title: Biologic response to peripheral and central administration of recombinant human leptin in dogs.
abstract: OBJECTIVE
  Because leptin is believed to act within the central nervous system, the objective of this study was to test that presumption by comparing the biologic responses to recombinant human leptin (rHuLeptin) when delivered either subcutaneously or intrathecally in a large animal species, the beagle dog.
  
  
  METHODS
  Adult beagle dogs were used for all studies (n=3 to 14). Treatment with rHuLeptin was either as daily subcutaneous or intermittent intrathecal injections.
  
  
  RESULTS
  Subcutaneously administered rHuLeptin was absorbed with peak concentrations appearing at 2 to 4 hours. After intrathecal administration, cerebral spinal fluid concentrations declined in a bi-phasic manner with a terminal half-life of -6 to 8 hours. When lean beagles were given leptin subcutaneously, at 0.05 to 5 g/kg/day for up to 6 months, reductions in body weight (up to 30%) and food intake (up to 75%) were observed. Body fat loss was observed in both lean and obese dogs, and confirmed by dual energy X-ray absorptiometry and histology of adipose tissue. When rHuleptin was delivered intrathecally at 4 to 1000 microg/dose for up to 3 months, the primary effects observed were reductions in body weight and food intake. In general all findings reported in the intrathecal studies were consistent with those noted in the subcutaneous studies; however, the required intrathecal dose was substantially lower than that for subcutaneous delivery.
  
  
  CONCLUSIONS
  These studies demonstrate that both subcutaneous and intrathecal treatment of rHuLeptin was associated with effects on body weight, food intake, and body fat in dogs. These results support the concept that the central nervous system is the probable primary site of action for leptin and suggest that rHuLeptin has similar physiologic activities that influence body weight, body fat, and metabolism in large animals to those reported previously in rodents.
authors.affiliation: Department of Product Develoment, Amgen, Inc., Thousand Oaks, CA 91320-1789, USA. clebel@amgen.com
authors.forename: C
authors.initials: C
authors.lastname: LeBel
authors.forename: A
authors.initials: A
authors.lastname: Bourdeau
authors.forename: D
authors.initials: D
authors.lastname: Lau
authors.forename: P
authors.initials: P
authors.lastname: Hunt
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007700:Kinetics; D020738:Leptin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D015431:Weight Loss / Q000187:drug effects
chemical_list: D020738:Leptin; D011994:Recombinant Proteins