appetite enhancement and weight gain by peripheral administration of trkb agonists in non-human primates增强食欲和体重增加的外围政府trkb受体激动剂在非人类的灵长类动物.pdfVIP

Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-Human Primates 1 1 3 2 4 1 1 John C. Lin *, David Tsao , Paul Barras , Raul A. Bastarrachea , Bob Boyd , Joyce Chou , Rodnie Rosete , 1 1 1 1 1 1 Hua Long , Alison Forgie , Yasmina Abdiche , Jeanette Dilley , Jennifer Stratton , Carlos Garcia , 1 2 1 David L. Sloane , Anthony G. Comuzzie , Arnon Rosenthal 1 Rinat, Pfizer Inc., South San Francisco, California, United States of America, 2 Southwest Foundation for Biomedical Research, San Antonio, Texas, United States of America, 3 Alpha Genesis, Inc., Yemassee, South Carolina, United States of America, 4 Northern Biomedical Research, Muskegon, Michigan, United States of America 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 retenti