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Nutrient-Gene Interactions

New Leptin Receptor Mutations in Mice: Lepr^db-rtnd, Lepr^db-dmpg and Lepr^db-rlpy

Department of Nutrition, The University of Tennessee, Knoxville, TN 37996 and ^* The Jackson Laboratory, Bar Harbor, ME 04609

³To whom correspondence should be addressed. E-mail: jhkim{at}utk.edu.

Three new spontaneous recessive mouse mutations in the leptin receptor gene (Lepr), Lepr^db-rtnd, Lepr^db-dmpg and Lepr^db-rlpy, originated in the CBA/J (CBA), B10.D2-H8^b(57N)/Sn (B10) and NU/J strains, respectively. Lepr^db-rtnd and Lepr^db-dmpg were maintained on C57BL/6J (B6), resulting in congenic lines of B6.CBA-Lepr^db-rtnd and B6.B10-Lepr^db-dmpg. Lepr^db-rtnd was also maintained on CBA post F1 generation of a cross between the B6 and the CBA, generating the congenic line CBA.B6CBA-Lepr^db-rtnd. Lepr^db-rlpy was maintained as a coisogenic strain. The aims of this study were to determine the molecular bases for these new Lepr mutations and to characterize the new mutant stocks, with respect to obesity and diabetes. Mutations were analyzed by Southern blot analysis, reverse transcriptase–polymerase chain reaction and sequencing. Body weights and plasma glucose and insulin levels were measured, and the histology of the pancreas was carried out. Lepr^db-rtnd contained one G deletion in exon 4 of Lepr, introducing a frameshift and premature termination. Lepr^db-dmpg had a deletion in the extracellular domain of Lepr. Lepr^db-rlpy exhibited a large DNA deletion, leading to a complete lack of Lepr. All three mutations led to morbid obesity and diabetes. It is noteworthy that Lepr^db-rtnd caused milder hyperglycemia accompanied by higher plasma and pancreatic insulin contents on B6 compared to that on CBA backgrounds. In summary, we discovered three new mutations of Lepr, providing new mouse models for obesity and diabetes. Furthermore, our mutant stocks will be useful in elucidating the effects of the genetic background on the Lepr mutations and in testing the specificity of antibodies to LEPR.

KEY WORDS: • coisogenic • congenic • Lepr • mice • mutations

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