Everyone dreams of indulging in treats without facing the consequences, but is it truly achievable? A recent study suggests it is possible…

A groundbreaking development offers hope to the one billion people worldwide 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 fresh insights into the regulation of fat metabolism.

Their investigation centers on astrocytes, star-shaped non-neuronal cells in the brain. Remarkably, they have also announced successful animal trials employing a newly developed drug, ‘KDS2010,’ which facilitated significant weight loss in mice without necessitating dietary restrictions.

The hypothalamus in the brain is in charge of maintaining the intricate balance between food intake and energy expenditure.

While it has been established that neurons in the lateral hypothalamus are connected to fat tissue and play a role in fat metabolism, their precise function remained elusive.

They have now pinpointed a cluster of neurons in the hypothalamus that express the receptor for the inhibitory neurotransmitter ‘GABA (Gamma-Aminobutyric Acid).’ This cluster, associated with the α5 subunit of the GABAA receptor, has been dubbed the GABRA5 cluster.

In a mouse model with diet-induced obesity, they observed a significant slowdown in the firing rate of the GABRA5 neurons. They furthered their study by attempting to inhibit the activity of these neurons through chemogenetic methods.

This inhibition led to a decrease in heat production (energy consumption) in brown fat tissue, resulting in fat accumulation and weight gain. Conversely, when the GABRA5 neurons were activated in the hypothalamus, the mice achieved successful weight reduction, indicating that these neurons may serve as a switch for weight regulation.

In a surprising twist, the research team also discovered that astrocytes in the lateral hypothalamus regulate the activity of the GABRA5 neurons. Reactive astrocytes increased in number and size and began to overexpress the MAO-B enzyme (Monoamine Oxidase B).

This enzyme plays a pivotal role in neurotransmitter metabolism in the nervous system and is predominantly expressed in reactive astrocytes. This excess leads to the production of a substantial amount of tonic GABA, inhibiting the surrounding GABRA5 neurons.

Notably, suppressing the expression of the MAO-B gene in reactive astrocytes can reduce GABA secretion, effectively reversing the inhibitory effect on GABRA5 neurons. Employing this method, researchers managed to boost heat production in the fat tissue of obese mice, facilitating weight loss even when they consumed a high-calorie diet. This experimental evidence underscores that the MAO-B enzyme in reactive astrocytes can be a viable target for obesity treatment without compromising appetite.

Additionally, ‘KDS2010,’ a selective and reversible MAO-B inhibitor transferred to the biotech company Neurobiogen in 2019 and currently undergoing Phase 1 clinical trials, was tested on an obese mouse model. This novel drug produced remarkable results, leading to a substantial reduction in fat accumulation and weight without affecting food intake.

Postdoctoral researcher S.A. Moonsun remarked, “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 emphasized, “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.”

These groundbreaking research findings have been published in ‘Nature Metabolism,’ a globally renowned academic journal in the field of metabolism with an Impact Factor of 20.8.

The findings of the study were published in the journal Nature Metabolism.

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