A human leptin mutant induces weight gain in normal mice

被引：64

作者：

Verploegen, SABW ^{[1
]}

Plaetinck, G ^{[1
]}

Devos, R ^{[1
]}

VanderHeyden, J ^{[1
]}

Guisez, Y ^{[1
]}

机构：

[1] ROCHE RES GENT,B-9000 GHENT,BELGIUM

来源：

FEBS LETTERS | 1997年 / 405卷 / 02期

关键词：

leptin; antagonist; mutagenesis; body weight; anorexia; cachexia;

D O I：

10.1016/S0014-5793(97)00192-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Leptin, a fat secreted hormone, regulates ingestive behaviour and energy balance by binding to a specific receptor. Using site-directed mutagenesis, we screened for single amino acid residues in human leptin which are critical for receptor binding and biological activity. Here we report that one of these mutants has in vivo antagonistic properties. An Arg to Gln substitution at position 128 of human leptin does not affect receptor binding but knocks out biological activity. Repeated injection of R128Q in normal C57BL/6J mice results in a progressive increase in body weight. This demonstrates that R128Q is able to interfere with the negative feedback control of endogenous leptin. This mutant could be of therapeutic use for wasting disorders, such as anorexia and cachexia, where weight gain would be beneficial. (C) 1997 Federation of European Biochemical Societies.

引用

收藏

页码：237 / 240

页数：4

相关论文

共 19 条

[1] The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors [J].

Baumann, H ;

Morella, KK ;

White, DW ;

Dembski, M ;

Bailon, PS ;

Kim, HK ;

Lai, CF ;

Tartaglia, LA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (16) :8374-8378

[2] RECOMBINANT MOUSE OB PROTEIN - EVIDENCE FOR A PERIPHERAL SIGNAL LINKING ADIPOSITY AND CENTRAL NEURAL NETWORKS [J].

CAMPFIELD, LA ;

SMITH, FJ ;

GUISEZ, Y ;

DEVOS, R ;

BURN, P .

SCIENCE, 1995, 269 (5223) :546-549

[3]

CHEN H, 1996, CELL, V84, P546

[4] DETAILED ANALYSIS OF THE IL-5-IL-5R-ALPHA INTERACTION - CHARACTERIZATION OF CRUCIAL RESIDUES ON THE LIGAND AND THE RECEPTOR [J].

CORNELIS, S ;

PLAETINCK, G ;

DEVOS, R ;

VANDERHEYDEN, J ;

TAVERNIER, J ;

SANDERSON, CJ ;

GUISEZ, Y ;

FIERS, W .

EMBO JOURNAL, 1995, 14 (14) :3395-3402

[5] SITE-DIRECTED MUTAGENESIS OF VIRTUALLY ANY PLASMID BY ELIMINATING A UNIQUE SITE [J].

DENG, WP ;

NICKOLOFF, JA .

ANALYTICAL BIOCHEMISTRY, 1992, 200 (01) :81-88

[6] Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters - A role for leptin in the anorexia of infection [J].

Grunfeld, C ;

Zhao, C ;

Fuller, J ;

Pollock, A ;

Moser, A ;

Friedman, J ;

Feingold, KR .

JOURNAL OF CLINICAL INVESTIGATION, 1996, 97 (09) :2152-2157

[7] WEIGHT-REDUCING EFFECTS OF THE PLASMA-PROTEIN ENCODED BY THE OBESE GENE [J].

HALAAS, JL ;

GAJIWALA, KS ;

MAFFEI, M ;

COHEN, SL ;

CHAIT, BT ;

RABINOWITZ, D ;

LALLONE, RL ;

BURLEY, SK ;

FRIEDMAN, JM .

SCIENCE, 1995, 269 (5223) :543-546

[8]

LEE GH, 1996, NATURE, V379, P623

[9] THREADING ANALYSIS SUGGESTS THAT THE OBESE GENE-PRODUCT MAY BE A HELICAL CYTOKINE [J].

MADEJ, T ;

BOGUSKI, MS ;

BRYANT, SH .

FEBS LETTERS, 1995, 373 (01) :13-18

[10] Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization [J].

Mercer, JG ;

Hoggard, N ;

Williams, LM ;

Lawrence, CB ;

Hannah, LT ;

Trayhurn, P .

FEBS LETTERS, 1996, 387 (2-3) :113-116