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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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.
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.
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Kuo, L., Kitlinska, J., Tilan, J. et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 13, 803–811 (2007). https://doi.org/10.1038/nm1611
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