“Hope on the Horizon: New Discovery Offers Obesity Solution Without Dieting” Researchers at the Institute for Basic Science (IBS) have made a breakthrough in the battle against obesity, offering hope to the billion people worldwide affected by this condition. Led by Director C. Justin LEE from the Center for Cognition and Sociality (CCS), the team has uncovered insights into how fat metabolism is regulated. The key to their discovery lies in star-shaped brain cells called ‘astrocytes’. Excitingly, they’ve also developed a drug called ‘KDS2010’ that successfully helped mice lose weight without needing to cut back on food.
The brain’s hypothalamus plays a crucial role in balancing food intake and energy expenditure. Although scientists knew that neurons in the lateral hypothalamus were connected to fat tissue and influenced fat metabolism, the exact way they did so remained a mystery. The researchers found a group of neurons in the hypothalamus that contain a receptor for the inhibitory neurotransmitter ‘GABA (Gamma-Aminobutyric Acid)’. This group, named the GABRA5 cluster, is associated with the α5 subunit of the GABAA receptor.
In experiments with diet-induced obese mice, the researchers noticed that the GABRA5 neurons’ activity slowed down significantly. To explore this further, they used methods to inhibit the GABRA5 neurons and observed that this led to reduced energy consumption in brown fat tissue, resulting in weight gain. Conversely, when the GABRA5 neurons were activated, the mice successfully shed weight. This indicates that these neurons act as a switch for weight regulation.
In a surprising twist, the researchers discovered that astrocytes in the lateral hypothalamus control the GABRA5 neurons’ activity. These astrocytes become more numerous and produce more of the MAO-B enzyme, which plays a role in neurotransmitter metabolism. This leads to increased production of GABA, which inhibits the surrounding GABRA5 neurons.
Suppressing the MAO-B gene expression in these reactive astrocytes reduces GABA secretion, reversing the inhibition of GABRA5 neurons. By doing so, the researchers increased heat production in the fat tissue of obese mice, resulting in weight loss even when they consumed a high-calorie diet. This demonstrates that targeting the MAO-B enzyme in reactive astrocytes could be an effective obesity treatment without affecting appetite.
Additionally, the researchers tested a reversible MAO-B inhibitor called ‘KDS2010’, which is currently undergoing Phase 1 clinical trials. This drug yielded impressive results in obese mice, significantly reducing fat accumulation and weight without affecting food intake.
Postdoctoral researcher SA Moonsun noted, “Previous obesity treatments focused on appetite regulation in the hypothalamus. We took a different approach by looking at ‘astrocytes’, the non-neuronal cells, and found that reactive astrocytes are behind obesity.”
Center Director C. Justin LEE emphasized, “As obesity is recognized by the World Health Organization (WHO) as a major health concern, we see KDS2010 as a potential game-changer in obesity treatment, effectively tackling the issue without suppressing appetite.”
