
tance interferes with signaling by the IR (reviewed in (
56-58
)).
A conformational change in the IR triggered by binding of insulin
to the IR activates its protein tyrosine kinase activity. The activated
IR autophosphorylates itself and tyrosine phosphorylates IRS1-4
proteins, and several SH-2 domain containing (SHC) proteins.
Several proteins containing SH-2 domains including PI3K are
activated by recruitment to tyrosine phosphorylated IRS and SHC
proteins. Activated PI3K converts PI-3-phosphate to PI-3,4-
bisphosphate and PI-3,4,5-trisphosphate which recruit protein
kinase B (PKB/AKT) isoforms and phosphoinositide-dependent
kinases (PDK) 1 and 2 to the plasma membrane. There PDKs
activate PKB1, -2, and -3 by phosphorylation. Activated PKB controls
several cellular events, such as protein and glycogen synthesis,
glucose transport, and cell survival and proliferation.
ER stress interferes with insulin signaling through at least
three mechanisms (Fig.
4
). Activation of JNK by IRE1a results in
serine phosphorylation of IRS proteins, which inhibits IRS
tyrosine phosphorylation by the IR (
59
), recruitment of PI3K to
IRS proteins (
60
), and stimulates degradation of IRS1 (
61
).
Induction of BiP, elevated eIF2a, and PERK phosphorylation in
mouse models of obesity (
59
) show that ER stress is an early
molecular hallmark of the metabolic syndrome. In cultured cells,
saturated fatty acids induce
XBP-1
splicing (
62, 63
), suggesting
that elevated circulating saturated fatty acid levels in obese indi-
viduals (
64
) cause ER stress. Elevated plasma homocysteine in
obese patients is the second cause for ER stress in obesity (
48
).
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