Discoveries in Brain Cells Offer Hope for Weight Loss

In a groundbreaking development offering hope to the global population grappling with obesity, a team of researchers led by Director C. Justin Lee at the Center for Cognition and Sociality (CCS) within the Institute for Basic Science (IBS) has unveiled novel insights into the regulation of fat metabolism. They focus on a specific type of non-neuronal brain cells known as ‘astrocytes.’ Moreover, the team has revealed promising results from animal experiments involving a newly developed drug called ‘KDS2010,’ which enabled mice to lose weight without resorting to restrictive diets.

The intricate balance between food consumption and energy expenditure is orchestrated by a region in the brain known as the hypothalamus. While it has long been understood that neurons in the lateral hypothalamus play a role in fat metabolism, the precise nature of their involvement remained elusive. The research team identified a cluster of neurons within the hypothalamus that express receptors for the inhibitory neurotransmitter ‘GABA’ (Gamma-Aminobutyric Acid). This cluster, closely associated with the α5 subunit of the GABAA receptor, was aptly named the ‘GABRA5 cluster.’

The research:

In mice models of diet-induced obesity, the researchers noted a significant decrease in the firing rate of the GABRA5 neurons. To probe further, they employed chemogenetic techniques to dampen the activity of these neurons. This intervention reduced heat production (energy consumption) in the brown fat tissue, leading to fat accumulation and subsequent weight gain. Conversely, when the GABRA5 neurons in the hypothalamus were stimulated, the mice successfully shed excess weight. It implies that the GABRA5 neurons may function as a pivotal switch for regulating body weight.

In an unexpected twist, the research team uncovered that astrocytes in the lateral hypothalamus play a crucial role in modulating the activity of GABRA5 neurons. These astrocytes exhibited an increase in both numbers and size, and they began to overexpress the MAO-B enzyme (Monoamine Oxidase B), which holds a vital role in neurotransmitter metabolism within the nervous system. Reactive astrocytes predominantly express MAO-B, producing substantial amounts of tonic GABA, which, in turn, inhibits the surrounding GABRA5 neurons.

Remarkably, when the researchers suppressed the expression of the MAO-B gene in reactive astrocytes, they could diminish GABA secretion, thus reversing the undesirable inhibition of GABRA5 neurons. This approach resulted in increased heat production within the fat tissue of obese mice, facilitating weight loss even when the mice consumed a high-calorie diet. This groundbreaking discovery underscores the potential of targeting the MAO-B enzyme in reactive astrocytes as an effective strategy for treating obesity without compromising appetite.

Furthermore, the researchers tested a selective and reversible MAO-B inhibitor, ‘KDS2010,’ which had been transferred to the biotech company Neurobiogen in 2019 and is currently undergoing Phase 1 clinical trials. This experimental drug yielded remarkable results in an obese mouse model, demonstrating a substantial reduction in fat accumulation and weight without any discernible impact on food intake.

Postdoctoral researcher SA Moonsun commented, “Previous obesity treatments targeting the hypothalamus mainly focused on neuronal mechanisms related to appetite regulation.” She added, “To overcome this, we focused on the non-neuronal ‘astrocytes’ and identified that reactive astrocytes are the cause of obesity.”

Center Director C. Justin Lee further emphasized the significance of their findings, stating, “Given that obesity has been designated by the World Health Organization (WHO) as the ’21st-century emerging infectious disease,’ we look to KDS2010 as a potential next-generation obesity treatment that can effectively combat obesity without suppressing appetite.”

This research offers a ray of hope for the one billion individuals worldwide who battle obesity and suggests a promising avenue for developing innovative, non-invasive treatments that could revolutionize the approach to tackling this global health challenge.