Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis.
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 (p85alpha) 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.
Rondinone
Cristina M
CM
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. cristina.rondinone@abbott.com
Trevillyan
James M
JM
Clampit
Jill
J
Gum
Rebecca J
RJ
Berg
Cathy
C
Kroeger
Paul
P
Frost
Leigh
L
Zinker
Bradley A
BA
Reilly
Regina
R
Ulrich
Roger
R
Butler
Madeline
M
Monia
Brett P
BP
Jirousek
Michael R
MR
Waring
Jeffrey F
JF
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000503:physiopathology*; D017398:Alternative Splicing; D000818:Animals; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D014644:Genetic Variation; D006706:Homeostasis; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis*; D051379:Mice; D008820:Mice, Obese; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D015431:Weight Loss / Q000502:physiology*
D017931:DNA Primers; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D007527:Isoenzymes; D008055:Lipids; D020319:Oligodeoxyribonucleotides, Antisense; D010750:Phosphoproteins; D014280:Triglycerides; D019869:Phosphatidylinositol 3-Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse