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Diabetes 51:2405-2411, 2002
© 2002 by the American Diabetes Association, Inc.

Protein Tyrosine Phosphatase 1B Reduction Regulates Adiposity and Expression of Genes Involved in Lipogenesis

Cristina M. Rondinone1, James M. Trevillyan1, Jill Clampit1, Rebecca J. Gum1, Cathy Berg1, Paul Kroeger1, Leigh Frost1, Bradley A. Zinker1, Regina Reilly1, Roger Ulrich1, Madeline Butler2, Brett P. Monia2, Michael R. Jirousek1, and Jeffrey F. Waring1

1 Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois
2 Isis Pharmaceuticals, Carlsbad, California

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin action. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity and are resistant to weight gain. To investigate the role of PTP1B in adipose tissue from obese animals, hyperglycemic obese (ob/ob) mice were treated with PTP1B antisense oligonucleotide (ISIS-113715). A significant reduction in adiposity correlated with a decrease of PTP1B protein levels in fat. Antisense treatment also influenced the triglyceride content in adipocytes, correlating with a downregulation of genes encoding proteins involved in lipogenesis, such as sterol regulatory element-binding protein 1 and their downstream targets spot14 and fatty acid synthase, as well as other adipogenic genes, lipoprotein lipase, and peroxisome proliferator-activated receptor {gamma}. In addition, an increase in insulin receptor substrate-2 protein and a differential regulation of the phosphatidylinositol 3-kinase regulatory subunit (p85{alpha}) isoforms expression were found in fat from antisense-treated animals, although increased insulin sensitivity measured by protein kinase B phosphorylation was not observed. These results demonstrate that PTP1B antisense treatment can modulate fat storage and lipogenesis in adipose tissue and might implicate PTP1B in the enlargement of adipocyte energy stores and development of obesity.


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