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J Biol Chem, Vol. 273, Issue 29, 18365-18373, July 17, 1998

Altered Cell Surface Expression and Signaling of Leptin Receptors Containing the fatty Mutation

Jill A. Crouse, Gary E. Elliott^§, Teresa L. Burgess^¶, Laura Chiu^§, Larry Bennett, Jason Moore^**, Margery Nicolson^**, and Robert E. Pacifici

From the  Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90033 and the Departments of ^§ Cell Biology, ^¶ Mammalian Cell Molecular Biology,  Molecular Genomics, ^** Neuroscience, and  Computational Biology, Amgen Inc., Thousand Oaks, California 91320

Leptin and the leptin receptor are key players in the regulation of body weight. In an attempt to dissect the molecular mechanism of the Zucker fatty rat leptin receptor mutation (Gln²⁶⁹  Pro) we analyzed the effects of this mutation on leptin receptor signaling and expression in three different expression systems: 1) 32D cells expressing leptin/erythropoietin receptor chimeras, 2) COS-7 cells expressing a leptin receptor short form, and 3) 293 cells expressing soluble receptor forms. To determine if the Gln²⁶⁹  Pro mutation is critical for the observed phenotype, we made a similar Gln  Pro mutation at a vicinal residue two amino acids upstream of the fatty mutation to see if it would have similar effects. Incorporation of either of the Gln  Pro mutations into wild type receptor forms did not interfere with leptin binding, but it resulted in a signaling-incompetent receptor. In addition, the majority of the mutant receptor protein was localized intracellularly. Our results suggest that the obese phenotype resulting from the Gln²⁶⁹  Pro mutation in the leptin receptor of the Zucker fatty rat may be due not only to a reduced cell surface expression of this form of the leptin receptor, but also to a post-leptin binding malfunction of the receptor that interferes with subsequent signal transduction.

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