Want to lose weight but can’t control your diet? Let your brain help!

Obesity, as a complex chronic disease, leads to a wide range of health problems. For a long time, there have been limited treatments for obesity. Intervention of lifestyle as the basic treatment for obesity is simply summarized as "control your mouth and move your legs." However, "control your mouth" is not so easy to achieve.

Drug therapy can help achieve and maintain weight loss on the basis of lifestyle intervention, and bring more metabolic and cardiovascular benefits. In recent years, glucagon-like peptide 1 (GLP-1) receptor agonists have performed outstandingly in weight loss. Science ranked GLP-1 receptor agonists as the No. 1 breakthrough of 2023.

However, the development and research of weight loss drugs focusing solely on GLP-1 is far from enough and cannot fulfill people’s desire to “control their diet”.

GLP-1 receptor agonists

The research and development of glucagon-like peptide 1 (GLP-1) agonists was originally intended to treat diabetes. After the drug binds to the GLP-1 receptors of organs or systems such as the pancreas, gastrointestinal tract, brain, and kidneys, it increases glucose concentration-dependent insulin secretion, inhibits glucagon, delays gastric emptying, and reduces appetite. More and more research evidence shows that GLP-1 receptor agonists have multiple benefits, including effectively lowering blood sugar, partially restoring pancreatic β cell function, reducing body weight, improving blood lipid profiles, and lowering blood pressure.

In order to maximize the metabolic benefits of drug therapy and reduce side effects, the development and research of GLP-1, GLP-1 and other complementary and/or synergistic gastrointestinal hormones, such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, YY peptide, etc. as obesity treatment drugs are also underway. Due to multiple pharmacological effects, tirpotide (GLP-1/GIP dual receptor agonist) and peptide 20 (a GIPR/GLP-1R/GCGR triple receptor agonist) have shown superior efficacy compared to single receptor agonists (such as semaglutide). Although they have multiple pharmacodynamics, the development and research of the above drugs are still mainly based on GLP-1 gastrointestinal hormones.

Let your brain control your mouth

The brain is responsible for regulating the amount of calories we consume and burn each day, but in obese patients, this balance is disrupted, leading to weight gain. Although GLP-1 receptor agonists have the effect of suppressing appetite, problems such as compliance with drug treatment always exist.

It is reported that about two-thirds of people who started using GLP-1 receptor agonists in 2021 stopped using them within a year, and the weight rebound and corresponding disappearance of metabolic benefits after stopping the drug confirmed that obesity is a chronic disease. Obesity treatment requires continuity and more options are available.

Targeting the pathophysiological mechanisms of obesity, multimodal weight loss drugs that integrate the agonist or antagonist effects of two or more receptor systems are also emerging, such as the combination of GLP-1 receptor agonists and receptor antagonists involved in regulating appetite in the brain.

GLP-1 receptor agonist coupled to NMDA receptor antagonist (GLP-1-MK-801)

N-methyl-D-aspartate (NMDA) is a glutamate-activated cation channel. Genome-wide association studies have shown that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for maintaining body weight homeostasis.

Researchers from the University of Copenhagen in Denmark have developed a molecule (GLP-1-MK-801) that combines GLP-1 receptor agonism with NMDA receptor antagonism. In animal models, it achieved the dual effects of GLP-1 agonism and NMDA antagonism, effectively reversing metabolic diseases such as obesity, hyperglycemia and dyslipidemia. The relevant research results were recently published in Nature.

The study found that compared with dose-matched monotherapy (i.e., GLP-1 receptor agonist alone and MK-801 alone), GLP-1-MK-801 treatment can effectively reduce body weight. Weight loss is associated with reduced food intake, effectively achieving "control of diet."

Treatment with MK-801 coupled to inactive GLP-1 did not produce additional weight loss compared with GLP-1 receptor agonist monotherapy, suggesting that weight loss in mice is caused by the synergistic pharmacological effects of NMDA receptor antagonism and GLP-1 receptor agonism in the hypothalamus.

Moreover, GLP-1-MK-801 showed a better weight loss effect compared with the combined administration of GLP-1 and MK-801, although the effects on food intake were similar. This suggests that GLP-1-MK-801 treatment offsets the effects of reduced adaptive energy expenditure caused by reduced intake, and the weight loss benefits associated with GLP-1-MK-801 treatment may come from the combined effects on energy homeostasis and eating behavior.

To evaluate the safety of the conjugate, the researchers evaluated key markers of the liver, cardiovascular system, etc. No adverse effects were found, and the safety of GLP-1-MK-801 treatment was good.
Although the exact mechanism by which GLP-1 receptor agonism and NMDA receptor antagonism synergistically correct metabolic disorders remains to be further elucidated, this dual-effect "mouth-control" weight-loss drug may be more effective and longer-lasting than the weight-loss drugs currently on the market.

The future of obesity treatment

Obesity is a chronic disease based on physiology, not simply a lack of willpower. The enthusiasm for studying the pathophysiological mechanisms of obesity, drugs or other treatment options makes the future of obesity treatment full of hope. Multi-hormonal and multi-modal weight loss therapies seem to be more effective.

With the deepening of our understanding of the physiological mechanisms of obesity and the continuous development and optimization of various treatment methods such as drugs, interventions, and surgeries, more effective, longer-lasting, safer, and more diverse obesity treatment options may emerge.

References:

[1] https://www.science.org/content/article/breakthrough-of-the-year-2023

[2] Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowan BM, Oral TK, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF; STEP 1 Study Group. Weight gain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564. doi: 10.1111/dom.14725. Epub 2022 May 19. PMID: 35441470; PMCID: PMC9542252.

[3] Prillaman M. Obesity drugs aren't always forever. What happens when you quit? Nature. 2024 Apr;628(8008):488-490. doi: 10.1038/d41586-024-01091-8. PMID: 38627513.

[4] Cook TM, Sandoval D. Dual-action obesity drug rewires brain circuits for appetite. Nature. 2024 May 15. doi: 10.1038/d41586-024-01352-6. Epub ahead of print. PMID: 38750199.

[5] Petersen J, Ludwig MQ, Juozaityte V, Ranea-Robles P, Svendsen C, Hwang E, Kristensen AW, Fadahunsi N, Lund J, Breum AW, Mathiesen CV, Sachs L, Moreno-Justicia R, Rohlfs R, Ford JC, Douros JD, Finan B, Portillo B, Grose K, Petersen JE, Trauelsen M, Feuchtinger A, DiMarchi RD, Schwartz TW, Deshmukh AS, Thomsen MB, Kohlmeier KA, Williams KW, Pers TH, Frølund B, Strømgaard K, Klein AB, Clemmensen C. GLP-1-directed NMDA receptor antagonism for obesity treatment. Nature. 2024 May 15. doi: 10.1038/s41586-024-07419-8. Epub ahead of print. PMID: 38750368.