This is an important advance that brings hope to the 1 billion obese patients around the world. Researchers led by C. Justin Lee, his director of the Center for Cognitive Sociality (CCS) within the Institute of Basic Sciences (IBS), have discovered new insights into the control of fat metabolism. Their research focuses on star-shaped non-neuronal cells in the brain known as “astrocytes.” Furthermore, in an animal experiment using the newly developed drug “KDS2010,” the company announced that mice were able to lose weight without relying on dietary restrictions.
The complex balance between food intake and energy expenditure is monitored by the hypothalamus in the brain. Although it is known that neurons in the lateral hypothalamus are connected to adipose tissue and involved in fat metabolism, their precise role in regulating fat metabolism remains a mystery. Researchers have discovered a cluster of neurons in the hypothalamus that specifically express receptors for the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). This cluster was found to be associated with the α5 subunit of GABA.a It was named the GABRA5 cluster because it is a receptor.
The researchers observed a significant slowing of pacemaker firing in GABRA5 neurons in a mouse model of diet-induced obesity. The researchers continued their work trying to inhibit the activity of these her GABRA5 neurons using chemogenetic techniques. This reduced thermogenesis (energy expenditure) in brown adipose tissue, leading to fat accumulation and weight gain. On the other hand, when GABRA5 neurons in the hypothalamus were activated, the mice lost weight. This suggests that GABRA5 neurons may function as a switch for body weight regulation.
In another surprising and unexpected event, the researchers found that astrocytes in the lateral hypothalamus regulate the activity of GABRA5 neurons. Reactive astrocytes increase in number and size and begin to overexpress the MAO-B enzyme (monoamine oxidase B). This enzyme plays an important role in neurotransmitter metabolism in the nervous system and is more predominantly expressed in reactive astrocytes. This causes large amounts of tonic GABA (gamma-aminobutyric acid) to be produced, inhibiting surrounding her GABRA5 neurons.
We also found that suppressing MAO-B gene expression in reactive astrocytes decreased GABA secretion, which could reverse the unwanted inhibition of GABRA5 neurons. Using this approach, researchers were able to increase thermogenesis in adipose tissue in obese mice, allowing them to achieve weight loss even on high-calorie diets. This experimentally demonstrates that the MAO-B enzyme within reactive astrocytes can be an effective target for the treatment of obesity without impairing appetite.
In addition, KDS2010, a selective and reversible MAO-B inhibitor that was transferred to biotechnology company NeuroBiogen in 2019 and is currently undergoing phase 1 clinical trials, was tested in an obese mouse model. The new drug has shown surprising results, demonstrating a significant reduction in fat accumulation and body weight without affecting food intake.
Postdoctoral fellow SA Moonsun said, “Previous hypothalamic-targeted obesity treatments have largely focused on the neural mechanisms involved in appetite regulation.” “To overcome this, we looked at non-neurogenic ‘astrocytes’ and identified reactive astrocytes as the cause of obesity,” she added.
C. Justin Lee, director of the center, also said, “Given that obesity has been designated as an ’emerging infectious disease of the 21st century’ by the World Health Organization (WHO), we have a next-generation disease that can effectively treat KDS2010.” We have high hopes for this as a treatment for obesity.” Fight obesity without suppressing appetite. ”
The research results are “Natural metabolism”a world-renowned academic journal in the field of metabolism with an impact factor of 20.8.