GLP-1-Directed NMDA Receptor Antagonism for Obesity Treatment

In recent decades, obesity has become a global health problem, seriously affecting the quality of life and health of millions of people. Obesity is not only associated with numerous health issues such as diabetes, hypertension, and cardiovascular diseases but also severely impacts mental health. Therefore, finding effective treatment methods for obesity is particularly important.

Against this backdrop, a team of scientists led by Jonas Petersen conducted an innovative study to explore the potential of a dual-mode molecule combining GLP-1 (Glucagon-Like Peptide-1) receptor agonist and NMDA (N-Methyl-D-Aspartate) receptor antagonist (GLP-1–MK-801) in the treatment of obesity. This paper will be published in the journal “Nature”.

Research Background and Objectives

NMDA receptors are ion channels activated by glutamate and play critical roles in many brain processes. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity play important roles in weight balance. However, current NMDA receptor antagonists on the market, such as Memantine and MK-801, while showing weight loss effects in animal models, have limited clinical applications due to severe side effects such as hyperthermia and hyperactivity symptoms.

The objective of the research is to combine GLP-1 receptor agonists and NMDA receptor antagonists to develop a dual-mode molecule that targets the appetite-regulating brain regions rich in GLP-1 receptors. The aim is to create a molecule that can effectively reduce weight, lower blood sugar, and improve lipid irregularities while avoiding the severe side effects of existing NMDA receptor antagonists.

Research Methods

Study Subjects and Samples

The study subjects were diet-induced obesity (DIO) mice, including experimental and control groups, with each group consisting of 10 mice.

Chemical Synthesis and Structural Optimization

The research team developed a stable GLP-1–MK-801 conjugate through chemical synthesis and structural optimization. The conjugate has a C-terminal L-penicillamine residue and a self-inactivating disulfide bond. High-concentration glutathione degradation experiments in vitro confirmed that the conjugate has good degradation performance within cells.

Metabolic Phenotype Analysis

After determining the dosage, the research team conducted a 14-day in vivo metabolic effect evaluation on DIO mice, comparing the effects of GLP-1–MK-801 with GLP-1 analogs, MK-801, and vehicle treatment. Subcutaneous injection was administered at a dose of 100 nmol kg−1. Changes in body weight, food intake, fat mass, and lean body mass of the mice were recorded in detail.

Safety Evaluation

To assess the cardiometabolic safety of GLP-1–MK-801, the research team measured liver injury markers and key indicators of cardiovascular health in mice. Additionally, a series of experiments were conducted, such as body temperature measurement and open field behavior tests, to evaluate the side effects of long-term and acute drug administration.

Molecular and Behavioral Analysis

Through genomic and proteomic analyses, the research team explored the effects of GLP-1–MK-801 on synaptic transmission and neural activity in the hypothalamus, further verifying its efficacy.

Research Results

Chemical Synthesis and Structural Optimization

The research team successfully synthesized and optimized the GLP-1–MK-801 conjugate, confirming its good degradation performance in high-concentration glutathione degradation experiments in vitro. Its signal transduction properties at the GLP-1 receptor were comparable to those of parental GLP-1 analogs and GLP-1 receptor agonists Semaglutide and Liraglutide.

Metabolic Phenotype Analysis

During the 14-day treatment period, GLP-1–MK-801 significantly reduced body weight and food intake in mice, showing a pronounced synergistic weight loss effect. Compared to other treatments, GLP-1–MK-801 induced a greater reduction in fat mass and lean body mass. Additionally, GLP-1–MK-801 treatment significantly lowered plasma insulin, cholesterol, and triglyceride levels in mice, demonstrating good metabolic regulatory capabilities.

Safety Evaluation

Safety evaluation results showed that the GLP-1–MK-801 conjugate did not cause elevated liver injury markers or adverse effects on heart weight and blood pressure. Furthermore, body temperature and behavior test results indicated that GLP-1–MK-801 effectively avoided the hyperthermia and hyperactivity side effects associated with MK-801 monotherapy.

Molecular and Behavioral Analysis

Molecular and behavioral analyses indicated that GLP-1–MK-801 treatment led to significant changes in genes and proteins related to synaptic transmission in the hypothalamus, emphasizing its weight-loss mechanism through dual-action on hypothalamic GLP-1 receptor activation and NMDA receptor antagonism. Additionally, whole-brain activity analysis results showed that neural activity changes induced by GLP-1–MK-801 were significantly different from those induced by GLP-1 receptor agonists alone (such as Semaglutide), further validating its unique mechanism of action.

Research Conclusion

This study successfully demonstrated the potential of a peptide-mediated specific targeting NMDA receptor antagonism as a new approach for obesity treatment. The GLP-1–MK-801 conjugate effectively reduced body weight and significantly improved symptoms of metabolic diseases such as diabetes and lipid irregularities through the dual-action of GLP-1 receptor activation and NMDA receptor antagonism.

Research Significance

The breakthrough of this study lies in the creation of a single molecule combining a small molecule antagonist and a peptide agonist, showcasing the potential of lipidized GLP-1 analogs as drug delivery tools. Future research can continue to explore the application of this method in other metabolic diseases and promote the development of new treatment strategies for obesity and related metabolic diseases.

GLP-1–MK-801 is a novel obesity treatment method with enormous potential. By specifically targeting NMDA receptors, it achieved effective weight control and metabolic improvement while avoiding the severe side effects of traditional NMDA receptor antagonists. This research provides new ideas and hope for the treatment of obesity and metabolic diseases.