Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy

• Published in: Endocrinology (Philadelphia) 2007-12, Vol.148 (12), p.5933-5942
• Main Authors: Sevillano, Julio, de Castro, Javier, Bocos, Carlos, Herrera, Emilio, Ramos, M. Pilar
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 3-Phosphoinositide-Dependent Protein Kinases; Adaptor Proteins, Signal Transducing - metabolism; Adipocytes; Adiponectin; Adiponectin - metabolism; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; AKT protein; Animals; Benzopyrans - pharmacology; Biological and medical sciences; Body fat; Body Weight - drug effects; Corrosion resistance; Diabetes mellitus; Extracellular signal-regulated kinase; Female; Fundamental and applied biological sciences. Psychology; Glucose tolerance; Glucose Tolerance Test; Hypoglycemic Agents - pharmacology; Immunoblotting; Immunoprecipitation; Insulin; Insulin - pharmacology; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins; Insulin receptors; Insulin Resistance; Kinases; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular modelling; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Phosphorylation - drug effects; Pregnancy; Protein-Serine-Threonine Kinases - metabolism; Protein-tyrosine-phosphatase; PTEN Phosphohydrolase - metabolism; PTEN protein; Rats; Rats, Sprague-Dawley; Receptor, Insulin - metabolism; Receptors; Serine; Serine - metabolism; Thiazolidinediones - pharmacology; Thymoma; Tyrosine; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-0352

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.