[Reading Science] Humanity Is Close to 'Conquering Obesity'

Game-Changing Obesity Treatments Emerging
Korean Researchers Develop New Drug to Boost Fat Metabolism 'Good News'

Obesity is one of the top ten enemies of human health. Many people rank dieting as their number one New Year's hope or resolution for beauty, longevity, and health. However, giving up delicious food or enduring strenuous exercise is difficult. Even with exercise, dietary therapy, medication, and surgery, side effects and yo-yo effects are common. Recently, obesity drugs have been developed, but their effects are limited or they are expensive. Side effects such as depression, tolerance, appetite loss, and vomiting are also significant. However, truly 'revolutionary' obesity treatments are emerging one after another, bringing good news to the one billion obese patients worldwide.

"Lose weight even after eating to your heart's content"

For those who cannot give up their appetite, the idea of enjoying food freely and still losing weight is an incredibly sweet temptation. This is why advertisements for existing diet drugs with severe side effects use such slogans. Even approved treatments dared not make such claims. They always had to add explanations like "dietary therapy must accompany for better effects." But now, a truly 'dream drug' has been developed and entered full clinical trials, attracting attention. And it was developed by Korean researchers. It could be cheaper and easier to obtain. The new drug 'KDS 2010,' announced on the 1st by the Institute for Basic Science (IBS) in the international journal Nature Metabolism, surprised the world. The research team led by Lee Chang-jun, head of the Cognitive and Sociality Research Center at IBS, discovered an unexpected target for obesity treatment while developing a dementia drug. They found the principle of fat metabolism regulation in star-shaped non-neuronal brain cells called 'astrocytes.' It has long been known that the hypothalamus controls hunger and energy balance in the body. Hypothalamic neurons connect to fat tissue and are involved in fat metabolism. However, the detailed mechanism was unclear. The team discovered a cluster of neurons in the hypothalamus that specifically express the receptor for the inhibitory neurotransmitter GABA, called GABRA5. They confirmed that the periodic firing of GABRA5 neurons was significantly reduced in obese mouse models. Using chemogenetic methods to inhibit GABRA5 neuron activity decreased heat production (energy expenditure) in fat tissue, causing fat accumulation and weight gain. Conversely, activating GABRA5 neurons in the hypothalamus led to weight loss. GABRA5 neurons act as a weight control switch.

The team particularly found that astrocytes in the hypothalamus regulate the activity of GABRA5 neurons. Reactive astrocytes, which increase in number and size, express the enzyme monoamine oxidase B (MAO-B) and produce large amounts of persistent GABA, inhibiting nearby GABRA5 neurons. Suppressing MAO-B gene expression in reactive astrocytes reduced GABA secretion, activated GABRA5 neurons, promoted fat consumption, and decreased weight without controlling food intake. Experiments proved that MAO-B in reactive astrocytes is an effective target for obesity treatment. Previously, the team had already licensed the selective and reversible MAO-B inhibitor 'KDS2010' to Neurobiogen in 2019, which is currently in Phase 1 clinical trials and scheduled for Phase 2 in 2024. Experiments administering KDS2010 to obese mouse models also significantly reduced fat accumulation and weight without affecting food intake.

Schematic diagram of the new drug developed by IBS that allows you to lose weight even after eating to your heart's content.

How was it discovered?

This research was the result of long-term efforts using world-class advanced equipment at IBS, in collaboration with researchers from the Korea Advanced Institute of Science and Technology (KAIST), Ulsan National Institute of Science and Technology (UNIST), and Korea Institute of Science and Technology (KIST). Through experiments including electrophysiology, immunohistochemical staining, chemogenetic inhibition, gene expression reduction, metabolic measurements, and hematoxylin and eosin staining, they studied the relationship between neurons and astrocytes in brain regions related to obesity from multiple angles. They discovered that overexpressed MAO-B in reactive astrocytes excessively secretes persistent GABA, inhibiting GABRA5 neurons and causing and worsening obesity.

Notably, during the final stages, the team posted their paper on the preprint server bioRxiv, and the prestigious metabolic journal Nature Metabolism, recognizing its importance and impact, invited them to publish it formally first. This underscores the significance and influence of the research.

There were challenges. When they injected the drug to reduce MAO-B expression in mice fed a high-fat diet, the mice lost weight without changes in food intake. They hypothesized that total energy metabolism would increase, but the results showed no difference. After much deliberation, the team confirmed that although total energy metabolism did not change, fat metabolism increased, leading to their success.

Lee Chang-jun, the team leader, said, "Until now, obesity research has focused on causes in peripheral tissues, including fat cells, but this is the first study to clearly show that the cause of obesity lies in the brain." He added, "This study presents a new therapeutic target that can treat obesity without suppressing appetite, moving away from the traditional focus on neurons in obesity treatments." He further noted, "We observed hypertrophy of hypothalamic astrocytes in mice on a high-fat diet, and further research is needed to understand how a high-fat diet causes astrocyte hypertrophy and GABA production."

Game changers overcoming previous limitations

Recently, more effective, easier-to-take, and affordable obesity drugs have emerged overseas. Examples include Orforglipron and Retatrutide, which Nature reported successful Phase 2 clinical trials for in June. Existing drugs like Trizepatide (brand name Mounjaro) and Semaglutide (brand names Wegovy or Ozempic) exist but are injectable, making administration difficult and expensive. They cost over $1,000 per month and face supply shortages. Although approved in Korea in April, they are not yet on the market. In the U.S., the New York Times reported on the 24th that these drugs are mostly sold in wealthy neighborhoods, becoming 'drugs for the rich.'

In contrast, Orforglipron and Retatrutide are breaking these limitations. Orforglipron is an oral pill with inexpensive ingredients, making it expected to be affordable. Retatrutide has attracted attention for its stronger effects. In Phase 2 trials, it showed up to 24.2% weight loss, far exceeding existing treatments (15-20%). While about 10% of patients do not respond to existing drugs, all patients lost weight with Retatrutide. It is also expected to have fewer side effects. Some users of Wegovy and Mounjaro report nausea and vomiting. Orforglipron and Retatrutide showed similar tendencies in Phase 2 trials, but researchers are confident that Phase 3 trials will improve dosing methods to minimize side effects.