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

To: Miljenko Zuanic who wrote (578)	10/15/2001 7:47:03 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 3559

No gut, no glory! J Clin Invest, Vol. 108, Issue 8, 1113-1121, October 15, 2001 J Clin Invest, October 2001, Volume 108, Number 8, 1113-1121 Copyright ©2001 by the American Society for Clinical Investigation -------------------------------------------------------------------------------- Article Selective deletion of leptin receptor in neurons leads to obesity Paul Cohen1, Connie Zhao1, Xiaoli Cai1, Jason M. Montez1, S. Christy Rohani1, Paul Feinstein2, Peter Mombaerts2 and Jeffrey M. Friedman1,3 1 Laboratory of Molecular Genetics, 2 Laboratory of Developmental Biology and Neurogenetics, and 3 Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA Address correspondence to: Jeffrey M. Friedman, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, Box 305, New York, New York 10021, USA. Phone: (212) 327-8800; Fax: (212) 327-7420; E-mail: friedj@mail.rockefeller.edu. Received for publication August 6, 2001, and accepted in revised form September 10, 2001. Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin’s effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObRSynIKO) and hepatocyte-specific (ObRAlbKO) disruption of ObR. Among the ObRSynIKO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObRAlbKO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObRSynIKO mice have enlarged fatty livers, ObRAlbKO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.