A Novel Leptin Receptor Variant with a Conservative Amino Acid Substitution (I359 V) in Body Weight Selected and Unselected Mouse Lines

U. Reichart; U. Renne; B. Aigner; J. Kratzsch; G. A. Brockmann

doi:10.1055/s-2003-41754

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2003; 111(5): 283-287
DOI: 10.1055/s-2003-41754

Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

A Novel Leptin Receptor Variant with a Conservative Amino Acid Substitution (I359 V) in Body Weight Selected and Unselected Mouse Lines

U. Reichart¹ , U. Renne² , B. Aigner³ , J. Kratzsch⁴ , G. A. Brockmann²

¹Ludwig-Boltzmann Institute for Immuno-, Cyto- and Molecular Genetic Research Vienna,Vienna, Austria
²Research Institute for the Biology of Farm Animals, Dummerstorf, Germany
³Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
⁴Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany

Abstract

Recently published results revealed linkage of obesity traits to a chromosomal region near the leptin receptor gene (Lepr) locus in high body weight selected big and fat DU6i mice. The purpose of this study was the search for variants of the Lepr gene in selected and unselected mouse lines as a candidate for different body composition traits. The complete Lepr cDNA sequence was analysed in DU6i mice. In addition, body weight, abdominal fat weight and serum leptin levels were measured in 42 day old, male mice of the strains DU6i, DUKs, Him : OF1 and DBA/2. Sequence comparison to the published wild type sequence revealed three silent mutations and an amino acid exchange (I359 V) in the C2 domain of the putative leptin binding site in the line DU6i. Compared to the high body weight selected mice also unselected lean control DUKs mice and Him : OF1 mice harbour the amino acid substitution, although they show significantly lower values for body weight, abdominal fat weight and serum leptin levels. Therefore, we assume that the mutation in the C2 domain of Lepr alone might not result in impaired leptin binding or signaling.

