Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling

Area of Science:

• Neuroscience
• Metabolic research
• Endocrinology

Background:

• Growth differentiation factor 15 (GDF15) and glucagon-like peptide-1 (GLP-1) receptor agonists reduce food intake and body weight.
• These pathways involve brainstem neurons co-expressing GDNF-family receptor α-like (GFRAL) and GLP1R.
• Sickness-like behaviors and aversion, mediated by the exterolateral parabrachial nucleus, limit their clinical application.

Purpose of the Study:

• To identify novel neural pathways mediating the weight-reducing effects of GDF15 and GLP-1 analogues.
• To investigate the role of brain-derived neurotrophic factor (BDNF) neurons in the medial nucleus of the tractus solitarius (mNTS) in appetite regulation.
• To explore potential therapeutic targets for weight management.

Main Methods:

• Utilized mouse models to investigate neural pathways downstream of GFRAL/GLP1R neurons.
• Focused on a distinct population of BDNF-expressing cells in the mNTS.
• Examined the necessity and sufficiency of BDNFmNTS neuron activation for weight-reducing effects.

Main Results:

• BDNFmNTS neurons are essential for the body weight-reducing effects of both GDF15 and the GLP-1 receptor agonist Exendin-4.
• Acute activation of BDNFmNTS neurons effectively reduces food intake.
• Activation of these neurons also promotes fatty acid oxidation.

Conclusions:

• A distinct neural pathway involving BDNFmNTS neurons mediates the anorectic and weight-reducing effects of GDF15 and GLP-1 analogues.
• Targeting BDNFmNTS neurons represents a potential strategy for developing more effective weight-loss therapies.
• This pathway may offer a route for achieving longer-term weight management.