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VOL. 73 (4), 987-1008, 2007 CONTRIBUTION OF TNF-a TO OBESITY...

LACK OF PTP1B CONFERS PROTECTION AGAINST TNF-a-
INDUCED INSULIN RESISTANCE IN SKELETAL MUSCLE

In pathological insulin-resistant states such as obesity, PTP1B
expression and activity are increased in muscle and WAT of humans
and rodents (27). Moreover, noncoding polymorphisms in the PTP1B
gene have been found in different populations, displaying increased
phosphatase muscle expression and being associated with insulin
resistance (28). In this regard, transgenic overexpression of ptp1b in
muscle causes insulin resistance, showing impaired insulin signaling
and decreased glucose uptake in this tissue (29). By contrast, mice
lacking PTP1B exhibit increased insulin sensitivity at 12 wk of age
(attributable to enhanced phosphorylation of IR in liver and skeletal
muscle), resistance to weight gain on a high-fat diet, and an
increased basal metabolic rate (30, 31). The PTP1B-deficient mice
had circulating insulin concentrations that were about half those of
control animals. Thus, these mice appeared to be more insulin
sensitive, because they maintained lower glucose concentration with
significantly reduced amounts of insulin. In the fasted state, there
were no significant differences in concentrations of glucose or insulin
(30). Furthermore, PTP1B-deficiency also reduces the diabetic
phenotype in mice with polygenic insulin resistance (32). Moreover,
treatment with PTP1B antisense oligonucleotide improves insulin
sensitivity in db/db mice and increases insulin signaling in WAT and
liver in ob/ob mice (33).

The fact that primary neonatal myotubes developed in our
laboratory have provided a unique tool for in vitro study of insulin
sensitivity (24), prompted us to generate immortalized myocytes
from wild-type and PTP1B-deficient neonates. Cell lines lacking
PTP1B display enhanced insulin sensitivity in IR autophosphoryla-
tion and downstream signaling, including IRS-1 and IRS-2 tyrosine
phosphorylation, PI3K associated activation and AKT serine/
threonine phosphorylation. The phosphorylation was detected at
lower insulin doses and at shorter times in PTP1B-deficient cells
than in wild-type cells (34). Because activation of PI3K and AKT
controls glucose transport, we detect an increased insulin-stimulated
glucose uptake and GLUT4 translocation to plasma membrane in
PTP1B–/– cells versus wild-type cells (34). This result was not

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