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Pro Extracellular Domain Mutation of the Fatty Rat1
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 glnpro and
Ob-Ra269 glnpro have decreased cell-surface expression
and decreased leptin binding affinity. Ob-Rb269 glnpro
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 glnpro was observed for
activation of egr-1-luc but only under conditions when
JAK2 was coexpressed with Ob-Rb269 glnpro. Finally,
Ob-Ra269 glnpro has an increased ability to internalize
leptin but is less efficient at degrading leptin, as compared with
Ob-Ra. In conclusion, both Ob-Ra269 glnpro and
Ob-Rb269 glnpro have multiple functional defects.
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