In a groundbreaking development, scientists have uncovered a pivotal mechanism in the brain responsible for regulating fat metabolism and obesity. This newfound insight hinges on the role of astrocytes, star-shaped non-neuronal cells residing in the brain, which act as a critical “switch” for weight regulation by influencing a cluster of neurons known as the GABRA5 cluster.
The spotlight of this breakthrough is the introduction of a novel drug, KDS2010, which has demonstrated the ability to facilitate weight loss in obese mice without necessitating a reduction in food intake, even when consuming a high-fat diet. This discovery has the potential to revolutionize obesity treatment, offering a path for individuals to shed excess weight without compromising their appetite or eschewing fats.
Astrocytes in the lateral hypothalamus govern a cluster of neurons called GABRA5, which serves as a weight regulation “switch.”
Researchers have pinpointed the MAO-B enzyme within these astrocytes as a target for obesity treatment, as it modulates GABA secretion and, consequently, weight regulation.
KDS2010, a selective and reversible MAO-B inhibitor, has successfully induced weight loss in obese mice without impacting their food intake, even on a high-calorie diet. It has now advanced to Phase 1 clinical trials.
This breakthrough holds tremendous promise for the one billion people grappling with obesity globally. Led by Director C. Justin LEE of the Center for Cognition and Sociality (CCS) within the Institute for Basic Science (IBS), this research venture delves deep into the intricacies of fat metabolism regulation.
The focal point of the investigation revolves around non-neuronal brain cells referred to as ‘astrocytes.’ Furthermore, the team has unveiled the remarkable outcomes of animal experiments conducted using the innovative drug ‘KDS2010,’ which allowed mice to achieve weight loss without the constraints of dietary restrictions.
The brain’s hypothalamus plays a crucial role in overseeing the delicate balance between food consumption and energy expenditure. While it has long been known that neurons in the lateral hypothalamus have a connection to fat tissue and participate in fat metabolism, the precise extent of their involvement has remained an enigma.
Researchers have now stumbled upon a cluster of neurons within the hypothalamus distinguished by their expression of receptors for the inhibitory neurotransmitter ‘GABA’ (Gamma-Aminobutyric Acid). This cluster, known as the GABRA5 cluster, has been implicated as the central player in weight regulation.
In a diet-induced obese mouse model, scientists observed a significant deceleration in the rhythmic activity of GABRA5 neurons. They proceeded to inhibit these GABRA5 neurons using chemogenetic methods, which led to a reduction in heat production (energy consumption) within the brown fat tissue, ultimately culminating in fat accumulation and weight gain. Conversely, activation of GABRA5 neurons prompted successful weight reduction in the mice, strongly indicating their role as a weight regulation “switch.”
In an unexpected twist, the research team discovered that astrocytes residing in the lateral hypothalamus regulate the activity of GABRA5 neurons. These reactive astrocytes exhibit an increase in both quantity and size, accompanied by an overexpression of the MAO-B enzyme (Monoamine Oxidase B).
MAO-B, a pivotal enzyme involved in neurotransmitter metabolism within the nervous system, is prominently expressed in reactive astrocytes. Consequently, a surplus of tonic GABA is produced, inhibiting the neighboring GABRA5 neurons.
Remarkably, suppressing the expression of the MAO-B gene in reactive astrocytes proved effective in reducing GABA secretion, effectively reversing the inhibitory effect on GABRA5 neurons. Employing this approach, researchers successfully augmented heat production in the fat tissue of obese mice, enabling weight loss even on a high-calorie diet. This experimentation conclusively underscores the potential of the MAO-B enzyme in reactive astrocytes as a viable target for obesity treatment without compromising appetite.
Furthermore, ‘KDS2010,’ a selective and reversible MAO-B inhibitor, has made significant strides since its transfer to the biotech company Neurobiogen in 2019. Currently undergoing Phase 1 clinical trials, this new drug has exhibited remarkable results in obese mouse models, notably reducing fat accumulation and weight without affecting food intake.
Postdoctoral researcher SA Moonsun noted, “Previous obesity treatments aimed at the hypothalamus primarily focused on neuronal mechanisms related to appetite regulation.” She added, “To overcome this, we focused on non-neuronal ‘astrocytes’ and identified that reactive astrocytes are the cause of obesity.”