Regulation of energy metabolism and obesity by modulating b cell activating factor (baff, blys) or baff signaling

Abstract

Provided herein are methods and compositions for modulating energy metabolism and weight in mammals, in particular by modulating thermogenesis associated with brown fat, including thermogenesis by brown fat or brown fat cells, adaptive thermogenesis by brown fat or brown fat cells, thermogenic capacity of brown fat or brown fat cells, or a combination thereof. More specifically, methods and compositions provided herein for treating or preventing obesity, or methods and compositions for identifying compounds effective for treating or preventing obesity are taught in connection with ligands such as B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), their receptors, and molecules that modulate the interactions between the ligands and receptors.

What is claimed is: 
     
         1 . A method of preventing obesity and/or one or more sequelae thereof in a subject, comprising:
 administering to a subject at risk for developing obesity and/or one or more sequelae thereof, a therapeutically effective amount of a pharmaceutical composition to enhance thermogenesis associated with brown fat or brown fat cells,   wherein said pharmaceutical composition is selected from the group consisting of a recombinant B-cell activating factor (BAFF) protein or an agonistic variant thereof, a BAFF-based peptide or peptide analogue, a BAFF transcription regulator, a nucleic acid encoding at least a partial sequence of BAFF, a first factor upstream or downstream from the interaction between BAFF and a first receptor, a proliferation-inducing ligand (APRIL) that is recombinant or an agonistic variant thereof, an APRIL-based peptide or peptide analogue, an APRIL transcription regulator, a nucleic acid encoding at least a partial sequence of APRIL, a second factor upstream or downstream from the interaction between an APRIL and a second receptor, a regulator of a BAFF-first receptor interaction or an APRIL-second receptor interaction, and a combination thereof.   
     
     
         2 . The method of  claim 1 , wherein thermogenesis associated with brown fat comprises thermogenesis by brown fat or brown fat cells, adaptive thermogenesis by brown fat or brown fat cells, thermogenic capacity of brown fat or brown fat cells, or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein thermogenesis associated with brown fat or brown fat cells is enhanced by increasing the level or activity of BAFF. 
     
     
         4 . The method of  claim 3 , wherein thermogenesis associated with brown fat or brown fat cells is further enhanced by increasing the level or activity of APRIL. 
     
     
         5 . The method of  claim 1 , wherein said first receptor of BAFF is a BAFF-receptor (BAFF-R), cytophilin ligand interactor (TACI) or B-cell maturation antigen (BCMA). 
     
     
         6 . The method of  claim 1 , wherein said pharmaceutical composition is a regulator of a BAFF-first receptor interaction selected from the group consisting of a BAFF-based peptide or an analogue thereof, a BAFF receptor analogue, a co-activator of a BAFF-first receptor interaction, and a combination thereof. 
     
     
         7 . The method of  claim 1 , wherein said pharmaceutical composition is a recombinant BAFF protein. 
     
     
         8 . The method of  claim 1 , wherein said pharmaceutical composition is an agonistic variant of a recombinant BAFF protein. 
     
     
         9 . The method of  claim 1 , wherein said first factor upstream or downstream from the interaction between BAFF and said first receptor is radioprotective protein 105 kDa (RP105). 
     
     
         10 . The method of  claim 1 , wherein said pharmaceutical composition is administered to a subject via parenteral, topical, oral, or local administration, injection, or a combination thereof. 
     
     
         11 . The method of  claim 10 , wherein said subject is a human at risk for developing obesity and/or one or more sequelae thereof. 
     
     
         12 . The method of  claim 1 , further comprising:
 identifying said subject at risk for developing obesity and/or one or more sequelae thereof.   
     
     
         13 . The method of  claim 1 , wherein said BAFF transcription regulator comprises toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), reactive oxygen species (ROS) production and NF-κB activation, p65, co-activator p300, or a combination thereof. 
     
     
         14 . The method of  claim 1 , wherein said second receptor of APRIL is TACI or BCMA. 
     
     
         15 . The method of  claim 1 , wherein thermogenesis associated with brown fat or brown fat cells is enhanced by increasing the level or activity of APRIL. 
     
     
         16 . The method of  claim 1 , wherein thermogenesis associated with brown fat or brown fat cells is enhanced by increasing the level or activity of APRIL, BAFF, or some combination thereof. 
     
     
         17 . The method of  claim 1 , wherein said pharmaceutical composition is a regulator of APRIL-second receptor interaction selected from the group consisting of an APRIL-based peptide or an analogue thereof, an APRIL receptor analogue, and a co-activator of an APRIL-second receptor interaction. 
     
     
         18 . The method of  claim 1 , wherein said first receptor and said second receptor are the same. 
     
     
         19 . The method of  claim 1 , wherein said pharmaceutical composition is a recombinant APRIL, a fragment of APRIL, an APRIL agonistic variant, or a combination thereof.