TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits

Area of Science:

• Neuroscience
• Endocrinology
• Genetics

Background:

• The TrkB receptor (encoded by NTRK2) is vital for energy balance.
• Mutations in NTRK2 cause hyperphagia and obesity.
• The specific brain regions mediating TrkB's appetite control are largely unknown.

Purpose of the Study:

• To identify the neural substrates of TrkB's appetite-suppressing activity.
• To investigate the role of paraventricular hypothalamus (PVH) TrkB-expressing neurons in regulating food intake and body weight.

Main Methods:

• Selective deletion of Ntrk2 in PVH neurons.
• Chemogenetic manipulation of PVH^TrkB neurons.
• Tracing neuronal projections from PVH to VMH and LPBN.
• Electrophysiological recordings of PVH neuron activity.

Main Results:

• Selective Ntrk2 deletion in PVH induced severe hyperphagic obesity.
• Chemogenetic activation/inhibition of PVH^TrkB neurons suppressed/increased food intake.
• PVH^TrkB neurons project to VMH and LPBN, with distinct populations targeting each.
• Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN caused hyperphagia and obesity.
• BDNF-mediated TrkB activation increased PVH neuron firing.

Conclusions:

• TrkB signaling in PVH neurons is essential for regulating appetite and preventing obesity.
• PVH^TrkB neurons represent a critical, previously uncharacterized neuronal population governing energy balance.
• TrkB signaling impacts multiple hypothalamic and brainstem circuits to control food intake.