Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice.
Phosphorylation of stress-activated kinase p38, a MAPK family member, was increased in liver of ob/ob diabetic mice relative to lean littermates. Treatment of ob/ob mice with protein tyrosine phosphatase 1B (PTP1B) antisense oligonucleotides (ASO) reduced phosphorylation of p38 in liver-to below lean littermate levels-and normalized plasma glucose while reducing plasma insulin. Phosphorylation of ERK, but not JNK, was also decreased in ASO-treated mice. PTP1B ASO decreased TNFalpha protein levels and phosphorylation of the transcription factor cAMP response element binding protein (CREB) in liver, both of which can occur through decreased phosphorylation of p38 and both of which have been implicated in insulin resistance or hyperglycemia. Decreased p38 phosphorylation was not directly due to decreased phosphorylation of the kinases that normally phosphorylate p38-MKK3 and MKK6. Additionally, p38 phosphorylation was not enhanced in liver upon insulin stimulation of ASO-treated ob/ob mice (despite increased activation of other signaling molecules) corroborating that p38 is not directly affected via the insulin receptor. Instead, decreased phosphorylation of p38 may be due to increased expression of MAPK phosphatases, particularly the p38/ERK phosphatase PAC1 (phosphatase of activated cells). This study demonstrates that reduction of PTP1B protein using ASO reduces activation of p38 and its substrates TNFalpha and CREB in liver of diabetic mice, which correlates with decreased hyperglycemia and hyperinsulinemia.
Gum
Rebecca J
RJ
Abbott Laboratories, Department R-4CK, AP10-1, 100 Abbott Park Road, Abbott Park, Illinois 60064-3502, USA. rebecca.gum@abbott.com
Gaede
Lori L
LL
Heindel
Matthew A
MA
Waring
Jeffrey F
JF
Trevillyan
James M
JM
Zinker
Bradley A
BA
Stark
Margery E
ME
Wilcox
Denise
D
Jirousek
Michael R
MR
Rondinone
Cristina M
CM
Ulrich
Roger G
RG
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D054641:Dual Specificity Phosphatase 2; D007328:Insulin / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009765:Obesity; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011897:Random Allocation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D054641:Dual Specificity Phosphatase 2; C517033:Dusp2 protein, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse