Obesity gene

Abstract

The invention describes a previously unknown gene, termed 5′OT-EST, which is responsible for inducing an obesity and/or infertility phenotype in transgenic animals, and transgenic animals comprising mutants of 5′OT-EST which are useful for assaying compounds for the treatment of obesity and/or infertility.

1 . A 5′OT-EST polypeptide having a sequence selected from the group comprising the sequences set forth in any one of SEQ. ID. Nos. 2, 4 or 6, and sequences substantially homologous to any one of the polypeptides set forth in SEQ. ID. Nos. 2, 4 or 6.  
     
     
         2 . The polypeptide of  claim 1  comprising an amino acid sequence encoded by at least one exon selected from the group consisting of exons w, x, y and z as set forth in SEQ. ID. No. 16, or equivalents thereof as set forth in any one of SEQ. ID. Nos. 3 or 5.  
     
     
         3 . The polypeptide of  claim 2 , which comprises an amino acid sequence encoded by at least part of exon w set forth in SEQ. ID. No. 16, or equivalents thereof as set forth in any one of SEQ. ID. Nos. 3 or 5.  
     
     
         4 . A mutant of a 5′OT-EST polypeptide according to  claim 1  which, in vivo, of modultes the obesity of an animal expressing it.  
     
     
         5 . A mutant of  claim 1 , wherein the animal is a transgenic animal expressing the mutant as a result of transformation with a transgene.  
     
     
         6 . A mutant of  claim 1 , which comprises the sequence PRPRSFSAPFSSQDS, or a sequence substantially homologous thereto.  
     
     
         7 . A mutant of  claim 1  which comprises the sequence MLRALNRLAARPGGQPPTLLLLPVRGPRPRSFSAPFSSQDS, or a sequence substantially homologous thereto.  
     
     
         8 . A transgenic non-human animal expressing, as a result of transgene expression, a 5′OT-EST polypeptide or mutant 5′OT-EST polypeptide of  claim 1 .  
     
     
         9 . A transgenic animal of  claim 8 , which has been transformed with a nucleic acid vector comprising a nucleic acid encoding a 5′OT-EST polypeptide comprising an amino acid sequence selected from the group consisting of (a) the sequences set forth in any one of SEQ ID NOs 2, 4, or 6, and (b) sequences which are at least 90% homologous, as determined by BLAST analysis using default parameters, to the full length of said sequence set forth in any one of SEQ ID NOs 2, 4, or 6.  
     
     
         10 . A transgenic animal of  claim 8 , comprising more than one copy of the transgene.  
     
     
         11 . A transgenic animal of  claim 8 , which is a mammal.  
     
     
         12 . A transgenic animal of  claim 11  which is a rat.  
     
     
         13 . A transgenic rat comprising at least four concatameric copies of a transgene having the structure of cVO14 as set forth in  FIG. 4  (SEQ. ID. No. 17).  
     
     
         14 . A non-human mammal possessing the following obese phenotype: (i) a very late onset of obesity, (ii) a highly selective visceral distribution of fat developing on a normal rodent diet, without hyperphagia, (iii) an effect greatly preponderant in males, (iv) a predisposition to excessive dietary-fat induced obesity at an early age, before the phenotype becomes apparent on a normal diet, and (v) a dominant pattern of inheritance; the non-human mammal being obtainable by transformation with a vector comprising a nucleic acid encoding a 5′OT-EST polypeptide comprising an amino acid sequence selected from the group consisting of (a) the sequences set forth in any one of SEQ ID NOs 2, 4, or 6, and (b) sequences which are at least 90% homologous, as determined by BLAST analysis using default parameters, to the full length of said sequence set forth in any one of SEQ ID NOs 2, 4, or 6.  
     
     
         15 . A method of screening an animal  claim 8  for changes in the animal's phenotype associated with obesity, comprising comparing the animal as a model for human late onset obesity, human dietary-fat associated juvenile obesity, human female post-menopausal obesity and/or human male infertility with an identical animal that has been subjected to environmental conditions or a drug.  
     
     
         16 . A method for identifying a compound or compounds capable of modulating obesity and/or infertility in a mammal, comprising the steps of: 
 a) exposing an animal of  claim 8  to the compound or compounds to be tested;    b) determining the effect of the compound on the obesity and/or infertility phenotype; and    c) selecting the compound or compounds which are capable of modulating the obesity and/or infertility phenotype in the desired manner.    
     
     
         17 . A method for producing a compound or compounds capable of modulating obesity and/or infertility in a mammal, comprising the steps of: 
 a) exposing an animal of  claim 1  to the compound or compounds to be tested;    b) determining the effect of the compound on the obesity and/or infertility phenotype;    c) selecting the compound or compounds which are capable of modulating the obesity and/or infertility phenotype in the desired manner; and    d) producing the compound or compounds by conventional isolation or synthesis techniques.    
     
     
         18 . A method for identifying a candidate compound capable of influencing lipid transport, comprising the step of: 
 contacting 5′OT-EST polypeptide with a candidate compound or compounds and determining which candidate compound or compounds is capable of interacting with 5′OT-EST.    
     
     
         19 . A method of screening a tissue derived from a transgenic animal of  claim 8  in a screen to identify a genetic cause of obesity, comprising the steps of: 
 a) isolating one or more gene products from tissue derived from a transgenic animal of  claim 8;  and    b) determining whether the expression of a gene product is correlated with obesity.