Treatment of obesity

Abstract

The present invention relates generally to a method of increasing lipid oxidation in a mammal and to agents useful for same. More particularly, the present invention relates to a method of increasing lipid oxidation in a mammal by administering a ligand which interacts with the IL-6 receptor and signals via interaction with a gp130/LIF receptor heterodimer. In a related aspect, the present invention provides a method of increasing insulin sensitivity in a mammal. The method of present invention is useful, inter alia, in the treatment and/or prophylaxis of conditions characterised by unwanted lipid accumulation (such as obesity, obesity induced-metabolic disorders, type II diabetes, dyslipidemia, glucose intolerance, insulin resistance, obstructive sleep apnea, cardiovascular disease or non-alcoholic fatty liver disease) or inadequate insulin sensitivity.

1 . A method of inducing lipid oxidation or increasing insulin sensitivity in a mammal, said method comprising administering to said mammal a ligand which binds to the IL-6 receptor and signals via a gp130/LIF receptor heterodimer. 
   
   
       2 . A method of treating a condition in a mammal, which condition is characterized by either unwanted lipid accumulation or inadequate insulin sensitivity, said method comprising administering to said mammal a ligand which binds to the IL-6 receptor and signals via a gp130/LIF receptor heterodimer. 
   
   
       3 . (canceled) 
   
   
       4 . The method according to  claim 1 , wherein said ligand has greater affinity for the IL-6 receptor than the CNTF receptor. 
   
   
       5 . The method of  claim 1  wherein said ligand comprises an IL-6 receptor binding site, a gp130 binding site and a LIF receptor binding site. 
   
   
       6 . The method according to  claim 5  wherein the IL-6 receptor binding site of said ligand is substantially similar to the IL-6 receptor binding site of IL-6. 
   
   
       7 . The method according to  claim 6  wherein said ligand comprises a binding site substantially similar to the IL-6R binding site of IL-6, a binding site substantially similar to the gp130 binding site of IL-6 and a binding site substantially similar to the LIF receptor binding site of CNTF. 
   
   
       8 . The method according to  claim 7  wherein said ligand is an IL-6/CNTF chimera. 
   
   
       9 . The method according to  claim 8  wherein said ligand is one in which the site III loop of CNTF is inserted in IL-6 in place of the site III loop of IL-6. 
   
   
       10 . The method according to  claim 9  wherein amino acid residues Glu36-Met56 (SEQ ID NO: 4) are substituted in place of the IL-6 residues between Arg40-Asn60 of SEQ ID NO: 2, the amino acid residue Gly147-Leu162 (SEQ ID NO: 6) are substituted in place of IL-6 residues between Leu151-Arg168 or SEQ ID NO: 2 and amino acid residues Leu91-Ile109 (SEQ ID NO: 5) are substituted in place of the IL-6 residues between Leu101-Arg113 of SEQ ID NO: 2. 
   
   
       11 . The method according to  claim 10  wherein said ligand is IC7 or a ligand comprising the SEQ ID NO: 7 amino acid sequence or a substantially similar ligand or a functional fragment thereof. 
   
   
       12 . The method according to  claim 2  wherein said condition is selected from the group consisting of obesity, insulin resistance, glucose intolerance, dyslipidemia, non-alcoholic fatty liver disease, sleep apnea, obesity associated metabolic disorders such as osteoarthritis, type II diabetes mellitis, hypertension, stroke or cardiovascular disease, unwanted weight gain or body mass index and excessive appetite resulting in unwanted weight gain. 
   
   
       13 . The method according to  claim 1  wherein said ligand comprises a region or is complexed to a molecule which prevents or retards said ligand from crossing the blood-brain barrier. 
   
   
       14 . The method according to  claim 13  wherein said region or molecule is all or part of an antibody. 
   
   
       15 . The method according to  claim 14  wherein said region or molecule is the Fc portion of IgG. 
   
   
       16 . An isolated ligand which binds to the IL-6 receptor and signals via a gp130/LIF receptor heterodimer, which ligand is not IC7. 
   
   
       17 . The ligand according to  claim 16  wherein said ligand has greater affinity for the IL-6 receptor than the CNTF receptor. 
   
   
       18 . The ligand according to  claim 17  wherein the IL-6 receptor binding site of said ligand is substantially similar to the IL-6 receptor binding site of IL-6. 
   
   
       19 . The ligand according  claim 16  wherein said ligand comprises an IL-6 receptor binding site, a gp130 binding site and a LIF receptor binding site. 
   
   
       20 . The ligand according to  claim 19  wherein said ligand comprises a binding site substantially similar to the IL-6R binding site of IL-6, a binding site substantially similar to the gp130 binding site of IL-6 and a binding site substantially similar to the LIF receptor binding site of CNTF. 
   
   
       21 . The ligand according to  claim 20  wherein said ligand is an IL-6/CNTF chimera. 
   
   
       22 . The ligand according to  claim 21  wherein said ligand is one in which the site III loop of CNTF is inserted in IL-6 in place of the site III loop of IL-6. 
   
   
       23 . The ligand according to  claim 16  wherein said ligand comprises a region or is complexed to a proteinaceous or non-proteinaceous molecule such that the ligand is prevented or retarded from crossing the blood brain barrier. 
   
   
       24 . A pharmaceutical composition comprising a ligand according to  claim 16  together with a pharmaceutically acceptable carrier. 
   
   
       25 . A ligand according to  claim 16  for use in therapy.