Key words

Leptin receptor - obesity - polymorphism

Full Text

References

1 Brockmann G A, Haley C, Renne U, Knott S A, Schwerin M. QTLs affecting body weight and fatness from a mouse line selected for high growth. Genetics. 1998; 150 369-381
2 Brockmann G A, Kratzsch J, Haley C S, Renne U, Schwerin M, Karle S. Single QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F₂ variance of growth and obesity in DU6i x DBA/2 mice. Genome Res. 2000; 10 1941-1957
3 Brown J A, Chua Jr S C, Liu S M, Andrews M T, Vanderbergh J G. Spontaneous mutation in the db gene results in obesity and diabetes in CD-1 outbred mice. Am J Physiol Regul Integr Comp Physiol. 2000; 278 R320-R330
4 Bunger L, Herrendörfer G, Renne U. Results of long term selection for growth traits in laboratory mice. Edinburgh, Scotland: Proceedings of the 4th World Congress on Genetics Applied to Livestock Production. 1990; 13 321-324
5 Bunger L, Laidlaw A, Bulfield G, Eisen E J, Medrano J F, Bradford G E, Pirchner F, Renne U, Schlote W, Hill W G. Inbred lines of mice derived from long-term growth selected lines: unique resources for mapping growth genes. Mamm Genome. 2001; 12 678-686
6 Chagnon Y C, Chung W K, Perusse L, Chagnon M, Leibel R L, Bouchard C. Linkages and associations between the leptin receptor (LEPR) gene and human body composition in the Quebec Family Study. Int J Obes Relat Metab Disord. 1999; 23 278-286
7 Chagnon Y C, Wilmore J H, Borecki I B, Gagnon J, Perusse L, Chagnon M, Collier G R, Leon A S, Skinner J S, Rao D, Bouchard C. Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study. J Clin Endocrinol Metab. 2000; 85 29-34
8 Chen H, Charlat O, Tartaglia L A, Woolf E A, Weng X, Elli S J, Lakey N D, Culpepper J, Moore K J, Breitbart R E, Duyk G M, Tepper R I, Morgenstern J P. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996; 84 491-495
9 Chua Jr S C, White D W, Wu-Peng X S, Liu S M, Okada N, Kershaw E E, Chung W K, Power-Kehoe L, Chua M, Tartaglia L A, Leibel R L. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). Diabetes. 1996; 45 1141-1143
10 De Silva A M, Walder K R, Aitman T J, Gotoda T, Goldstone A P, Hodge A M, de Courten M P, Zimmet P Z, Collier G R. Combination of polymorphisms in OB-R and the OB gene associated with insulin resistance in Nauruan males. Int J Obes Relat Metab Disord. 1999; 23 816-822
11 Endo K, Yanagi H, Hirano C, Hamaguchi H, Tsuchiya S, Tomura S. Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity. Int J Obes Relat Metab Disord. 2000; 24 443-449
12 Fong T M, Huang R R, Tota M R, Mao C, Smith T, Varnerin J, Karpitskiy V V, Krause J E, Van der Ploeg L H. Localization of leptin binding domain in the leptin receptor. Mol Pharmacol. 1998; 53 234-240
13 Gotoda T, Manning B S, Goldstone A P, Imrie H, Evans A L, Strosberg A D, McKeigue P M, Scott J, Aitman T J. Leptin receptor gene variation and obesity: lack of association in a white British male population. Hum Mol Genet. 1997; 6 869-876
14 Hoger H. Genetic drift in an outbred stock of mice. Jikken Dobutsu. 1992; 41 215-220
15 Igel M, Becker W, Herberg L, Joost H G. Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse. Endocrinology. 1997; 138 4234-4239
16 Igel M, Taylor B A, Phillips S J, Becker W, Herberg L, Joost H G. Hyperleptinemia and leptin receptor variant Asp600Asn in the obese, hyperinsulinemic KK mouse strain. J Mol Endocrinol. 1998; 21 337-345
17 Kluge R, Giesen K, Bahrenberg G, Plum L, Ortlepp J R, Joost H G. Quantitative trait loci for obesity and insulin resistance (Nob1, Nob2) and their interaction with the leptin receptor allele (LeprA720 T/T1044I) in New Zealand obese mice. Diabetologia. 2000; 43 1565-1572
18 Reichart U, Kappler R, Scherthan H, Wolf E, Müller M, Brem G, Aigner B. Partial leptin receptor gene deletion in transgenic mice prevents expression of the membrane-bound isoforms except for Ob-Rc. Biochem Biophys Res Commun. 2000; 269 496-501
19 Schüler L. Mouse strain Fzt:Du and its use as model in animal breeding research. Arch Tierzucht. 1985; 28 357-363
20 Strosberg A D, Issad T. The involvement of leptin in humans revealed by mutations in leptin and leptin receptor genes. Trends Pharmacol Sci. 1999; 20 227-230
21 Timtchenko D, Kratzsch J, Sauerwein H. Wegner J, Souffrant WB, Schwerin M, Brockmann GA. Fat storage capacity in growth-selected and control mouse lines is associated with line-specific gene expression and plasma hormone levels. Int J Obes Relat Metab Disord. 1999; 23 586-594
22 Ukkola O, Tremblay A, Despres J P, Chagnon Y C, Campfield L A, Bouchard C. Leptin receptor Gln223Arg variant is associated with a cluster of metabolic abnormalities in response to long-term overfeeding. J Intern Med. 2000; 248 435-439
23 Van der Kallen C J, Cantor R M, van Greevenbroek M M, Geurts J M, Bouwman F G, Aouizerat B E, Allayee H, Buurman W A, Lusis A J, Rotter J I, de Bruin T W. Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1 A. Int J Obes Relat Metab Disord. 2000; 24 1381-1391

G. A. Brockmann

Research Institute for the Biology of Farm Animals

Wilhelm-Stahl-Allee 2

18196 Dummerstorf

Germany

Phone: + 0493820868703

Fax: + 0 49 38 20 86 87 02

Email: Gudrun.Brockmann@fbn-dummerstorf.de