Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced
insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of
insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the
insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and
insulin-stimulated conditions. We found that the levels of relevant signaling
proteins, such as
insulin receptor (IR), IR substrate-1 (IRS-1),
phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and
phosphatase and
tensin homolog (PTEN) did not change at late pregnancy. However,
insulin-stimulated
tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse
thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at
serine 307 and a decrease in
adiponectin levels. To corroborate the role of IRS-1 in adipose tissue
insulin resistance during pregnancy, we treated pregnant rats with the
antidiabetic drug englitazone.
Englitazone improved
glucose tolerance, and this pharmacological reversal of
insulin resistance was paralleled by an increase of
adiponectin levels in adipose tissue as well as by a reduction of IRS-1
serine phosphorylation. Furthermore, the impaired
insulin-stimulated
tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with
adiponectin. Together, our findings support a role for
adiponectin and
serine phosphorylation of IRS-1 in the modulation of
insulin resistance in adipose tissue at late pregnancy.