Identification of the principle of regulation of astrocyte fat metabolism
Schematic diagram of fat metabolism control in astrocytes
[충청뉴스 이성현 기자] The Institute for Basic Science (IBS) announced on the 31st that a research team led by Director Lee Chang-joon of the Center for Cognition and Sociality had found the principle of fat metabolism control in star-shaped non-neuronal cells in the brain, ‘star cells’.
The research team succeeded in losing weight without adjusting the amount of food in an animal experiment in which the new drug ‘KDS2010’ developed by the research team was administered.
Hunger and energy balance in the body are governed by the lateral hypothalamus of the brain. It is known that neurons in the hypothalamus are connected to adipose tissue and are involved in fat metabolism, but the exact mechanism of fat metabolism control has not been elucidated.
The research team discovered GABRA5, a cluster of neurons that specifically expresses the receptor for the inhibitory neuron substance ‘GABA’ in the hypothalamus. Subsequently, it was confirmed that periodic firing of GABRA5 neurons was significantly reduced in the obese mouse model.
When the activity of GABRA5 neurons was suppressed using a chemical genetic method, the generation of heat (energy exhaustion) in adipose tissue decreased, and fat was accumulated, resulting in an increase in body weight. Conversely, activation of GABRA5 neurons in the lateral hypothalamus resulted in weight loss. In other words, GABRA5 neurons are weight control switches.
The researchers found that astrocytes in the lateral hypothalamus regulate the activity of GABRA5 neurons. Reactive astrocytes, in which the number and size of astrocytes increased, expressed the enzyme MAO-B to produce a large amount of persistent GABA, suppressing surrounding GABRA5 neurons.
Suppressing the expression of the Maobi gene in reactive astrocytes reduced GABA secretion, activated GABRA5 neurons, and promoted thermogenesis in adipose tissue, resulting in weight loss without control of food intake. The experiment proved that the Maobi enzyme of reactive astrocytes is an effective target for obesity treatment.
Furthermore, the technology was transferred to Neurobiogen in 2019 and is currently undergoing a phase 1 clinical trial, and an experiment was conducted in which a selective and reversible Maobi inhibitor ‘KDS2010’, which is scheduled for a phase 2 clinical trial in 2024, was administered to an obese mouse model. This also significantly reduced fat accumulation and body weight without affecting food intake.
Director Lee Chang-joon said, “Obesity is a serious threat to modern people’s health to the extent that the World Health Organization (WHO) classifies it as a ‘new infectious disease of the 21st century’ and designates it as one of the world’s top 10 health risk factors.” With KDS2010, we hope that effective obesity treatment can be achieved without suppressing appetite.”
The research results were published online on September 1 in Nature Metabolism (IF=20.8), a sister journal of Nature and a world-renowned journal in the field of metabolism.
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2023-08-31 15:00:00
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