Tyrosine-dependent and -independent actions of leptin receptor in control of energy balance and glucose homeostasis

Lei  Jiang; Jia  You; Xinxin  Yu; Lety  Gonzalez; Yue  Yu; Qiong  Wang; Guoqing  Yang; Wenjun  Li; Cai  Li; Yong  Liu

doi:10.1073/pnas.0804589105

New Research In

↵¹L.J. and J.Y. contributed equally to this work.
Edited by Roger H. Unger, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 16, 2008 (received for review May 13, 2008)

Abstract

Leptin regulates energy balance and glucose metabolism by activation of multiple signaling cascades mediated by the long-form leptin receptor Ob-Rb. However, the whole spectrum of signaling actions through the 3 cytoplasmic tyrosines of mouse Ob-Rb remains to be completely defined in vivo. Here, we generated 2 knockin lines of mice expressing mutant leptin receptors with phenylalanine substitution for all 3 tyrosines (Y123F) or for Tyr¹¹³⁸ alone (Y3F). Y123F animals developed overt obesity similar to that of Y3F animals with abrogated hypothalamic activation of STAT3 by leptin, but they exhibited more severe impairment in glucose tolerance. In striking contrast to db/db mice, however, both Y123F and Y3F mice showed attenuated adiposity with reduced hyperphagia, marked improvement in physical activity and adaptive thermogenesis, and significantly ameliorated glycemic control. Further, Y123F mice had hypothalamic neuropeptide Y/agouti-related protein expression maintained at prominently lower levels compared with db/db mice. Thus, these results provide direct physiological evidence that Ob-Rb exerts crucial metabolic actions not only through tyrosine-dependent, but also tyrosine-independent mechanisms in control of energy balance and glucose homeostasis.

Footnotes

³To whom correspondence may be sent at the present address: Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065. E-mail: cai_li{at}merck.com
⁴To whom correspondence may be addressed. E-mail: liuy{at}sibs.ac.cn
Author contributions: W.L., C.L., and Y.L. designed research; L.J., J.Y., X.Y., L.G., Y.Y., Q.W., and G.Y. performed research; L.J., J.Y., C.L., and Y.L. analyzed data; and L.J., J.Y., C.L., and Y.L. wrote the paper.
↵²Present address: Biomedical Sciences Institute, Agency for Science, Technology and Research, Singapore.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
© 2008 by The National Academy of Sciences of the USA