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

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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 alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, 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
Pages (from-to)4563-4573
Number of pages11
JournalMolecular and Cellular Biology
Volume29
Issue number16
Early online date15 Jun 2009
DOIs
Publication statusPublished - Aug 2009

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
AMP-Activated Protein Kinases
Protein Isoforms
Leptin
Brown Adipose Tissue
Energy Metabolism
Muscles
Acetyl-CoA Carboxylase
Thinness
Adiposity
Organelle Biogenesis
Neuropeptides
Hypothalamus
Hypersensitivity
Fatty Acids
Obesity
Diet
Gene Expression
Neurons

Keywords

  • AMP-activated protein kinases
  • adipose tissue, brown
  • animals
  • body weight
  • enzyme activation
  • hypothalamus
  • isoenzymes
  • male
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • muscle, skeletal
  • neurons
  • protein tyrosine phosphatase, non-receptor type 1
  • signal transduction
  • tissue distribution

Cite this

Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. / Xue, Bingzhong; Pulinilkunnil, Thomas; Murano, Incoronata; Bence, Kendra K; He, Huamei; Minokoshi, Yasuhiko; Asakura, Kenji; Lee, Anna; Haj, Fawaz; Furukawa, Noboru; Catalano, Karyn J; Delibegovic, Mirela; Balschi, James A; Cinti, Saverio; Neel, Benjamin G; Kahn, Barbara B.

In: Molecular and Cellular Biology, Vol. 29, No. 16, 08.2009, p. 4563-4573.

Research output: Contribution to journalArticle

Xue, B, Pulinilkunnil, T, Murano, I, Bence, KK, He, H, Minokoshi, Y, Asakura, K, Lee, A, Haj, F, Furukawa, N, Catalano, KJ, Delibegovic, M, Balschi, JA, Cinti, S, Neel, BG & Kahn, BB 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, vol. 29, no. 16, pp. 4563-4573. https://doi.org/10.1128/MCB.01914-08
Xue, Bingzhong ; Pulinilkunnil, Thomas ; Murano, Incoronata ; Bence, Kendra K ; He, Huamei ; Minokoshi, Yasuhiko ; Asakura, Kenji ; Lee, Anna ; Haj, Fawaz ; Furukawa, Noboru ; Catalano, Karyn J ; Delibegovic, Mirela ; Balschi, James A ; Cinti, Saverio ; Neel, Benjamin G ; Kahn, Barbara B. / Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. In: Molecular and Cellular Biology. 2009 ; Vol. 29, No. 16. pp. 4563-4573.
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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 alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, 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.",
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T1 - Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues

AU - Xue, Bingzhong

AU - Pulinilkunnil, Thomas

AU - Murano, Incoronata

AU - Bence, Kendra K

AU - He, Huamei

AU - Minokoshi, Yasuhiko

AU - Asakura, Kenji

AU - Lee, Anna

AU - Haj, Fawaz

AU - Furukawa, Noboru

AU - Catalano, Karyn J

AU - Delibegovic, Mirela

AU - Balschi, James A

AU - Cinti, Saverio

AU - Neel, Benjamin G

AU - Kahn, Barbara B

PY - 2009/8

Y1 - 2009/8

N2 - 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 alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, 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.

AB - 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 alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, 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.

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KW - animals

KW - body weight

KW - enzyme activation

KW - hypothalamus

KW - isoenzymes

KW - male

KW - mice

KW - mice, inbred C57BL

KW - mice, knockout

KW - muscle, skeletal

KW - neurons

KW - protein tyrosine phosphatase, non-receptor type 1

KW - signal transduction

KW - tissue distribution

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DO - 10.1128/MCB.01914-08

M3 - Article

C2 - 19528236

VL - 29

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JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

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ER -