Abstract
To investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-beta subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes.
Highlights
Reduction of low-molecularweight protein tyrosine phosphatase (LMW-protein tyrosine phosphatase (PTP)) expression enhances insulin signaling in mouse hepatocytes- To investigate the role of LMW-PTP in insulin signaling, mouse primary hepatocytes were transfected with LMW-PTP antisense oligonucleotide (ASO) or vehicle
To further confirm that these insulin enhancing effects were secondary to a specific antisense reduction of LMW-PTP, we evaluated the effect of second ASO (#2) that was targeted to a different region of the LMW-PTP mRNA
The results presented in this study demonstrate for the first time that LMW-PTP is a key negative regulator of insulin signaling in vivo and reduction of its expression can improve hyperglycemia and insulin sensitivity in insulin-resistant diet-induced obese (DIO) and ob/ob mice
Summary
Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-β subunit, PI3-kinase, and Akt in response to insulin stimulation. Western blot analysis revealed that there was no significant difference in the protein levels of both these phosphatases between LMW-PTP ASO treatment group and saline or control ASO treatment group in liver or fat tissues of DIO mice (Fig. 2B, upper and middle panels).
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