Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates.
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.
Lin
John C
JC
Rinat, Pfizer Inc., South San Francisco, California, United States of America. john.lin@rinat.pfizer.com
Tsao
David
D
Barras
Paul
P
Bastarrachea
Raul A
RA
Boyd
Bob
B
Chou
Joyce
J
Rosete
Rodnie
R
Long
Hua
H
Forgie
Alison
A
Abdiche
Yasmina
Y
Dilley
Jeanette
J
Stratton
Jennifer
J
Garcia
Carlos
C
Sloane
David L
DL
Comuzzie
Anthony G
AG
Rosenthal
Arnon
A
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
D019208:Brain-Derived Neurotrophic Factor; D020738:Leptin; D008024:Ligands; D044105:Receptor, Melanocortin, Type 4; D011994:Recombinant Proteins; D020813:Receptor, trkB