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Neuronal PTP1B regulates body weight, adiposity and leptin action

A Corrigendum to this article was published on 01 February 2010

An Addendum to this article was published on 01 February 2010

This article has been updated

Abstract

Obesity is a major health problem and a risk factor for type 2 diabetes. Leptin, an adipocyte-secreted hormone, acts on the hypothalamus to inhibit food intake and increase energy expenditure. Most obese individuals develop hyperleptinemia and leptin resistance, limiting the therapeutic efficacy of exogenously administered leptin. Mice lacking the tyrosine phosphatase PTP1B are protected from diet-induced obesity and are hypersensitive to leptin, but the site and mechanism for these effects remain controversial. We generated tissue-specific PTP1B knockout (Ptpn1−/−) mice. Neuronal Ptpn1−/− mice have reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose PTP1B deficiency increases body weight, whereas PTP1B deletion in muscle or liver does not affect weight. Neuronal Ptpn1−/− mice are hypersensitive to leptin, despite paradoxically elevated leptin levels, and show improved glucose homeostasis. Thus, PTP1B regulates body mass and adiposity primarily through actions in the brain. Furthermore, neuronal PTP1B regulates adipocyte leptin production and probably is essential for the development of leptin resistance.

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Figure 1: Generation and characterization of mice with tissue-specific deletion of PTP1B.
Figure 2: Neuronal Ptpn1−/− mice are lean, and have increased energy expenditure and activity.
Figure 3: Leptin sensitivity and neuropeptide expression in neuronal Ptpn1−/− mice.
Figure 4: Altered adipokine levels in neuronal Ptpn1−/− mice.
Figure 5

Change history

  • 07 January 2010

    In the version of this article initially published, the source of the Nestin-Cre mice was incorrectly stated as Jackson Labs. The correct source of the Nestin-Cre mice (which were on a mixed 129/Sv × C57BL/6 hybrid background) was R. Klein (Max Planck Institute of Neurobiology). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank C. Ronald Kahn (Joslin Diabetes Center) for MCK-Cre mice, H. Keilhack (BIDMC) for advice on ES cell work, and V. Petkova for technical assistance with the real-time PCR. This work was supported by US National Institutes of Health grants DK60838 (to B.G.N.) and DK60839 (to B.B.K.), DK56116 (to B.B.K.), the Physiology Core of DK57521 (to B.B.K.), DK64360 (to G.S.H.), and a Research Grant from the American Diabetes Association (to B.G.N.). K.K.B. was supported by the Charles A. King Trust (The Medical Foundation) and the Boston Obesity and Nutrition Research Center (DK046200). M.D. is the recipient of a postdoctoral fellowship from the American Heart Association.

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Correspondence to Kendra K Bence, Benjamin G Neel or Barbara B Kahn.

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Benjamin G. Neel is a member of the Scientific Advisory Board at Ceptyr, Inc. and holds equity in the company. Barbara B. Kahn is a member of the Scientific Advisory Board at Ceptyr, Inc.

Supplementary information

Supplementary Fig. 1

PTP1B deficiency in peripheral tissues. (PDF 694 kb)

Supplementary Fig. 2

Muscle and liver insulin receptor phosphorylation in neuronal Ptpn1−/− mice. (PDF 82 kb)

Supplementary Methods (PDF 83 kb)

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Bence, K., Delibegovic, M., Xue, B. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12, 917–924 (2006). https://doi.org/10.1038/nm1435

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