The key to brain weight has been found: eat what you want, and lose weight with a new treatment

summary: A revolutionary discovery reveals that astrocytes, star-shaped cells in the brain, play a key role in regulating fat metabolism and obesity. These cells act on a group of neurons, known as the GABRA5 group, and effectively act as a ‘switch’ for weight regulation.

A new drug, KDS2010, has been shown to facilitate weight loss in obese mice without reducing their food intake, even while eating a high-fat diet. This could be a groundbreaking advance in obesity treatment, allowing people to lose weight without compromising appetite or avoiding fat.

Key facts:

• Researchers have identified that astrocytes in the lateral hypothalamus regulate a group of neurons (GABRA5) that act as a “switch” for weight regulation.
• The MAO-B enzyme found in these astrocytes has been identified as a target for the treatment of obesity, as it affects GABA secretion and thus weight regulation.
• KDS2010, a selective, reversible MAO-B inhibitor, successfully reduced weight in obese mice without affecting their food intake, even while on a high-fat diet, and is now in phase I clinical trials.

source: Institute of Basic Sciences

This is an important development that brings hope to the one billion obese people around the world. Researchers led by Director C. Justin Lee of the Center for Cognitive and Social (CCS) within the Institute for Basic Sciences (IBS) have discovered new insights into the regulation of lipid metabolism.

The focus of their study lies in the star-shaped, non-neuronal cells in the brain, known as “astrocytes.” Furthermore, the group announced successful animal trials using the newly developed drug KDS2010, which allowed mice to successfully achieve weight loss without resorting to dietary restrictions.

The complex balance between food intake and energy expenditure is supervised by the hypothalamus in the brain. While it is known that neurons in the lateral hypothalamus are associated with adipose tissue and involved in fat metabolism, their precise role in regulating fat metabolism has remained a mystery.

Researchers have discovered a group of neurons in the hypothalamus that specifically express the receptor for the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). This group has been found to bind to the α5 subunit of GABA_a The receiver is hence named the GABRA5 group.

In a mouse model of diet-induced obesity, the researchers observed a significant slowing of the pacemaker firing of GABRA5 neurons. The researchers continued the study by trying to inhibit the activity of these GABRA5 neurons using chemical methods.

This in turn led to decreased heat production (energy expenditure) in brown adipose tissue, leading to fat accumulation and weight gain. On the other hand, when GABRA5 neurons were activated in the hypothalamus, the mice were able to achieve successful weight loss. This indicates that GABRA5 neurons may act as a switch for weight regulation.

In a surprising and unexpected new turn of events, the research team discovered that astrocytes located in the lateral hypothalamus regulate the activity of GABRA5 neurons. The numbers and sizes of reactive astrocytes are increased, and they begin to overexpress the enzyme MAO-B (monoamine oxidase B).

This enzyme plays a critical role in the metabolism of neurotransmitters in the nervous system and is predominantly expressed in reactive astrocytes. This ends up producing a large amount of the tonic GABA (gamma-aminobutyric acid), which inhibits surrounding GABRA5 neurons.

It was also discovered that inhibiting the expression of the MAO-B gene in reactive astrocytes can reduce GABA secretion, thus reversing the unwanted inhibition of GABRA5 neurons. Using this approach, the researchers were able to increase heat production in the adipose tissue of obese mice, allowing them to achieve weight loss even while eating a high-calorie diet. This experimentally proves that the MAO-B enzyme present in reactive astrocytes could be an effective target for treating obesity without compromising appetite.

Furthermore, the selective and reversible MAO-B inhibitor, “KDS2010”, which was transferred to the biotech company Neurobiogen in 2019 and is currently undergoing phase I clinical trials, was tested in an obese mouse model. The new medications achieved remarkable results, as they showed a significant reduction in fat accumulation and weight without any effect on the amount of food eaten.

“Previous obesity treatments targeting the hypothalamus have mainly focused on neural mechanisms related to appetite regulation,” said postdoctoral researcher SA Moonsun. “To overcome this, we focused on non-neuronal astrocytes and identified reactive astrocytes as the cause of obesity,” she added.

The director of the center, C. Justin Lee also: “Given that the World Health Organization has classified obesity as an ’emerging infectious disease of the 21st century’, we look forward to KDS2010 as a potential next-generation obesity treatment that can effectively fight obesity without suppressing appetite.

About news of obesity research, neuroscience and neuropharmacology

author: William Suh
source: Institute of Basic Sciences
communication: William Suh – Institute for Basic Sciences
picture: Image credited to Neuroscience News

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“GABRA5-positive hypothalamic neurons control obesity via Astrocytic GABABy C. Justin Lee et al. normal metabolism

a summary

GABRA5-positive hypothalamic neurons control obesity via Astrocytic GABA

The lateral hypothalamus (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissue, the identity of adipose-regulating neurons is ill-defined.

Here we show that GABRA5-positive neurons in the LHA (GABRA5^LHA) polydispersely projecting brown and white adipose tissue at the periphery. Gabra5^LHA are a distinct subpopulation of GABAergic neurons that show reduced pacemaker firing in mouse models of male diet-induced obesity.

Chemical inhibition of GABRA5^LHA It inhibits fat thermogenesis and increases weight gain, while silencing the GABRA5 gene in LHA reduces weight gain. In a mouse model of diet-induced obesity, GABRA5^LHA They are inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob).

Silencing of the Maob astrocyte genes in the LHA facilitates fat thermogenesis and significantly reduces weight gain without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We suggest that GABRA5 be launched^LHA Prevents lipid accumulation and selective inhibition of astrocytes GABA is a molecular target for the treatment of obesity.