Involvement of AMP-Activated Protein Kinase in Glucose Uptake Stimulated by the Globular Domain of Adiponectin in Primary Rat Adipocytes

  1. Xiangdong Wu1,
  2. Hiroyuki Motoshima1,
  3. Kalyankar Mahadev1,
  4. Timothy J. Stalker2,
  5. Rosario Scalia2 and
  6. Barry J. Goldstein1
  1. 1Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania
  2. 2Department of Physiology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

    Abstract

    Adiponectin is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties that suppresses hepatic glucose production and enhances glucose uptake into skeletal muscle. To characterize the potential effects of adiponectin on glucose uptake into adipose cells, we incubated isolated epididymal rat adipocytes with the globular domain of recombinant adiponectin purified from an E. coli expression system. Globular adiponectin increased glucose uptake in adipocytes without stimulating tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1, and without enhancing phosphorylation of Akt on Ser-473. Globular adiponectin further enhanced insulin-stimulated glucose uptake at submaximal insulin concentrations and reversed the inhibitory effect of tumor necrosis factor-α on insulin-stimulated glucose uptake. Cellular treatment with globular adiponectin increased the Thr-172 phosphorylation and catalytic activity of AMP-activated protein kinase and enhanced the Ser-79 phosphorylation of acetyl CoA carboxylase, an enzyme downstream of AMP kinase in adipose cells. Inhibition of AMP kinase activation using two pharmacological inhibitors (adenine 9-β-d-arabinofuranoside and compound C) completely abrogated the increase in glucose uptake stimulated by globular adiponectin, indicating that AMP kinase is integrally involved in the adiponectin signal transduction pathway. Coupled with recent evidence that the effects of adiponectin are mediated via AMP kinase activation in liver and skeletal muscle, the findings reported here provide an important mechanistic link in the signaling effects of adiponectin in diverse metabolically responsive tissues.

    Footnotes

    • Address correspondence and reprint requests to Dr. Barry J. Goldstein, Director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Rm. 349 Alumni Hall, 1020 Locust St., Philadelphia, PA 19107-6799. E-mail: barry.goldstein{at}mail.tju.edu.

      Received for publication 13 December 2002 and accepted in revised form 28 February 2003.

      ACC, acetyl CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; AMP kinase, AMP-activated protein kinase; araA, adenine 9-β-d-arabinofuranoside; IRS-1, insulin receptor substrate-1; KRBH, Krebs-Ringer bicarbonate HEPES; PVDF, polyvinylidine fluoride; TNF-α, tumor necrosis factor-α.

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