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Insulin-Like Growth Factor-I Stimulates Both Cell Growth and Lipogenesis during Differentiation of Human Mesenchymal Stem Cells into Adipocytes

Division of Neonatology (L.M.S.), Children’s National Medical Center, George Washington University School of Medicine, Washington, D.C. 20010; BioWhittaker Inc. (M.K.), Walkersville, Maryland 21793; and Diabetes Branch (M.M., D.L.), National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1758

Address all correspondence and requests for reprints to: Derek Le Roith, M.D., Ph.D., Chief, Diabetes Branch, Room 8D12, Building 10, National Institutes of Health, MSC 1758, Bethesda, Maryland 20892-1758. E-mail: derek{at}helix.nih.gov.

Insulin is known to regulate adipocyte differentiation and lipid accumulation, but the specific mechanism by which precursor cells differentiate into adipocytes is not clearly understood. This study evaluated the role of the IGF-I receptor in the process of adipocyte differentiation in bone marrow-derived human mesenchymal stem cells (HMSCs). The results demonstrated that nanomolar concentrations of IGF-I adequately replaced micromolar concentrations of insulin in supporting differentiation and lipid accumulation in HMSCs. The addition of IGF-I specifically increased cell proliferation and lipid accumulation in HMSCs, but a mixture of differentiation factors including dexamethasone, indomethacin, and 3-isobutyl-1-methylxanthine did not. These effects were blocked by the IR-3 antibody, which inhibits IGF-I receptor activity. We also describe the pattern of differentiation with regard to cell growth, lipid accumulation, and morphologic changes and define the changes in these parameters that are influenced by IGF-I. Finally, peroxisome proliferator activating receptor- immunoreactivity was also increased in response to IGF-I, and this effect was blocked in cells treated with the IR-3 antibody. Taken together, these findings suggest that IGF-I plays a critical role in adipocyte differentiation and lipid accumulation.

Abbreviations: Ab, Antibody; C/EBP, CCAAT/enhancer binding protein; D, mix of three differentiation factors of dexamethasone, indomethacin, and IBMX; FBS, fetal bovine serum; HMSC, human mesenchymal stem cell; HMSCGM, HMSC growth medium; IBMX, 3-isobutyl-1-methylxanthine; IGF-BP, IGF binding protein; IGF-IR, IGF-I receptor; IR, insulin receptor; IRS, IR substrate; K_D, dissociation constant; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator activating receptor.

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