Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues

Bingzhong Xue, Thomas Pulinilkunnil, Incoronata Murano, Kendra K. Bence, Huamei He, Yasuhiko Minokoshi, Kenji Asakura, Anna Lee, Fawaz Haj, Noboru Furukawa, Karyn J. Catalano, Mirela Delibegovic, James A. Balschi, Saverio Cinti, Benjamin G. Neel, Barbara B. Kahn

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

PTP1B-/- mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that α1 and α2 AMPK activity are elevated and acetylcoenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B-/- mice. The effects of PTP1B deficiency on α2, but not α1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B-/- mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B-/- mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.

Original languageEnglish (US)
Pages (from-to)4563-4573
Number of pages11
JournalMolecular and Cellular Biology
Volume29
Issue number16
DOIs
StatePublished - Aug 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Xue, B., Pulinilkunnil, T., Murano, I., Bence, K. K., He, H., Minokoshi, Y., Asakura, K., Lee, A., Haj, F., Furukawa, N., Catalano, K. J., Delibegovic, M., Balschi, J. A., Cinti, S., Neel, B. G., & Kahn, B. B. (2009). Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Molecular and Cellular Biology, 29(16), 4563-4573. https://doi.org/10.1128/MCB.01914-08