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Impaired Activation of Protein Kinase C- by Insulin and Phosphatidylinositol-3,4,5-(PO₄)₃ in Cultured Preadipocyte-Derived Adipocytes and Myotubes of Obese Subjects

Research Service (M.P.S., M.L.S., A.M., G.B., R.V.F.), James A. Haley Hospital Veterans Hospital, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612; Department of Internal Medicine (P.V.), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and Zen-Bio Inc. (D.M.F., R.L.-C.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Robert V. Farese, M.D., Research Service, James A. Haley Hospital Veterans Hospital, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612. E-mail: rfarese{at}hsc.usf.edu.

Insulin resistance in obesity is partly due to diminished glucose transport in myocytes and adipocytes, but underlying mechanisms are uncertain. Insulin-stimulated glucose transport requires activation of phosphatidylinositol (PI) 3-kinase (3K), operating downstream of insulin receptor substrate-1. PI3K stimulates glucose transport through increases in PI-3,4,5-(PO₄)₃ (PIP₃), which activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). However, previous studies suggest that activation of aPKC, but not PKB, is impaired in intact muscles and cultured myocytes of obese subjects. Presently, we examined insulin activation of glucose transport and signaling factors in cultured adipocytes derived from preadipocytes harvested during elective liposuction in lean and obese women. Relative to adipocytes of lean women, insulin-stimulated [³H]2-deoxyglucose uptake and activation of insulin receptor substrate-1/PI3K and aPKCs, but not PKB, were diminished in adipocytes of obese women. Additionally, the direct activation of aPKCs by PIP₃ in vitro was diminished in aPKCs isolated from adipocytes of obese women. Similar impairment in aPKC activation by PIP₃ was observed in cultured myocytes of obese glucose-intolerant subjects. These findings suggest the presence of defects in PI3K and aPKC activation that persist in cultured cells and limit insulin-stimulated glucose transport in adipocytes and myocytes of obese subjects.

Abbreviations: aPKC, Atypical protein kinase C; BMI, body mass index; IRS-1, insulin receptor substrate-1; 3K, 3-kinase; PI, phosphatidylinositol; PIP₃, PI-3,4,5-(PO₄)₃; PKB/Akt, protein kinase B.

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