Good news!
"If human trials are successful, the drug could revolutionize treatment for people with obesity, enabling weight loss that doesn't involve losing appetite or avoiding fats.
The drug targets an enzyme found in brain cells called astrocytes, which can regulate body weight by acting on a distinct group of neurons, according to new research led by the Institute for Basic Science (IBS) in Korea. ...
On the other hand, stimulating GABRA5 neurons in the hypothalamus led to significant weight loss in obese mice, indicating GABRA5 neurons can function like a reversible toggle to control weight. ...
That's where the promising new drug comes in. Called KDS2010, it inhibits the MAOB enzyme in reactive astrocytes, thereby blocking production of GABA and allowing GABRA5 neurons to function normally and promote weight loss.
KDS2010 treatment yielded remarkable results in obese mice. Their fat tissue metabolism increased, fat storage decreased, and they lost weight despite being fed a high-fat diet, without impacting the amount of food they ate. ..."
"... Furthermore, a selective and reversible MAO-B inhibitor, 'KDS2010', which was transferred to a biotech company Neurobiogen in 2019 and is currently undergoing Phase 1 clinical trials, was tested on an obese mouse model. The new drugs yielded remarkable results, demonstrating a substantial reduction in fat accumulation and weight without any impacts on the amount of food intake. ..."
From the abstract:
"The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity."
Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA (no public access)
Figure 1. Left) Reactive astrocytes express a high level of MAOB and release a high level of GABA, which results in the inhibition of GABRA5 neurons. This results in decreased thermogenesis in brown fat tissues, and an increase in white fat storage. Right) When the GABRA5 neuron activity is restored, brown fat thermogenesis is increased and white fat storage is decreased. In both cases, mice are fed a high-fat diet.
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