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Mol. Cell. Biol. 30 (7): 1650-1659

Copyright © 2010 by the American Society for Microbiology. All rights reserved.

Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance{triangledown}

Jia You,1 Yue Yu,1 Lei Jiang,1 Wenxia Li,1 Xinxin Yu,2 Lety Gonzalez,2 Guoqing Yang,2,{ddagger} Zunji Ke,1 Wenjun Li,1 Cai Li,2*, and Yong Liu1*

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, and Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China,1 Touchstone Center for Diabetes Research, Departments of Physiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-88542

Received for publication 28 September 2009. Revision received 13 November 2009. Accepted for publication 11 January 2010.

Abstract: Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.

* Corresponding author. Mailing address for Yong Liu: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China. Phone: (086) 21-54920244. Fax: (086) 21-54920291. E-mail: liuy{at}sibs.ac.cn. Mailing address for Cai Li: Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. Phone: (732) 594-2862. Fax: (732) 594-3570. E-mail: cai_li{at}merck.com

{triangledown} Published ahead of print on 19 January 2009.

{ddagger} Present address: Biomedical Sciences Institute, Agency for Science, Technology and Research, Singapore, Singapore.

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