title: Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates.
abstract: Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.
authors.affiliation: Rinat, Pfizer Inc., South San Francisco, California, United States of America. john.lin@rinat.pfizer.com
authors.forename: John C
authors.initials: JC
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Tsao
authors.forename: Paul
authors.initials: P
authors.lastname: Barras
authors.forename: Raul A
authors.initials: RA
authors.lastname: Bastarrachea
authors.forename: Bob
authors.initials: B
authors.lastname: Boyd
authors.forename: Joyce
authors.initials: J
authors.lastname: Chou
authors.forename: Rodnie
authors.initials: R
authors.lastname: Rosete
authors.forename: Hua
authors.initials: H
authors.lastname: Long
authors.forename: Alison
authors.initials: A
authors.lastname: Forgie
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Abdiche
authors.forename: Jeanette
authors.initials: J
authors.lastname: Dilley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stratton
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia
authors.forename: David L
authors.initials: DL
authors.lastname: Sloane
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.forename: Arnon
authors.initials: A
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D001066:Appetite; D001835:Body Weight; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017353:Gene Deletion; D020738:Leptin / Q000097:blood; D008024:Ligands; D008253:Macaca mulatta; D009154:Mutation; D009765:Obesity / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D020813:Receptor, trkB / Q000819:agonists*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015430:Weight Gain
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020738:Leptin; D008024:Ligands; D044105:Receptor, Melanocortin, Type 4; D011994:Recombinant Proteins; D020813:Receptor, trkB