PMID- 18063676
OWN - NLM
STAT- MEDLINE
DCOM- 20080422
LR  - 20161124
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 149
IP  - 3
DP  - 2008 Mar
TI  - TrkB agonists ameliorate obesity and associated metabolic conditions in mice.
PG  - 1038-48
AB  - Mutations in the tyrosine kinase receptor trkB or in one of its natural ligands, 
      brain-derived neurotrophic factor (BDNF), lead to severe hyperphagia and obesity 
      in rodents and/or humans. Here, we show that peripheral administration of 
      neurotrophin-4 (NT4), the second natural ligand for trkB, suppresses appetite and 
      body weight in a dose-dependent manner in several murine models of obesity. NT4 
      treatment increased lipolysis, reduced body fat content and leptin, and elicited 
      long-lasting amelioration of hypertriglyceridemia and hyperglycemia. After 
      treatment termination, body weight gradually recovered to control levels in obese 
      mice with functional leptin receptor. A single intrahypothalamic application of 
      minute amounts of NT4 or an agonist trkB antibody also reduced food intake and 
      body weight in mice. Taken together with the genetic evidence, our findings 
      support the concept that trkB signaling, which originates in the hypothalamus, 
      directly modulates appetite, metabolism, and taste preference downstream of the 
      leptin and melanocortin 4 receptor. The trkB agonists mediate anorexic and 
      weight-reducing effects independent of stress induction, visceral discomfort, or 
      pain sensitization and thus emerge as a potential therapeutic for metabolic 
      disorders.
FAU - Tsao, David
AU  - Tsao D
AD  - Rinat Laboratories, Pfizer Inc., 230 East Grand Avenue, South San Francisco, 
      California 94080, USA.
FAU - Thomsen, Heather Koenig
AU  - Thomsen HK
FAU - Chou, Joyce
AU  - Chou J
FAU - Stratton, Jennifer
AU  - Stratton J
FAU - Hagen, Michael
AU  - Hagen M
FAU - Loo, Carole
AU  - Loo C
FAU - Garcia, Carlos
AU  - Garcia C
FAU - Sloane, David L
AU  - Sloane DL
FAU - Rosenthal, Arnon
AU  - Rosenthal A
FAU - Lin, John C
AU  - Lin JC
LA  - eng
PT  - Journal Article
DEP - 20071206
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Leptin)
RN  - 0 (Melanocortins)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Receptors, Leptin)
RN  - 0 (Triglycerides)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - G4962QA067 (Lithium Chloride)
RN  - IY9XDZ35W2 (Glucose)
RN  - P658DCA9XD (neurotrophin 4)
SB  - IM
MH  - Animals
MH  - Body Weight/drug effects
MH  - Disease Models, Animal
MH  - Eating/drug effects
MH  - Energy Metabolism/drug effects
MH  - Glucose/metabolism
MH  - Homeostasis/drug effects
MH  - Leptin/metabolism
MH  - Lithium Chloride/pharmacology
MH  - Male
MH  - Melanocortins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Obese
MH  - Nerve Growth Factors/*pharmacology
MH  - Obesity/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*agonists/metabolism
MH  - Receptors, Leptin/metabolism
MH  - Taste/drug effects
MH  - Triglycerides/metabolism
EDAT- 2007/12/08 09:00
MHDA- 2008/04/23 09:00
CRDT- 2007/12/08 09:00
PHST- 2007/12/08 09:00 [pubmed]
PHST- 2008/04/23 09:00 [medline]
PHST- 2007/12/08 09:00 [entrez]
AID - en.2007-1166 [pii]
AID - 10.1210/en.2007-1166 [doi]
PST - ppublish
SO  - Endocrinology. 2008 Mar;149(3):1038-48. doi: 10.1210/en.2007-1166. Epub 2007 Dec 
      6.