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Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome

Nature Medicine volume 13, pages 803811 (2007) | Download Citation


  • A Corrigendum to this article was published on 01 September 2007

This article has been updated


The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

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Change history

  • 24 July 2007

    Nat. Med. 13, 803-811 (2007); published online 1 July; corrected after print 24 July 2007. The version of this article initially published contained several typographical errors affecting figure citations, units of measure and figure legends, none of which change the scientific conclusions of the manuscript in any way. In addition, the authors incorrectly stated that they had no competing financial interests. A proper description of these competing interests, as is required by journal policy, has now been attached to the HTML version of the article, and the typographical errors have been corrected in the HTML and PDF versions.


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We thank J.F. Mill, A.K. Myers and P.C. Fox for editorial comments, M. Czarnecka for assisting with graphical aspects of the figures, A.-M. Hageny for assistance with catecholamine assays, M.D. Lane (Johns Hopkins) for 3T3-L1 preadipocytes, W. Rasband for NIH ImageJ and plug-ins, M. Abramoff for VolumeJ plug-in, and F. Bunz (Johns Hopkins) for pAdTrack-Cre. This work was supported by US National Institutes of Health (NIH) grants HL067357 and HL055310 to Z.Z., NIH grant DE016050 and PSEF National Endowment Grant to S.B.B., a Predoctoral Mid-Atlantic Fellowship from the American Heart Association to L.K., and Slovak Research and Development Agency grant APVV0148-06 to R.K.

Author information

Author notes

    • Edward W Lee

    Present address: Department of Radiology, David Geffen School of Medicine at the University of California, Los Angeles, 10833 Le Conte Ave., Box 951721, Los Angeles, California 90095, USA.


  1. Department of Physiology & Biophysics, Georgetown University Medical Center, 3900 Reservoir Rd. NW, BSB 234, Washington, DC 20057, USA.

    • Lydia E Kuo
    • , Joanna B Kitlinska
    • , Jason U Tilan
    • , Lijun Li
    • , Edward W Lee
    •  & Zofia Zukowska
  2. Department of Plastic Surgery, Georgetown University Medical Center, 3900 Reservoir Rd. NW, 1 PHC, Washington, DC, 20007, USA.

    • Stephen B Baker
  3. Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Rd., NW W326A NRB, Washington, DC 20007, USA.

    • Michael D Johnson
  4. Cardiovascular Research Institute, MedStar Research Institute, 108 Irving Street NW, Room 214, Washington, DC 20010, USA.

    • Mary Susan Burnett
  5. Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd., NW WB-01 NRB, Washington, DC 20007, USA.

    • Stanley T Fricke
  6. Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06, Bratislava, Slovak Republic.

    • Richard Kvetnansky
  7. Garvan Institute of Medical Research, 384 Victoria St., NSW 2010 Darlinghurst, Sydney, Australia.

    • Herbert Herzog


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L.E.K. carried out most of the experiments (as her PhD thesis work); developed stress models; established adipocyte-endothelial-neuronal co-cultures; together with S.T.F., adapted the MRI technique to the assessment of fat volumes; prepared most of the figures; and wrote major parts of the manuscript. J.U.T. contributed to many experiments using stress models, and assisted with harvesting tissues and adenoviral vectors. J.B.K. designed primers for RT-PCR; carried out molecular analyses; assisted with adipocyte-endothelial-neuronal co-cultures; and made major contributions to experimental design, data analyses, interpretation and presentation, and manuscript writing. L.L. performed NPY ELISA measurements, developed and carried out immunocytochemistry protocols, and contributed to data analyses and interpretation. S.B.B. provided human fat tissue derived from plastic surgeries that he had performed, together with M.D.J.; established a xenograft model of human fat growth in nude mice; and made major conceptual contribution to the clinical significance of the study for fat grafting and remodeling. M.D.J. contributed to all aspects dealing with human fat, and was instrumental in the adenoviral work by providing the vectors, measuring viral titers and training L.E.K. in experimental techniques. E.W.L. started the project and carried out experiments on genetically obese B6.V-Lepob/J mice. M.S.B. carried out resistin analyses and contributed to discussions of stress effects on inflammation and metabolic syndrome. H.H. developed and provided the Npy−/− and Npy2rlox/lox mice for the study, trained J.U.T. in preparing adenoviral vectors, and contributed to discussion of the results. S.T.F. developed the MRI protocol for analyzing fat and contributed to discussion of the results. R.K. supervised catecholamine assays and contributed to analyses, interpretation and discussion of the data dealing with glucocorticoids and adrenergic system. Z.Z. developed the idea for and supervised the study, designed protocols, developed collaborations and wrote the manuscript.

Competing interests

Z.Z., L.E.K., S.B.B., M.D.J. and E.W.L. are listed as the inventors on the patent application “Compositions and Methods for Lipomodeling”, PCT/US2006/021873, filed 14 December 2006 by Georgetown University and based on the work described in this paper.

Corresponding author

Correspondence to Zofia Zukowska.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Npy and Npy2r expression and actions in adipocytes and endothelial cells in vitro and in vivo.

  2. 2.

    Supplementary Fig. 2

    Metabolic and neurohormonal effects of chronic stress, HFS and intra-fat Npy2r inhibition or deletion.

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