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Biotech / Medical : Regeneron Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (746)	2/22/2003 2:08:22 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 3557

Nature 421, 856 - 859 (2003); doi:10.1038/nature01388 STAT3 signalling is required for leptin regulation of energy balance but not reproduction SARAH H. BATES, WALTER H. STEARNS, TREVOR A. DUNDON, MARKUS SCHUBERT, ANNETTE W. K. TSO, YONGPING WANG†, ALEXANDER S. BANKS, HUGH J. LAVERY, ASMA K. HAQ, ELEFTHERIA MARATOS-FLIER, BENJAMIN G. NEEL†, MICHAEL W. SCHWARTZ‡ & MARTIN G. MYERS JR * Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA † Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, 1 Joslin Place, Boston, Massachusetts 02215, USA ‡ Harborview Medical Center, University of Washington, Seattle, Washington 98122, USA Correspondence and requests for materials should be addressed to M.G.M. (e-mail: martin.myers@joslin.harvard.edu). Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes1-4. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action5-8. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (leprS1138) that specifically disrupts the LRb–STAT3 signal. Here we show that, like db/db mice, leprS1138 homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb–STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.