The novel combination of glucagon-like peptide-1 receptor agonism and N-methyl-D-aspartate receptor antagonism significantly reduced food intake and body weight, according to study results. 

The study, published in Nature, presented a new treatment for obesity that successfully reversed obesity, hyperglycemia, and dyslipidemia in rodent models. The researchers focused on the N-methyl-D-aspartate (NMDA) receptor, a component in synaptic plasticity and body weight regulation.

Leveraging the weight-reducing effects of GLP-1 receptor agonists, they engineered a bimodal molecule that integrates NMDA receptor antagonism with GLP-1 receptor agonism (GLP-1–MK-801). This conjugate specifically targets the NMDA receptor antagonist MK-801 to GLP-1 receptor-expressing neurons, significantly reducing the adverse effects associated with NMDA receptor antagonists.

Key findings

• Significant weight loss: Daily subcutaneous injections of GLP-1–MK-801 conjugate led to a dose-dependent reduction in food intake and substantial weight loss in diet-induced obese rodents.
  
  
• Improved metabolic parameters: The conjugate treatment resulted in lower plasma insulin, cholesterol, and triglyceride levels compared with NMDA receptor antagonist MK-801 alone.
  
  
• Targeted neuroplasticity effects: The GLP-1–MK-801 conjugate influenced neuroplasticity, the brain's ability to form new neural connections and adapt to changes, in the hypothalamus and brainstem, enhancing therapeutic efficacy while limiting the adverse effects seen with MK-801 monotherapy.

The study's lead researcher, Christoffer Clemmensen, noted that in some cases, the mice lost twice as much weight as they would have if used GLP-1 alone. "We already know that GLP-1-based drugs can lead to weight loss. The molecule that we have attached to GLP-1 affects the so-called glutamatergic neurotransmitter system, which is involved in regulating appetite and metabolism, and in fact, other studies with human participants suggest that this family of compounds has significant weight loss potential. What is interesting here is the effect we get when we combine these two compounds into a single drug," said Clemmensen in a statement.

The study was supported by the Lundbeck Foundation, the BioInnovation Institute, and the Novo Nordisk Foundation, with researchers from the University of Copenhagen, UT Southwestern, and Novo Nordisk.