Reduction of hypothalamic protein tyrosine phosphatase improves insulin and leptin resistance in diet-induced obese rats

Endocrinology. 2008 Aug;149(8):3870-80. doi: 10.1210/en.2007-1506. Epub 2008 May 8.


Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats.

MeSH terms

  • Adiposity / drug effects
  • Adiposity / genetics
  • Animals
  • Body Weight / drug effects
  • Body Weight / genetics
  • Diet, Atherogenic
  • Drug Resistance / drug effects*
  • Drug Resistance / genetics
  • Eating / drug effects
  • Eating / genetics
  • Glucose / metabolism
  • Hypothalamus / drug effects*
  • Hypothalamus / enzymology
  • Hypothalamus / metabolism
  • Injections, Intraventricular
  • Insulin / pharmacology*
  • Leptin / pharmacology*
  • Male
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / pathology*
  • Oligonucleotides, Antisense / pharmacology
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / genetics
  • Rats
  • Rats, Wistar
  • Satiation / drug effects
  • Signal Transduction / drug effects


  • Insulin
  • Leptin
  • Oligonucleotides, Antisense
  • Protein Tyrosine Phosphatases
  • Glucose