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Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates

John C Lin1, David Tsao, Paul Barras

  • 1Rinat, Pfizer Inc., South San Francisco, California, United States of America. john.lin@rinat.pfizer.com

Plos One
|April 3, 2008
PubMed

Insights

Stimulating TrkB receptors centrally reduces appetite, but peripheral stimulation surprisingly increases appetite and weight in primates. This dual TrkB signaling offers potential targets for obesity or wasting disorder treatments.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Metabolic Research

Background:

  • Loss-of-function mutations in the TrkB pathway cause obesity.
  • TrkB stimulation by BDNF/NT4 reduces food intake in rodents, suggesting an anorexigenic role.
  • TrkB signaling is linked to the melanocortin-4 receptor (Mc4r) system in energy homeostasis.

Purpose of the Study:

  • To investigate the effects of TrkB agonists on energy homeostasis in non-human primates.
  • To determine if TrkB signaling has differential effects when administered centrally versus peripherally.

Main Methods:

  • Administration of TrkB agonists centrally and peripherally in non-human primates.
  • Monitoring of food intake, body weight, fat deposition, and serum leptin levels.
  • Dose-response analysis of peripheral TrkB agonist administration.

Main Results:

  • Central TrkB agonist administration resulted in anorexigenic effects.
  • Peripheral TrkB agonist administration unexpectedly caused orexigenic effects, increasing appetite, body weight, and fat.
  • Peripheral effects were dose-dependent and not linked to fluid retention or receptor downregulation.

Conclusions:

  • TrkB signaling exerts dual control over energy homeostasis in primates.
  • Central TrkB activation is anorexigenic, while peripheral activation is orexigenic.
  • Targeting TrkB signaling offers potential therapeutic strategies for obesity and wasting disorders.

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