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

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.

We thank J. Repa (UTSW) for animal care and handling, J. Shen (INS, CAS) for assistance with CLAMS, and X. Y. Lu (UTHSC) for insightful discussions.

This work was supported by grants from the National Natural Science Foundation (no. 30988002, 30830033, and 90713027), the Ministry of Science and Technology (973 Programs 2006CB503900 and 2007CB947100), the Chinese Academy of Sciences (Knowledge Innovation Programs KSCX1-YW-02 and KSCX2-YW-R-115, CS Program SIBS2008006, and CAS/SAFEA International Partnership Program), and the Science and Technology Commission of Shanghai Municipality (no. 08dj1400601) to Y.L., W.L., and Z.K. and by NIH grant R01-DK60137 to C.L.