TrkB agonists ameliorate obesity and associated metabolic conditions in mice
David Tsao1, Heather Koenig Thomsen, Joyce Chou
1Rinat Laboratories, Pfizer Inc., 230 East Grand Avenue, South San Francisco, California 94080, USA.
Abstract:
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.
Insights
Neurotrophin-4 (NT4) effectively reduces appetite and body weight in obese mice by targeting the trkB receptor. This suggests NT4 as a potential therapeutic for metabolic disorders.
Area of Science:
- Neuroscience
- Metabolic Research
- Pharmacology
Background:
- Mutations in tyrosine kinase receptor trkB or brain-derived neurotrophic factor (BDNF) cause severe hyperphagia and obesity.
- Genetic evidence links trkB signaling to appetite regulation and metabolic disorders.
Purpose of the Study:
- To investigate the effects of neurotrophin-4 (NT4), a natural ligand for trkB, on appetite and body weight in murine models of obesity.
- To explore the therapeutic potential of NT4 and trkB agonists for metabolic disorders.
Main Methods:
- Peripheral administration of NT4 to several murine models of obesity.
- Intrahypothalamic application of NT4 and a trkB agonist antibody.
- Assessment of body weight, food intake, lipolysis, body fat content, leptin levels, triglyceride, and glucose levels.
- Evaluation of trkB signaling pathways downstream of leptin and melanocortin 4 receptor.
Main Results:
- Peripheral NT4 administration dose-dependently suppressed appetite and reduced body weight in obese mice.
- NT4 treatment increased lipolysis, reduced body fat, and improved hypertriglyceridemia and hyperglycemia.
- Intrahypothalamic NT4 or trkB agonist antibody reduced food intake and body weight.
- Weight regain was observed after NT4 treatment cessation in mice with functional leptin receptors.
- trkB agonist effects were independent of stress, discomfort, or pain sensitization.
Conclusions:
- trkB signaling, originating in the hypothalamus, directly modulates appetite, metabolism, and taste preference.
- NT4 and other trkB agonists show potential as therapeutics for metabolic disorders due to their anorexic and weight-reducing effects.
