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Endocrinology Vol. 139, No. 9 3681-3690
Copyright © 1998 by The Endocrine Society

ARTICLES

Functional Properties of Leptin Receptor Isoforms Containing the Gln->Pro Extracellular Domain Mutation of the Fatty Rat1

Barbara A. da Silva2, Christian Bjørbæk2, Shigeo Uotani and Jeffrey S. Flier

Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Jeffrey S. Flier, M.D., Division of Endocrinology, Center, RN, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: jflier{at}bidmc.harvard.edu

Mutations of the leptin receptor have been found to cause obesity in rodents. The fa mutation that is responsible for obesity in Zucker rats is a missense mutation (269 gln->pro) in the extracellular domain of the leptin receptor. We have characterized the effects of this mutation on the two major isoforms of the leptin receptor, Ob-Rb and Ob-Ra, by studying cell-surface expression, leptin binding affinity, signaling capacity, and receptor-mediated internalization and degradation of leptin in transfected mammalian cell lines. Both Ob-Rb269 gln->pro and Ob-Ra269 gln->pro have decreased cell-surface expression and decreased leptin binding affinity. Ob-Rb269 gln->pro was shown to have defective signaling to the JAK-STAT pathway and markedly diminished ability to activate transcription of the egr-1 promoter. Constitutive ligand-independent activation of Ob-Rb269 gln->pro was observed for activation of egr-1-luc but only under conditions when JAK2 was coexpressed with Ob-Rb269 gln->pro. Finally, Ob-Ra269 gln->pro has an increased ability to internalize leptin but is less efficient at degrading leptin, as compared with Ob-Ra. In conclusion, both Ob-Ra269 gln->pro and Ob-Rb269 gln->pro have multiple functional defects.




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