title: DRF 2655: a unique molecule that reduces body weight and ameliorates metabolic abnormalities.
abstract: OBJECTIVE
  Preclinical evaluation of DRF 2655, a peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma agonist, as a body-weight lowering, hypolipidemic and euglycemic agent.
  
  
  METHODS
  DRF 2655 was studied in different genetic, normal, and hyperlipidemic animal models. HEK 293 cells were used to conduct the reporter-based transactivation of PPARalpha and PPARgamma. To understand the biochemical mechanism of lipid-, body-weight-, and glucose-lowering effects, activities of key beta-oxidation and lipid catabolism enzymes and gluconeogenic enzymes were studied in db/db mice treated with DRF 2655. 3T3L1 cells were used for adipogenesis study, and HepG2 cells were used to study the effect of DRF 2655 on total cholesterol and triglyceride synthesis using [(14)C]acetate and [(3)H]glycerol.
  
  
  RESULTS
  DRF 2655 showed concentration-dependent transactivation of PPARalpha and PPARgamma. In the 3T3L1 cell-differentiation study, DRF 2655 and rosiglitazone showed 369% and 471% increases, respectively, in triglyceride accumulation. DRF 2655 showed body-weight lowering and euglycemic and hypolipidemic effects in various animal models. db/db mice treated with DRF 2655 showed 5- and 3.6-fold inhibition in phosphoenolpyruvate carboxykinase and glucose 6-phosphatase activity and 651% and 77% increases in the beta-oxidation enzymes carnitine palmitoyltransferase and carnitine acetyltransferase, respectively. HepG2 cells treated with DRF 2655 showed significant reduction in lipid synthesis.
  
  
  CONCLUSIONS
  DRF 2655 showed excellent euglycemic and hypolipidemic activities in different animal models. An exciting finding is its body-weight lowering effect in these models, which might be mediated by the induction of target enzymes involved in hepatic lipid catabolism through PPARalpha activation.
authors.affiliation: Discovery Biology, Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad, India. ranjanchakrabarti@drreddys.com
authors.forename: Reeba K
authors.initials: RK
authors.lastname: Vikramadithyan
authors.forename: Jagadheshan
authors.initials: J
authors.lastname: Hiriyan
authors.forename: Juluri
authors.initials: J
authors.lastname: Suresh
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gershome
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Babu
authors.forename: Parimal
authors.initials: P
authors.lastname: Misra
authors.forename: Ramanujam
authors.initials: R
authors.lastname: Rajagopalan
authors.forename: Ranjan
authors.initials: R
authors.lastname: Chakrabarti
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D002454:Cell Differentiation; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D006224:Cricetinae; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D011345:Fenofibrate / Q000008:administration & dosage; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D010078:Oxazines / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage*; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014280:Triglycerides / Q000096:biosynthesis / Q000097:blood; D015431:Weight Loss
chemical_list: D019440:Anti-Obesity Agents; C476557:DRF 2655; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010078:Oxazines; D011422:Propionates; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D011345:Fenofibrate