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Molecular and Cellular Biology, August 2009, p. 4563-4573, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01914-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Neuronal Protein Tyrosine Phosphatase 1B Deficiency Results in Inhibition of Hypothalamic AMPK and Isoform-Specific Activation of AMPK in Peripheral Tissues{triangledown} ,{dagger}

Bingzhong Xue ,1,{ddagger},§ Thomas Pulinilkunnil,1,{ddagger},¶ Incoronata Murano,2 Kendra K. Bence,3,|| Huamei He,4,# Yasuhiko Minokoshi,1,{dagger}{dagger} Kenji Asakura,1 Anna Lee,1 Fawaz Haj,3,{ddagger}{ddagger} Noboru Furukawa,1 Karyn J. Catalano,1 Mirela Delibegovic,3,§§ James A. Balschi,4 Saverio Cinti,2 Benjamin G. Neel,3* and Barbara B. Kahn1*

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215,1 University of Ancona, Ancona 60020, Italy,2 Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215,3 Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 022154

Received 19 December 2008/ Returned for modification 27 January 2009/ Accepted 2 June 2009

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 {alpha}1 and {alpha}2 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 {alpha}2, but not {alpha}1, 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.

* Corresponding author. Mailing address for Barbara B. Kahn: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 735-3324. Fax: (617) 735-3323. E-mail: bkahn{at}bidmc.harvard.edu. Present address for Benjamin G. Neel: Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto Medical Discovery Tower, 101 College St. East Tower, Rm. 8-301, Toronto, Ontario M5G 1L7, Canada. Phone: (416) 581-7710. Fax: (416) 595-5719. E-mail: bneel{at}uhnresearch.ca

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

§ Present address: Department of Internal Medicine, Section on Endocrinology and Metabolism, Wake Forest University School of Medicine, Nutrition Research Center G64, Medical Center Blvd., Winston-Salem, NC 27157.

Present address: Department of Pediatrics, 430 Heritage Medical Research Center, University of Alberta, 112 St. and 87 Ave., Edmonton, AB T6G 2S2, Canada.

|| Present address: Department of Animal Biology, University of Pennsylvania, School of Veterinary Medicine, 3800 Spruce St., Philadelphia, PA 19104.

# Present address: Department of Anesthesia, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave., Enders Rm. 1209, Boston, MA 02115.

{dagger}{dagger} Present address: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.

{ddagger}{ddagger} Present address: Nutrition Department, University of California Davis, 3135 Meyer Hall, One Shields Ave., Davis, CA 95616.

§§ Present address: University of Aberdeen, College of Life Science and Medicine, IBES, Integrative Physiology, Aberdeen AB2Y 2T2, United Kingdom.

Molecular and Cellular Biology, August 2009, p. 4563-4573, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01914-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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