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

Mol. Cell. Biol., 1 April 2010
Vol. 30, Issue 7, p. 1650-1659
DOI: 10.1128/MCB.01307-09

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

  1. Jia You1,
  2. Yue Yu1,
  3. Lei Jiang1,
  4. Wenxia Li1,
  5. Xinxin Yu2,
  6. Lety Gonzalez2,
  7. Guoqing Yang2,,
  8. Zunji Ke1,
  9. Wenjun Li1,
  10. Cai Li2,* and
  11. Yong Liu1,*
  1. 1Key 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
  2. 2Touchstone Center for Diabetes Research, Departments of Physiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854

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.

FOOTNOTES

    • Received 28 September 2009.
    • Returned for modification 13 November 2009.
    • Accepted 11 January 2010.
  • *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
  • Present address: Biomedical Sciences Institute, Agency for Science, Technology and Research, Singapore, Singapore.

  • Published ahead of print on 19 January 2009.

Citation:

J. You, Y. Yu, L. Jiang, W. Li, X. Yu, L. Gonzalez, G. Yang, Z. Ke, W. Li, C. Li, and Y. Liu, Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance . Mol. Cell. Biol. 30, 1650-1659 (2010).

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